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Fu L, Yokus B, Gao B, Pacher P. An Update on IL-22 Therapies in Alcohol-Associated Liver Disease and Beyond. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00117-8. [PMID: 40254130 DOI: 10.1016/j.ajpath.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/14/2025] [Accepted: 03/21/2025] [Indexed: 04/22/2025]
Abstract
Excessive alcohol consumption drives the development of alcohol-associated liver disease (ALD), including steatohepatitis, cirrhosis, and hepatocellular carcinoma, and its associated complications, such as hepatorenal syndrome. Hepatocyte death, inflammation, and impaired liver regeneration are key processes implicated in the pathogenesis and progression of ALD. Despite extensive research, therapeutic options for ALD remain limited. IL-22 has emerged as a promising therapeutic target because of its hepatoprotective properties mediated through the activation of the STAT3 signaling pathway. IL-22 enhances hepatocyte survival by mitigating apoptosis, oxidative stress, and inflammation while simultaneously promoting liver regeneration through the proliferation of hepatocytes and hepatic progenitor cells and the up-regulation of growth factors. Additionally, IL-22 exerts protective effects on epithelial cells in various organs affected by ALD and its associated complications. Studies from preclinical models and early-phase clinical trials of IL-22 agonists, such as F-652 and UTTR1147A, have shown favorable safety profiles, good tolerability, and encouraging efficacy in reducing liver injury and promoting regeneration. However, the heterogeneity and multifactorial nature of ALD present ongoing challenges. Further research is needed to optimize IL-22-based therapies and clarify their roles within a comprehensive approach to ALD management. This review summarizes the current understanding of IL-22 biology and its role in ALD pathophysiology and ALD-associated complications along with therapeutic application of IL-22, potential benefits, and limitations.
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Affiliation(s)
- Lihong Fu
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Burhan Yokus
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIH/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
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2
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Shin JH, Bozadjieva-Kramer N, Shao Y, Mercer AJ, Lyons-Abbott S, Awan RR, Lewis A, Seeley RJ. Intraduodenal administration of Reg3g improves gut barrier function and mitigates hepatic steatosis in mice. Am J Physiol Endocrinol Metab 2025; 328:E447-E456. [PMID: 39970263 DOI: 10.1152/ajpendo.00132.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/01/2024] [Accepted: 02/05/2025] [Indexed: 02/21/2025]
Abstract
Regenerating islet-derived protein 3 gamma (Reg3g), a gut peptide has been implicated in host defense and various physiological functions including metabolic regulation. Emerging evidence has demonstrated that peripheral administration of Reg3g results in improved glucose regulation as a gut hormone. In this study, we explored the therapeutic potential of Reg3g through intraduodenal infusion in mouse models of metabolic disorders. The objective of this study was to test the hypothesis that administered Reg3g into the intestinal lumen contributes to metabolic improvements by enhancing gut barrier function. Our mouse studies revealed that duodenal infusion of Reg3g reduces gut permeability and systemic endotoxemia. Studies with intestinal organoids supported the role of Reg3g in preserving cellular integrity and antioxidant gene expression under fructose-induced stress. Although Reg3g treatment results in little change to body weight, food intake, or glucose tolerance, Reg3g-treated mice exhibited reduced hepatic lipid accumulation along with the downregulation of lipogenic pathway genes. These data point toward the positive impact of Reg3g administration through intraduodenal infusion to regulate the intricate cross talk between gut barrier function and hepatic steatosis with the gut-liver axis.NEW & NOTEWORTHY This study shows that intraduodenal administration of the gut peptide, regenerating islet-derived protein 3 g (Reg3g), reduces hepatic lipid accumulation, improves gut barrier function, and lowers systemic endotoxemia in mouse models of metabolic disorders. These findings elucidate the therapeutic benefits of Reg3g administration into the gut.
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Affiliation(s)
- Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States
| | - Nadejda Bozadjieva-Kramer
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States
- Veterans Affairs Ann Arbor Healthcare System, Research Service, Ann Arbor, Michigan, United States
| | - Yiaki Shao
- Center for Obesity and Hernia Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Aaron J Mercer
- Novo Nordisk Research Center Seattle, Seattle, Washington, United States
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
| | - Sally Lyons-Abbott
- Novo Nordisk Research Center Seattle, Seattle, Washington, United States
- Velia Therapeutics, San Diego, California, United States
| | - Rija Rahmat Awan
- University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Alfor Lewis
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States
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Luo M, Jin T, Fang Y, Chen F, Zhu L, Bai J, Ding J. Signaling Pathways Involved in Acute Pancreatitis. J Inflamm Res 2025; 18:2287-2303. [PMID: 40230438 PMCID: PMC11995411 DOI: 10.2147/jir.s485804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 01/25/2025] [Indexed: 04/16/2025] Open
Abstract
Acute pancreatitis (AP) is a common digestive emergency with high morbidity and mortality. Over the past decade, significant progress has been made in understanding the mechanisms of AP, including oxidative stress, disruptions in calcium homeostasis, endoplasmic reticulum stress, inflammatory responses, and various forms of cell death. This review provides an overview of the typical signaling pathways involved and proposes the latest clinical translation prospects. These strategies are important for the early management of AP, preventing multi-organ injury, and improving the overall prognosis of the disease.
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Affiliation(s)
- Mengchen Luo
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Ting Jin
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Yi Fang
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Feng Chen
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Lujian Zhu
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Jin Ding
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
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Bonetti L, Horkova V, Grusdat M, Longworth J, Guerra L, Kurniawan H, Franchina DG, Soriano-Baguet L, Binsfeld C, Verschueren C, Spath S, Ewen A, Koncina E, Gérardy JJ, Kobayashi T, Dostert C, Farinelle S, Härm J, Fan YT, Chen Y, Harris IS, Lang PA, Vasiliou V, Waisman A, Letellier E, Becher B, Mittelbronn M, Brenner D. A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation. Cell Metab 2024; 36:1726-1744.e10. [PMID: 38986617 DOI: 10.1016/j.cmet.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 02/06/2024] [Accepted: 06/12/2024] [Indexed: 07/12/2024]
Abstract
The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.
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Affiliation(s)
- Lynn Bonetti
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Veronika Horkova
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Melanie Grusdat
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Joseph Longworth
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Luana Guerra
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Henry Kurniawan
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Davide G Franchina
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Leticia Soriano-Baguet
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Carole Binsfeld
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Charlène Verschueren
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Sabine Spath
- Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland; Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Anouk Ewen
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Eric Koncina
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg
| | - Jean-Jacques Gérardy
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg; Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg
| | - Takumi Kobayashi
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Catherine Dostert
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Sophie Farinelle
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Janika Härm
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Yu-Tong Fan
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Isaac S Harris
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Philipp A Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg
| | - Burkhard Becher
- Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland
| | - Michel Mittelbronn
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg; Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg; Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), 1526 Luxembourg, Luxembourg
| | - Dirk Brenner
- Experimental and Molecular Immunology, Department of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
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5
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Mehran HS, Nady S, Kassab RB, Ahmed-Farid OA, El-Hennamy RE. Recombinant Interleukin - 2 2 Immunotherapy Ameliorates Inflammation and Promotes the Release of Monoamine Neurotransmitters in the Gut-Brain Axis of Schistosoma mansoni-Infected Mice. J Neuroimmune Pharmacol 2024; 19:37. [PMID: 39052165 DOI: 10.1007/s11481-024-10133-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 06/08/2024] [Indexed: 07/27/2024]
Abstract
Recombinant interleukin-22 (rIL-22) has been reported as a protective agent in murine models of diseases driven by epithelial injury. Parasites have a circadian rhythm and their sensitivity to a certain drug may vary during the day. Therefore, this work aimed to investigate the effect of rIL-22 administration at different times of the day on the inflammation, oxidative status, and neurotransmitter release in the gut-brain axis of the Schistosoma mansoni-infected mice. Sixty male BALB/c mice aged six weeks weighing 25-30 g were divided into a control group (injected intraperitoneally with PBS), mice infected with 80 ± 10 cercariae of S. mansoni (infected group) then injected intraperitoneally with PBS, and rIL-22 treated groups. rIL-22 was administrated intraperitoneally (400 ng/kg) either at the onset or offset of the light phase for 14 days. IL-22 administration reduced the levels of IL-1β, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa beta (NF-κβ), and enhanced the production of IL-22 and IL-17. The treatment with IL-22 increased glutathione (GSH) and reduced malondialdehyde (MDA) and nitric oxide (NO) levels both in the ileum and brain. The B-cell lymphoma 2 (BCL2) protein level in the ileum was diminished after IL-22 administration. Brain-derived neurotrophic factor (BDNF) and neurotransmitter release (serotonin, 5HT, norepinephrine, NE, dopamine, DA, Glutamate, Glu, and -amino butyric acid, GABA) were improved by rIL-22. In conclusion, rIL-22 showed promising immunotherapy for inflammation, oxidative damage, and neuropathological signs associated with schistosomiasis. The efficacy of IL-22 increased significantly upon its administration at the time of light offset.
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Affiliation(s)
- Heba S Mehran
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Soad Nady
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Rami B Kassab
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt
| | | | - Rehab E El-Hennamy
- Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, Egypt.
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Yang H, Cao R, Zhou F, Wang B, Xu Q, Li R, Zhang C, Xu H. The role of Interleukin-22 in severe acute pancreatitis. Mol Med 2024; 30:60. [PMID: 38750415 PMCID: PMC11097471 DOI: 10.1186/s10020-024-00826-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/02/2024] [Indexed: 05/18/2024] Open
Abstract
Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.
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Affiliation(s)
- Hongli Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - Ruofan Cao
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - Feifei Zhou
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
| | - Ben Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
| | - Qianqian Xu
- Department of Gastroenterology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Ji'nan, Shandong, 250021, P.R. China
| | - Rui Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China
| | - ChunHua Zhang
- Shandong First Medical University, Ji'nan, Shandong, 250117, P.R. China
| | - Hongwei Xu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong, 250021, P.R. China.
- Medical Science and Technology Innovation Center, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P.R. China.
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Herrnreiter CJ, Luck ME, Cannon AR, Li X, Choudhry MA. Reduced Expression of miR-146a Potentiates Intestinal Inflammation following Alcohol and Burn Injury. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:881-893. [PMID: 38189569 PMCID: PMC10922766 DOI: 10.4049/jimmunol.2300405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 12/13/2023] [Indexed: 01/09/2024]
Abstract
MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression. Within the intestinal epithelium, miRNAs play a critical role in gut homeostasis, and aberrant miRNA expression has been implicated in various disorders associated with intestinal inflammation and barrier disruption. In this study, we sought to profile changes in intestinal epithelial cell miRNA expression after alcohol and burn injury and elucidate their impact on inflammation and barrier integrity. Using a mouse model of acute ethanol intoxication and burn injury, we found that small intestinal epithelial cell expression of miR-146a is significantly decreased 1 d following injury. Using in vitro studies, we show that reduced miR-146a promotes intestinal epithelial cell inflammation by promoting p38 MAPK signaling via increased levels of its target TRAF6 (TNFR-associated factor 6). Furthermore, we demonstrate that in vivo miR-146a overexpression significantly inhibits intestinal inflammation 1 d following combined injury and potentially supports intestinal barrier homeostasis. Overall, this study highlights the important impact that miRNA expression can have on intestinal homeostasis and the valuable potential of harnessing aberrant miRNA expression as a therapeutic target to control intestinal inflammation.
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Affiliation(s)
- Caroline J. Herrnreiter
- Biochemistry, Molecular and Cancer Biology Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Marisa E. Luck
- Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Abigail R. Cannon
- Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Xiaoling Li
- Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Mashkoor A. Choudhry
- Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
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8
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Ravichandran P, Pruskowski KA. Pharmacologic Considerations for Antimicrobials and Anticoagulants after Burn Injury. EUROPEAN BURN JOURNAL 2023; 4:573-583. [PMID: 39600026 PMCID: PMC11571861 DOI: 10.3390/ebj4040038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/29/2024]
Abstract
Derangements in pharmacokinetics and pharmacodynamics (PK/PD) of burn patients are poorly understood and lacking consistent data. This leads to an absence of consensus regarding pharmacologic management of burn patients, complicating their care. In order to effectively manage burn critical illness, knowledge of pharmacologic parameters and their changes is necessary. It is also imperative that the clinician understands how these changes will affect drug dosing. A common practice is to increase antibiotic dosing and/or frequency; however, this may not be necessary and doses should be adjusted to patient- and drug-specific parameters. Additionally, monitoring assays for antibiotic levels as well as coagulation factors can be useful for adjusting dosages to best treat the patient. This review focuses on alterations in PK/PD as well as other physiologic changes after burn injury, with special reference to care in military and austere settings.
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Affiliation(s)
- Pranav Ravichandran
- F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Kaitlin A. Pruskowski
- F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- United States Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, TX 78234, USA
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Wu L, Hu J, Yi X, Lv J, Yao J, Tang W, Zhang S, Wan M. Gut microbiota interacts with inflammatory responses in acute pancreatitis. Therap Adv Gastroenterol 2023; 16:17562848231202133. [PMID: 37829561 PMCID: PMC10566291 DOI: 10.1177/17562848231202133] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/01/2023] [Indexed: 10/14/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common acute abdominal conditions, and its incidence has been increasing for years. Approximately 15-20% of patients develop severe AP (SAP), which is complicated by critical inflammatory injury and intestinal dysfunction. AP-associated inflammation can lead to the gut barrier and function damage, causing dysbacteriosis and facilitating intestinal microbiota migration. Pancreatic exocrine deficiency and decreased levels of antimicrobial peptides in AP can also lead to abnormal growth of intestinal bacteria. Meanwhile, intestinal microbiota migration influences the pancreatic microenvironment and affects the severity of AP, which, in turn, exacerbates the systemic inflammatory response. Thus, the interaction between the gut microbiota (GM) and the inflammatory response may be a key pathogenic feature of SAP. Treating either of these factors or breaking their interaction may offer some benefits for SAP treatment. In this review, we discuss the mechanisms of interaction of the GM and inflammation in AP and factors that can deteriorate or even cure both, including some traditional Chinese medicine treatments, to provide new methods for studying AP pathogenesis and developing therapies.
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Affiliation(s)
- Linjun Wu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Hospital of Chinese Traditional Medicine of Leshan, Leshan, China
| | - Jing Hu
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
- Hospital of Chinese Traditional Medicine of Leshan, Leshan, China
| | - Xiaolin Yi
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
- Intensive Care Unit, Suining Municipal Hospital of TCM, Suining, China
| | - Jianqin Lv
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Jiaqi Yao
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Wenfu Tang
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Chengdu, China
| | - Shu Zhang
- Department of Emergency Medicine, Emergency Medical Laboratory, West China
- Hospital, Sichuan University, Guo Xue Road 37, Chengdu 610041, Sichuan, China
| | - Meihua Wan
- Department of Integrated Traditional Chinese and Western Medicine, West China
- Hospital, Sichuan University, Guo Xue Road 37, Chengdu 610041, China
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10
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14:1205821. [PMID: 37841267 PMCID: PMC10570533 DOI: 10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 09/07/2023] [Indexed: 10/17/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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Affiliation(s)
| | | | | | - Palash Mandal
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
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11
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14. [DOI: https:/doi.org/10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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12
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Wagner F, Mansfield JC, Lekkerkerker AN, Wang Y, Keir M, Dash A, Butcher B, Harder B, Orozco LD, Mar JS, Chen H, Rothenberg ME. Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis. Gut 2023; 72:1451-1461. [PMID: 36732049 PMCID: PMC10359578 DOI: 10.1136/gutjnl-2022-328387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 01/24/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER NCT02749630.
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Affiliation(s)
| | - John C Mansfield
- Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | | | - Yehong Wang
- Genentech Inc, South San Francisco, California, USA
| | - Mary Keir
- Genentech Inc, South San Francisco, California, USA
| | - Ajit Dash
- Genentech Inc, South San Francisco, California, USA
| | | | | | - Luz D Orozco
- Genentech Inc, South San Francisco, California, USA
| | - Jordan S Mar
- Genentech Inc, South San Francisco, California, USA
| | - Hao Chen
- Genentech Inc, South San Francisco, California, USA
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13
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Bonetti L, Horkova V, Longworth J, Guerra L, Kurniawan H, Franchina DG, Soriano-Baguet L, Grusdat M, Spath S, Koncina E, Ewen A, Binsfeld C, Verschueren C, Gérardy JJ, Kobayashi T, Dostert C, Farinelle S, Härm J, Chen Y, Harris IS, Lang PA, Vasiliou V, Waisman A, Letellier E, Becher B, Mittelbronn M, Brenner D. A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.06.547932. [PMID: 37489135 PMCID: PMC10363291 DOI: 10.1101/2023.07.06.547932] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.
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Affiliation(s)
- Lynn Bonetti
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Veronika Horkova
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Joseph Longworth
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Luana Guerra
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Henry Kurniawan
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Davide G. Franchina
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Leticia Soriano-Baguet
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Melanie Grusdat
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Sabine Spath
- Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland
- Center for Fundamental Immunology, Benaroya Research Institute; Seattle, WA 98101, USA
| | - Eric Koncina
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg
| | - Anouk Ewen
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Carole Binsfeld
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Charlène Verschueren
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Jean-Jacques Gérardy
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg
| | - Takumi Kobayashi
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Catherine Dostert
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Sophie Farinelle
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Janika Härm
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA
| | - Isaac S. Harris
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Philipp A. Lang
- Department of Molecular Medicine II, Medical Faculty Heinrich Heine University Düsseldorf, Germany
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg
| | - Burkhard Becher
- Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland
| | - Michel Mittelbronn
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
- Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, L-4362, Luxembourg
- Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, L-1526, Luxembourg
| | - Dirk Brenner
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
- Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
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14
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Vashkevich K, Janiuk K, Maleki N. A model for irritable bowel syndrome and anxiety comorbidities in relation to alcohol use disorders. Front Med (Lausanne) 2023; 10:1161130. [PMID: 37293305 PMCID: PMC10244726 DOI: 10.3389/fmed.2023.1161130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/27/2023] [Indexed: 06/10/2023] Open
Abstract
About 95% of human body serotonin synthesis occurs in the gastrointestinal tract (GI). Lack of sufficient serotonin levels is thought to play a key role in mood disorders, including anxiety disorders. In this study, we looked at a disorder affecting the GI tract, irritable bowel syndrome (IBS), and aimed to determine whether IBS is differentially associated with anxiety disorders in 252 chronic pain patients in the presence of a history of alcohol use disorders (AUD) given that alcohol is an extremely aggressive substance for the GI mucosa. We found that while the prevalence of IBS was not affected by the presence of AUD in chronic pain patients, IBS had significantly higher comorbidity with anxiety disorders in chronic pain patients with comorbid alcohol use disorders. We argue that these findings highlight mechanistic differences in the comorbidity of anxiety disorders with chronic pain and AUD, implicating a central role for GI problems stemming from chronic alcohol use. The findings may have important implications for the treatment of IBS patients with AUD who commonly present with anxiety disorders which could motivate the continuation of problematic drinking and impede recovery success. We propose that addressing GI problems in patients with AUD may help manage AUD and recovery more effectively.
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Affiliation(s)
- Katsiaryna Vashkevich
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Kathryn Janiuk
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Nasim Maleki
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Psychology Research Service, VA Healthcare System, Boston, MA, United States
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15
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Novotny-Nuñez I, Perdigón G, Matar C, Martínez Monteros MJ, Yahfoufi N, Cazorla SI, Maldonado-Galdeano C. Evaluation of Rouxiella badensis Subsp Acadiensis (Canan SV-53) as a Potential Probiotic Bacterium. Microorganisms 2023; 11:1347. [PMID: 37317321 DOI: 10.3390/microorganisms11051347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/09/2023] [Accepted: 05/17/2023] [Indexed: 06/16/2023] Open
Abstract
The advent of omic platforms revealed the significant benefits of probiotics in the prevention of many infectious diseases. This led to a growing interest in novel strains of probiotics endowed with health characteristics related to microbiome and immune modulation. Therefore, autochthonous bacteria in plant ecosystems might offer a good source for novel next-generation probiotics. The main objective of this study was to analyze the effect of Rouxiella badensis acadiensis Canan (R. acadiensis) a bacterium isolated from the blueberry biota, on the mammalian intestinal ecosystem and its potential as a probiotic microorganism. R. acadiensis, reinforced the intestinal epithelial barrier avoiding bacterial translocation from the gut to deep tissues, even after feeding BALB/c mice for a prolonged period of time. Moreover, diet supplementation with R. acadiensis led to increases in the number of Paneth cells, well as an increase in the antimicrobial peptide α defensin. The anti-bacterial effect of R. acadiensis against Staphylococcus aureus and Salmonella enterica serovar Typhimurium was also reported. Importantly, R. acadiensis-fed animals showed better survival in an in vivo Salmonella enterica serovar Typhimurium challenge compared with those that received a conventional diet. These results demonstrated that R. acadiensis possesses characteristics of a probiotic strain by contributing to the reinforcement and maintenance of intestinal homeostasis.
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Affiliation(s)
- Ivanna Novotny-Nuñez
- Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán T4000, Argentina
| | - Gabriela Perdigón
- Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán T4000, Argentina
| | - Chantal Matar
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - María José Martínez Monteros
- Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán T4000, Argentina
| | - Nour Yahfoufi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Silvia Inés Cazorla
- Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán T4000, Argentina
- Cátedra de Inmunología, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán T4000, Argentina
| | - Carolina Maldonado-Galdeano
- Laboratorio de Inmunología, Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán T4000, Argentina
- Cátedra de Inmunología, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Miguel de Tucumán T4000, Argentina
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16
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Meyer F, Wendling D, Demougeot C, Prati C, Verhoeven F. Cytokines and intestinal epithelial permeability: A systematic review. Autoimmun Rev 2023; 22:103331. [PMID: 37030338 DOI: 10.1016/j.autrev.2023.103331] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/03/2023] [Indexed: 04/10/2023]
Abstract
BACKGROUND The intestinal mucosa is composed of a well-organized epithelium, acting as a physical barrier to harmful luminal contents, while simultaneously ensuring absorption of physiological nutrients and solutes. Increased intestinal permeability has been described in various chronic diseases, leading to abnormal activation of subepithelial immune cells and overproduction of inflammatory mediators. This review aimed to summarize and evaluate the effects of cytokines on intestinal permeability. METHODS A systematic review of the literature was performed in the Medline, Cochrane and Embase databases, up to 01/04/2022, to identify published studies assessing the direct effect of cytokines on intestinal permeability. We collected data on the study design, the method of assessment of intestinal permeability, the type of intervention and the subsequent effect on gut permeability. RESULTS A total of 120 publications were included, describing a total of 89 in vitro and 44 in vivo studies. TNFα, IFNγ or IL-1β were the most frequently studied cytokines, inducing an increase in intestinal permeability through a myosin light-chain-mediated mechanism. In situations associated with intestinal barrier disruption, such as inflammatory bowel diseases, in vivo studies showed that anti-TNFα treatment decreased intestinal permeability while achieving clinical recovery. In contrast to TNFα, IL-10 decreased permeability in conditions associated with intestinal hyperpermeability. For some cytokines (e.g. IL-17, IL-23), results are conflicting, with both an increase and a decrease in gut permeability reported, depending on the study model, methodology, or the studied conditions (e.g. burn injury, colitis, ischemia, sepsis). CONCLUSION This systematic review provides evidence that intestinal permeability can be directly influenced by cytokines in numerous conditions. The immune environment probably plays an important role, given the variability of their effect, according to different conditions. A better understanding of these mechanisms could open new therapeutic perspectives for disorders associated with gut barrier dysfunction.
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Affiliation(s)
- Frédéric Meyer
- PEPITE EA4267, Université de Franche-Comté, F-25000 Besançon, France; Department of rheumatology, University Hospital Besançon, F-25000 Besançon, France
| | - Daniel Wendling
- Department of rheumatology, University Hospital Besançon, F-25000 Besançon, France; EA 4266, EPILAB, Université de Franche-Comté, F-25000 Besançon, France
| | - Céline Demougeot
- PEPITE EA4267, Université de Franche-Comté, F-25000 Besançon, France
| | - Clément Prati
- PEPITE EA4267, Université de Franche-Comté, F-25000 Besançon, France; Department of rheumatology, University Hospital Besançon, F-25000 Besançon, France
| | - Frank Verhoeven
- PEPITE EA4267, Université de Franche-Comté, F-25000 Besançon, France; Department of rheumatology, University Hospital Besançon, F-25000 Besançon, France.
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Abstract
Infections are the leading cause of mortality in burn patients who survive their initial resuscitation. Burn injury leads to immunosuppression and a dysregulated inflammatory response which can have a prolonged impact. Early surgical excision along with support of the multidisciplinary burn team has improved mortality in burn patients. The authors review diagnostic and therapeutic challenges as well as strategies for management of burn related infections.
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Liu J, Zong C, Yu X, Ding Y, Chang B, Wang R, Sang L. Alanyl-Glutamine (Ala-Gln) Ameliorates Dextran Sulfate Sodium (DSS)-Induced Acute Colitis by Regulating the Gut Microbiota, PI3K-Akt/NF-κB/STAT3 Signaling, and Associated Pulmonary Injury. ACS Infect Dis 2023; 9:979-992. [PMID: 36917734 DOI: 10.1021/acsinfecdis.3c00014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
The aim of this study was to investigate the protective effect of alanyl-glutamine (Ala-Gln) on acute colitis complicated by pulmonary injury induced by dextran sulfate sodium (DSS) in C57BL/6 mice. The results showed that Ala-Gln intervention alleviated weight loss, the disease activity index (DAI), colon shortening, and pathological injury and regulated the absolute number of CD4+T-cell subsets in mesenteric lymph nodes (MLNs). In addition, Ala-Gln intervention significantly ameliorated the composition of the gut microbiota in mice with DSS- induced acute colitis, significantly decreasing the relative abundance of Desulfovibrionaceae and increasing the abundances of Gastranaerophilales, Clostridia-vadinBB60, and Alistipes. Moreover, Ala-Gln treatment significantly inhibited the activation of the PI3K-Akt/NF-κB/STAT3 inflammatory signaling pathways in the colon of mice with DSS-induced acute colitis. Notably, Ala-Gln intervention also alleviated the pulmonary injury as well as the imbalance in levels of CD4+T-cell subsets in pulmonary tissue in mice with DSS-induced acute colitis. In conclusion, Ala-Gln alleviates DSS-induced acute colitis by regulating the gut microflora and PI3K-Akt/NF-κB/STAT3 signaling pathways, as well as by alleviating accompanying pulmonary injury.
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Affiliation(s)
- Jing Liu
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Chengguo Zong
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Xin Yu
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Yan Ding
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang 110001, Liaoning, China
| | - Ruoyu Wang
- Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006, Liaoning, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian 116001, Liaoning, China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang 110022, Liaoning, China
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19
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McMahan RH, Hulsebus HJ, Najarro KM, Giesy LE, Frank DN, Kovacs EJ. Changes in gut microbiome correlate with intestinal barrier dysfunction and inflammation following a 3-day ethanol exposure in aged mice. Alcohol 2023; 107:136-143. [PMID: 36150609 DOI: 10.1016/j.alcohol.2022.08.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/17/2022] [Accepted: 08/25/2022] [Indexed: 11/01/2022]
Abstract
Alcohol use among older adults is on the rise. This increase is clinically relevant as older adults are at risk for increased morbidity and mortality from many alcohol-related chronic diseases compared to younger patients. However, little is known regarding the synergistic effects of alcohol and age. There are intriguing data suggesting that aging may lead to impaired intestinal barrier integrity and dysbiosis of the intestinal microbiome, which could increase susceptibility to alcohol's negative effects. To study the effects of alcohol in age we exposed aged and young mice to 3 days of moderate ethanol and evaluated changes in gut parameters. We found that these levels of drinking do not have obvious effects in young mice but cause significant alcohol-induced gut barrier dysfunction and expression of the pro-inflammatory cytokine TNFα in aged mice. Ethanol-induced downregulation of expression of the gut-protective antimicrobial peptides Defa-rs1, Reg3b, and Reg3g was observed in aged, but not young mice. Analysis of the fecal microbiome revealed age-associated shifts in microbial taxa, which correlated with intestinal and hepatic inflammatory gene expression. Taken together, these data demonstrate that age drives microbiome dysbiosis, while ethanol exposure in aged mice induces changes in the expression of antimicrobial genes important for separating these potentially damaging microbes from the intestinal lumen. These changes highlight potential mechanistic targets for prevention of the age-related exacerbation of effects of ethanol on the gut.
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Affiliation(s)
- Rachel H McMahan
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States; GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States.
| | - Holly J Hulsebus
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States; Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Kevin M Najarro
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Lauren E Giesy
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Daniel N Frank
- GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Elizabeth J Kovacs
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States; GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States; Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States
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20
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Wang YJ, Wang HY, Li QM, Zha XQ, Luo JP. Dendrobium fimbriatum polysaccharide ameliorates DSS-induced intestinal mucosal injury by IL-22-regulated intestinal stem cell regeneration. Int J Biol Macromol 2023; 230:123199. [PMID: 36634807 DOI: 10.1016/j.ijbiomac.2023.123199] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/26/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with unknown etiology and difficult treatment. In this study, the intervention effect of Dendrobium fimbriatum Hook polysaccharide (cDFPW1) on UC was verified by constructing a dextran sulfate sodium (DSS)-induced colitis mouse model, and the protective effect of cDFPW1 on intestinal mucosal integrity in UC was explored by the co-culture system consisting of intestinal organoids and lamina propria lymphocytes (LPLs) combined with the experiment of microbial depletion mice. Results showed that cDFPW1 significantly alleviated UC symptoms in mice and promoted the proliferation of intestinal epithelial cells. Importantly, cDFPW1 could directly improve DSS-induced morphological damage of intestinal organoids and increase the number of epithelial cells, which was validated in mice. During repair, an increase in the number of Lgr5+ cells in intestinal organoids and mouse intestines was promoted by cDFPW1. Meanwhile, cDFPW1 promoted intestinal stem cells (ISCs)-mediated intestinal epithelial regeneration by significantly upregulating IL-22 expression. We further confirmed that the secretion of IL-22 was mediated by LPLs. Together, these findings suggest that cDFPW1 promotes ISCs regeneration by LPLs-mediated up-regulation of IL-22 to protect the intestinal mucosal integrity, thereby playing an important role in improving UC.
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Affiliation(s)
- Yu-Jing Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China
| | - Hong-Yan Wang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea and Food Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Qiang-Ming Li
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China
| | - Xue-Qiang Zha
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China
| | - Jian-Ping Luo
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China.
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21
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Cannon AR, Shim EH, Kuprys PV, Choudhry MA. IL-22 and Lactobacillus delbrueckii mitigate alcohol-induced exacerbation of DSS-induced colitis. J Leukoc Biol 2022; 112:1471-1484. [PMID: 35916052 PMCID: PMC9701151 DOI: 10.1002/jlb.4a0122-068r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/29/2022] [Indexed: 01/04/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by cycles of active disease flare and inactive disease remission. During UC remission, IL-22 is up-regulated, acting as a hallmark of entrance into UC remission. Recently, we found that in our mouse model of binge alcohol and dextran sodium sulfate (DSS)-induced colitis, alcohol increases severity of UC pathology. In this study, we assessed not only whether alcohol influenced IL-22 expression and thereby perpetuates UC, but also whether recombinant IL-22 (rIL-22) or treatment with a probiotic could alleviate exacerbated symptoms of UC. Levels of large intestine IL-22 were significantly decreased ∼6.9-fold in DSS ethanol compared with DSS vehicle. Examination of lamina propria (LP) cells in the large intestine revealed IL-22+ γδ T cells in DSS vehicle-treated mice were significantly increased, while IL-22+ γδ T cells in DSS ethanol mice were unable to mount this IL-22 response. We administered rIL-22 and found it restored weight loss of DSS ethanol-treated mice. Colonic shortening and increased Enterobacteriaceae were also attenuated. Administration of Lactobacillus delbrueckii attenuated weight loss (p < 0.01), colon length (p < 0.001), mitigated increases in Enterobacteriaceae, increased levels of IL-22, and increased levels of p-STAT3 back to that of DSS vehicle group in DSS ethanol mice. In contrast, sole administration of L. delbrueckii supernatant was not sufficient to reduce UC exacerbation following alcohol. Our findings suggest L. delbrueckii contributes to repair mechanisms by increasing levels of IL-22, resulting in phosphorylation of STAT3, thus attenuating the alcohol-induced increases in intestinal damage after colitis.
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Affiliation(s)
- Abigail R. Cannon
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
- Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
| | - Esther H. Shim
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
| | - Paulius V. Kuprys
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
| | - Mashkoor A. Choudhry
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
- Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
- Department of Microbiology and Immunology, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA
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22
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Allen JM, Mackos AR, Jaggers RM, Brewster PC, Webb M, Lin CH, Ladaika C, Davies R, White P, Loman BR, Bailey MT. Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes. Gut Microbes 2022; 14:2035661. [PMID: 35184677 PMCID: PMC8865257 DOI: 10.1080/19490976.2022.2035661] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.
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Affiliation(s)
- Jacob M. Allen
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois,Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio,CONTACT Jacob M. Allen Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 906 S. Goodwin Ave, Urbana61820, Illinois
| | - Amy R. Mackos
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio,College of Nursing, The Ohio State University, Columbus, Ohio
| | - Robert M. Jaggers
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
| | - Patricia C. Brewster
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Mikaela Webb
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Chia-Hao Lin
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Chris Ladaika
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
| | - Ronald Davies
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
| | - Peter White
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio
| | - Brett R. Loman
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio,Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Michael T. Bailey
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio,Oral and Gi Microbiology Research Affinity Group, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio,Michael T. Bailey Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
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23
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Najarro KM, Boe DM, Walrath TM, Mullen JE, Paul MT, Frankel JH, Hulsebus HJ, Idrovo JP, McMahan RH, Kovacs EJ. Advanced age exacerbates intestinal epithelial permeability after burn injury in mice. Exp Gerontol 2022; 158:111654. [PMID: 34915110 PMCID: PMC9188353 DOI: 10.1016/j.exger.2021.111654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Advanced age is an independent risk factor for morbidity and mortality after burn injury. Following burn, the intestines can become permeable leading to the leakage of bacteria and their products from the lumen of the ileum to the portal and systemic circulation. Here, we sought to determine the effects of advanced age on intestinal permeability post burn injury and assess intestinal inflammatory biomarkers. METHODS Young (4-5 months) and aged (18-22 months) female BALB/cBy mice were subjected to a 12-15% total body surface area (TBSA) sham or burn injury. 24 h after injury, mice were euthanized, and organs collected. Colony-forming units (CFU) were counted from plated mesenteric lymph nodes (MLN). Gene expression of ileal tight junctional proteins, occludin and zonula occludens 1 (ZO-1), in addition to ileal damage associated molecular pattern (DAMP) proteins, S100A8 and S100A9, as well as ileal inflammatory markers IL-6 and TNF-α were measured by qPCR. Intestinal cell death was measured by ELISA. Intestinal permeability was determined by FITC fluorescence in serum; 4kD FITC-dextran was given by oral gavage 3 h before euthanasia. RESULTS Aged mice subjected to burn injury had increased intestinal permeability as evidenced by a 5.8-fold higher level of FITC-dextran in their serum when compared to all other groups (p < 0.05). In addition, aged burn-injured mice exhibited heightened bacterial accumulation in the MLN with a 15.5-fold increase over all other groups (p < 0.05). Histology of ileum failed to show differences in villus length among all groups. Analysis of ileal tight junctional proteins and inflammatory marker gene expression revealed no difference in Ocln, Tjp1, Il6, or Tnf expression among all groups, but 2.3 and 2.9-fold upregulation of S100a8 and S100a9, respectively, in aged burn-injured mice relative to both young groups and aged sham-injured mice (p < 0.05). Lastly, cell death in the ileum was elevated more than two-fold in aged burn-injured mice relative to young animals regardless of injury (p < 0.05). CONCLUSIONS These data demonstrate that advanced age exacerbates intestinal epithelial permeability after burn injury. Heightened apoptosis may be responsible for the elevated intestinal leakiness and accumulation of bacteria in mesenteric lymph nodes. In addition, S100a8/9 may serve as a biomarker of elevated inflammation within the intestine.
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Affiliation(s)
- Kevin M. Najarro
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Devin M. Boe
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States of America
| | - Travis M. Walrath
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Juliet E. Mullen
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Madison T. Paul
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - John H. Frankel
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Holly J. Hulsebus
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Juan-Pablo Idrovo
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Rachel H. McMahan
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Elizabeth J. Kovacs
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States of America,GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, United States of America,Corresponding author at: Department of Surgery, GITES, University of Colorado Denver/Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, Aurora, CO 80045, United States of America. (E.J. Kovacs)
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24
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Li X, Luck ME, Herrnreiter CJ, Cannon AR, Choudhry MA. IL-23 Promotes Neutrophil Extracellular Trap Formation and Bacterial Clearance in a Mouse Model of Alcohol and Burn Injury. Immunohorizons 2022; 6:64-75. [PMID: 35058308 DOI: 10.4049/immunohorizons.2100109] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 12/17/2023] Open
Abstract
Our previous studies have shown that ethanol intoxication combined with burn injury increases intestinal bacterial growth, disrupts the intestinal barrier, and enhances bacterial translocation. Additionally, studies show that Th17 effector cytokines IL-17 and IL-22, which are dependent on IL-23, play important roles in maintaining intestine mucosal barrier integrity. Recent findings suggest neutrophils are a significant source of IL-17 and IL-22. We determined the effect of ethanol and burn injury on neutrophil IL-17 and IL-22 production, as well as their ability to phagocytose and in bacterial clearance, and whether these effects are modulated by IL-23. Mice were given ethanol 4 h prior to receiving ∼12.5% total body surface area burn and were euthanized day 1 after injury. We observed that intoxication combined with burn injury significantly decreases blood neutrophil phagocytosis and bacteria killing, as well as their ability to produce IL-17 and IL-22, compared with sham vehicle mice. The treatment of neutrophils with rIL-23 significantly increases IL-22 and IL-17 release and promotes expression of IL-23R, retinoic acid-related orphan receptor γt, Lipocalin2, and Nod-like receptor 2 following ethanol and burn injury. Furthermore, IL-22- and IL-17-producing neutrophils have enhanced neutrophil extracellular trap formation and bacterial killing ability, which are dependent on IL-23. Finally, although we observed that peritoneal neutrophils harvested after casein treatment are functionally different from blood neutrophils, both blood and peritoneal neutrophils exhibited the same response to rIL-23 treatment. Together these findings suggest that IL-23 promotes neutrophil IL-22 and IL-17 production and their ability to kill bacteria following ethanol and burn injury.
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Affiliation(s)
- Xiaoling Li
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
| | - Marisa E Luck
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
| | - Caroline J Herrnreiter
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Biochemistry and Molecular Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL; and
| | - Abigail R Cannon
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
| | - Mashkoor A Choudhry
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL;
- Burn and Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
- Biochemistry and Molecular Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL; and
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL
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25
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Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications. Biomedicines 2021; 9:biomedicines9121912. [PMID: 34944732 PMCID: PMC8698419 DOI: 10.3390/biomedicines9121912] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/11/2021] [Accepted: 12/11/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.
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Chen L, Li L, Zou S, Liao Q, Lv B. Tong‑fu‑li‑fei decoction attenuates immunosuppression to protect the intestinal‑mucosal barrier in sepsis by inhibiting the PD‑1/PD‑L1 signaling pathway. Mol Med Rep 2021; 24:840. [PMID: 34633052 PMCID: PMC8524432 DOI: 10.3892/mmr.2021.12480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 03/01/2021] [Indexed: 12/29/2022] Open
Abstract
The aim of the present study was to investigate the therapeutic effects of Tong-fu-li-fei (TFL) decoction on sepsis-induced injury to the intestinal mucosal barrier and the underlying mechanism. Cecal ligation and puncture (CLP) was used to establish a sepsis model in rats. The post-surgery death of the rats was recorded to calculate the survival rate. A 4-kD fluorescein isothiocyanate (FITC)-dextran assay was used to evaluate the intestinal permeability of the rats. The pathological state of the intestine tissues was detected by hematoxylin and eosin staining and the ultrastructural changes in the endometrium were evaluated by transmission electron microscopy. Enzyme-linked immunosorbent assay was used to determine the concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in the intestinal tissues and cells. The expression levels of SHP-2 and PI3K were detected by reverse transcription-quantitative PCR and western blotting. Sorting by flow cytometry was used to obtain pure dendritic cells (DC), CD8+ T cells and natural killer cells. Western blotting was used to evaluate the expression levels of phosphorylated (p)-AKT and AKT. The results demonstrated that the significantly decreased survival rate caused by CLP surgery was elevated by glutamine (Gln) and TFL treatment. Intestinal permeability was increased by CLP, and greatly suppressed by Gln or TFL treatment. Histopathological changes in the intestinal tissues, such as thinner barrier and atrophied mucosa, and ultrastructure changes such as sharply decreased microvilli and mitochondria dropsy, were observed on sepsis animals; these effects were ameliorated by the introduction of Gln or TFL. The upregulation of SHP-2, PI3K and p-AKT induced by CLP was reversed by TFL. The release of IL-6 and TNF-α was elevated and the expression of SHP-2, PI3K and p-AKT was suppressed in the co-cultural system of DC cells and CD8+ T cells by TFL. Overall, TFL decoction may attenuate immunosuppression to protect intestinal mucosal barrier in sepsis via inhibiting the programmed death1/programmed cell death ligand 1 signal pathway.
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Affiliation(s)
- Li Chen
- Department of Intensive Care Unit, First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
| | - Lan Li
- Department of Intensive Care Unit, First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
| | - Suzhao Zou
- Department of Intensive Care Unit, First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
| | - Qianhua Liao
- Department of Intensive Care Unit, First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
| | - Bo Lv
- Department of Intensive Care Unit, First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
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McMahan RH, Najarro KM, Mullen JE, Paul MT, Orlicky DJ, Hulsebus HJ, Kovacs EJ. A novel murine model of multi-day moderate ethanol exposure reveals increased intestinal dysfunction and liver inflammation with age. IMMUNITY & AGEING 2021; 18:37. [PMID: 34556145 PMCID: PMC8459518 DOI: 10.1186/s12979-021-00247-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/08/2021] [Indexed: 12/23/2022]
Abstract
Background There are currently > 600 million people over the age of 65 globally and this number is expected to double by the year 2050. Alcohol use among this population is on the rise, which is concerning as aging is associated with increased risk for a number of chronic illnesses. As most studies investigating the effects of alcohol have focused on young/middle-aged populations, there is a dearth of information regarding the consequences of alcohol use in older consumers. In addition, most murine ethanol models have concentrated on exposure to very high levels of ethanol, while the vast majority of elderly drinkers do not consume alcohol in excess; instead, they drink on average 2 alcoholic beverages a day, 3–4 days a week. Methods We designed a murine model of aging and moderate ethanol consumption to determine if the deleterious effects of alcohol on the gut-liver axis are exacerbated in aged, relative to younger, animals. Aged and young mice were exposed to a multi-day moderate exposure ethanol regimen for 4 weeks and changes in gut permeability along with intestinal tight junction protein and antimicrobial peptide gene expression were measured. In addition, hepatic inflammation was assessed by histological analysis, inflammatory gene expression and flow cytometric analysis of inflammatory infiltrate. Results Our results reveal that in aged, but not young mice, moderate ethanol exposure yielded significantly worsened intestinal permeability, including increased bacterial translocation from the gut, elevated serum iFABP and leakage of FITC-dextran from the gut. Interestingly, moderate ethanol exposure in young animals led to gut protective transcriptional changes in the ileum while this protective response was blunted in aged mice. Finally, moderate ethanol exposure in aged mice also resulted in marked inflammatory changes in the liver. Conclusions These results demonstrate that aged mice are more susceptible to ethanol-induced gut barrier dysfunction and liver inflammation, even at moderate doses of ethanol. This increased vulnerability to ethanol’s gastrointestinal effects has important implications for alcohol use in the aging population. Future studies will explore whether improving intestinal barrier function can reverse these age-related changes.
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Affiliation(s)
- Rachel H McMahan
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA. .,GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Kevin M Najarro
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA
| | - Juliet E Mullen
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA
| | - Madison T Paul
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA
| | - David J Orlicky
- Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Holly J Hulsebus
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA.,Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Elizabeth J Kovacs
- Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA.,GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA.,Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA
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Bai J, Bai J, Yang M. Interleukin-22 Attenuates Acute Pancreatitis-Associated Intestinal Mucosa Injury in Mice via STAT3 Activation. Gut Liver 2021; 15:771-781. [PMID: 33495423 PMCID: PMC8444107 DOI: 10.5009/gnl20210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/26/2020] [Accepted: 11/06/2020] [Indexed: 11/04/2022] Open
Abstract
Background/Aims Interleukin-22 (IL-22) is an important cytokine maintaining homeostasis at barrier surfaces. In this study, the role of IL-22 in acute pancreatitis-associated intestinal injury was further explored. Methods Severe acute pancreatitis (SAP) was induced by administration of L-arginine in Balb/c mice at different time gradients. Histopathological examinations were made in both the pancreas and small intestine. Furthermore, recombinant murine IL-22 (rIL-22) was administrated to L-arginine-induced SAP mice by intraperitoneal injection. The mRNA levels of IL-22R1, Reg-IIIβ, Reg-IIIγ, Bcl-2, and Bcl-xL were detected in the small intestine by real-time polymerase chain reaction, and protein levels of total and phosphorylated STAT3 were assessed via Western blot. Results Compared with normal control group, 72 hours of L-arginine exposure induced the most characteristic histopathological changes of SAP, evidenced by pathological changes and serum amylase levels. Meanwhile, significant pancreatitis-associated intestinal mucosa injury was also observed. The gene expression levels of antimicrobial proteins Reg-IIIβ, Reg-IIIγ and anti-apoptosis proteins Bcl-2, Bcl-xL were downregulated in small intestine. Furthermore, Larginine- induced SAP was attenuated by rIL-22 treatment. Importantly, pancreatitis-associated intestinal mucosa injury was also ameliorated, reflected by improved pathological changes and significant increase in gene expression levels of Reg-IIIβ, Reg-IIIγ, Bcl-2 and Bcl-xL. Consistently, serum amylase levels and mortality were decreased in mice treated with rIL-22. Mechanistically, the upregulated expressions of these protective genes were achieved by activating STAT3. Conclusions Exogenous rIL-22 attenuates L-arginine-induced acute pancreatitis and intestinal mucosa injury in mice, via activating STAT3 signaling pathway and enhancing the expression of antimicrobial peptides and antiapoptotic genes.
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Affiliation(s)
- Jinxia Bai
- Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People’s Hospital, Shanghai, China
| | - Jinyun Bai
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Shanghai, China
| | - Meng Yang
- Dayi Primary Education Group, Shanghai, China
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Abstract
ABSTRACT Burn injuries are a common form of traumatic injury that leads to significant morbidity and mortality worldwide. Burn injuries are characterized by inflammatory processes and alterations in numerous organ systems and functions. Recently, it has become apparent that the gastrointestinal bacterial microbiome is a key component of regulating the immune response and recovery from burn and can also contribute to significant detrimental sequelae after injury, such as sepsis and multiple organ failure. Microbial dysbiosis has been linked to multiple disease states; however, its role in exacerbating acute traumatic injuries, such as burn, is poorly understood. In this article, we review studies that document changes in the intestinal microbiome after burn injury, assess the implications in post-burn pathogenesis, and the potential for further discovery and research.
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Affiliation(s)
- Marisa E. Luck
- Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Caroline J. Herrnreiter
- Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Biochemistry and Molecular Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Mashkoor A. Choudhry
- Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
- Biochemistry and Molecular Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
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Yang A, Wu Y, Yu G, Wang H. Role of specialized pro-resolving lipid mediators in pulmonary inflammation diseases: mechanisms and development. Respir Res 2021; 22:204. [PMID: 34261470 PMCID: PMC8279385 DOI: 10.1186/s12931-021-01792-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammation is an essential mechanism of various diseases. The development and resolution of inflammation are complex immune-modulation processes which induce the involvement of various types of immune cells. Specialized pro-resolving lipid mediators (SPMs) have been demonstrated to be signaling molecules in inflammation. SPMs are involved in the pathophysiology of different diseases, especially respiratory diseases, including asthma, pneumonia, and chronic obstructive pulmonary disease. All of these diseases are related to the inflammatory response and its persistence. Therefore, a deeper understanding of the mechanisms and development of inflammation in respiratory disease, and the roles of the SPM family in the resolution process, might be useful in the quest for novel therapies and preventive measures for pulmonary diseases.
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Affiliation(s)
- Ailin Yang
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xicheng, , Beijing, 100050, China
| | - Yanjun Wu
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xicheng, , Beijing, 100050, China
| | - Ganggang Yu
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xicheng, , Beijing, 100050, China.
| | - Haoyan Wang
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xicheng, , Beijing, 100050, China.
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Klooster JPT, Bol-Schoenmakers M, van Summeren K, van Vliet ALW, de Haan CAM, van Kuppeveld FJM, Verkoeijen S, Pieters R. Enterocytes, fibroblasts and myeloid cells synergize in anti-bacterial and anti-viral pathways with IL22 as the central cytokine. Commun Biol 2021; 4:631. [PMID: 34045640 PMCID: PMC8160143 DOI: 10.1038/s42003-021-02176-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 05/03/2021] [Indexed: 12/30/2022] Open
Abstract
IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNβ1 and subsequently IL7. IFNβ1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.
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Affiliation(s)
- Jean Paul Ten Klooster
- Research Centre Healthy and Sustainable Living, Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, The Netherlands.
| | - Marianne Bol-Schoenmakers
- Institute for Risk Assessment Sciences, Population Health Sciences Division, Utrecht University, Utrecht, The Netherlands
| | - Kitty van Summeren
- Research Centre Healthy and Sustainable Living, Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, The Netherlands
| | - Arno L W van Vliet
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Cornelis A M de Haan
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Frank J M van Kuppeveld
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Saertje Verkoeijen
- Research Centre Healthy and Sustainable Living, Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, The Netherlands
| | - Raymond Pieters
- Research Centre Healthy and Sustainable Living, Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, The Netherlands
- Institute for Risk Assessment Sciences, Population Health Sciences Division, Utrecht University, Utrecht, The Netherlands
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Yang J, Syed F, Xia Y, Sanyal A, Shah V, Chalasani N, Zheng X, Yu Q, Lou Y, Li W. Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis. Alcohol Clin Exp Res 2021; 45:720-731. [PMID: 33587293 PMCID: PMC8076084 DOI: 10.1111/acer.14579] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/11/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. RESULTS At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. CONCLUSIONS Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.
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Affiliation(s)
- Jing Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Fahim Syed
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ying Xia
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Xiaoqun Zheng
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yongliang Lou
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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Qin C, Hu J, Wan Y, Cai M, Wang Z, Peng Z, Liao Y, Li D, Yao P, Liu L, Rong S, Bao W, Xu G, Yang W. Narrative review on potential role of gut microbiota in certain substance addiction. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110093. [PMID: 32898589 DOI: 10.1016/j.pnpbp.2020.110093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/22/2020] [Accepted: 08/30/2020] [Indexed: 12/14/2022]
Abstract
As a neuropsychiatric disorder, substance addiction represents a major public health issue with high prevalence and mortality in many countries. Recently, gut microbiota has been certified to play a part in substance addiction through various mechanisms. Hence, we mainly focused on three substance including alcohol, cocaine and methamphetamine in this review, and summarized their relationships with gut microbiota, respectively. Besides, we also concluded the possible treatments for substance addiction from the perspective of applying gut microbiota. This review aims to build a bridge between substance addiction and gut microbiota according to existing evidences, so as to excavate the possible bi-directional function of microbiota-gut-brain axis in substance addiction for developing therapeutic strategies in the future.
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Affiliation(s)
- Chenyuan Qin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Jiawei Hu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yiming Wan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Mengyao Cai
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhenting Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhao Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yuxiao Liao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Dan Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Shuang Rong
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene, School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Wei Bao
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA
| | - Guifeng Xu
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA; Center for Disabilities and Development, University of Iowa Stead Family Children's Hospital, Iowa City, IA 52242, USA
| | - Wei Yang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China.
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Morris NL, Choudhry MA. Maintenance of gut barrier integrity after injury: Trust your gut microRNAs. J Leukoc Biol 2021; 110:979-986. [PMID: 33577717 DOI: 10.1002/jlb.3ru0120-090rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a highly dynamic structure essential for digestion, nutrient absorption, and providing an interface to prevent gut bacterial translocation. In order to maintain the barrier function, the gut utilizes many defense mechanisms including proliferation, apoptosis, and apical junctional complexes. Disruption of any of these parameters due to injury or disease could negatively impact the intestinal barrier function and homeostasis resulting in increased intestine inflammation, permeability, bacterial dysbiosis, and tissue damage. MicroRNAs are small noncoding RNA sequences that are master regulators of normal cellular homeostasis. These regulatory molecules affect cellular signaling pathways and potentially serve as candidates for providing a mechanism of impaired gut barrier integrity following GI-related pathologic conditions, ethanol exposure, or trauma such as burn injury. MicroRNAs influence cellular apoptosis, proliferation, apical junction complex expression, inflammation, and the microbiome. Due to their widespread functional affiliations, altered expression of microRNAs are associated with many pathologic conditions. This review explores the role of microRNAs in regulation of intestinal barrier integrity. The studies reviewed demonstrate that microRNAs largely impact intestine barrier function and provide insight behind the observed adverse effects following ethanol and burn injury. Furthermore, these studies suggest that microRNAs are excellent candidates for therapeutic intervention or for biomarkers to manage gut barrier integrity following trauma such as burn injury and other GI-related pathologic conditions.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Current address: Department of Medicine: Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Geogia, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA
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Advanced Age Impairs Intestinal Antimicrobial Peptide Response and Worsens Fecal Microbiome Dysbiosis Following Burn Injury in Mice. Shock 2021; 53:71-77. [PMID: 30672882 DOI: 10.1097/shk.0000000000001321] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Maintenance of the commensal bacteria that comprise the gut microbiome is essential to both gut and systemic health. Traumatic injury, such as burn, elicits a number of changes in the gut, including a shift in the composition of the microbiome (dysbiosis), increased gut leakiness, and bacterial translocation into the lymphatic system and bloodstream. These effects are believed to contribute to devastating secondary complications following burn, including pneumonia, acute respiratory distress syndrome, multi-organ failure, and septic shock. Clinical studies demonstrate that advanced age causes a significant increase in mortality following burn, but the role of the gut in this age-dependent susceptibility has not been investigated. In this study, we combined our well-established murine model of scald burn injury with bacterial 16S-rRNA gene sequencing to investigate how burn injury affects the fecal microbiome in aged versus young mice. Of our treatment groups, the most substantial shift in gut microbial populations was observed in aged mice that underwent burn injury. We then profiled antimicrobial peptides (AMPs) in the ileum, and found that burn injury stimulated a 20-fold rise in levels of regenerating islet-derived protein 3 gamma (Reg3γ), a 16-fold rise in regenerating islet-derived protein 3 beta (Reg3β), and an 8-fold rise in Cathelicidin-related antimicrobial peptide (Cramp) in young, but not aged mice. Advanced age alone elicited 5-fold higher levels of alpha defensin-related sequence1 (Defa-rs1) in the ileum, but this increase was lost following burn. Comparison of bacterial genera abundance and AMP expression across treatment groups revealed distinct correlation patterns between AMPs and individual genera. Our results reveal that burn injury drives microbiome dysbiosis and altered AMP expression in an age-dependent fashion, and highlight potential mechanistic targets contributing to the increased morbidity and mortality observed in elderly burn patients.
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Bruellman R, Llorente C. A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease. Int J Biol Sci 2021; 17:307-327. [PMID: 33390852 PMCID: PMC7757023 DOI: 10.7150/ijbs.53589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
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Affiliation(s)
- Ryan Bruellman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Li X, Luck ME, Hammer AM, Cannon AR, Choudhry MA. 6-Formylindolo (3, 2-b) Carbazole (FICZ)-mediated protection of gut barrier is dependent on T cells in a mouse model of alcohol combined with burn injury. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165901. [PMID: 32711051 PMCID: PMC7484351 DOI: 10.1016/j.bbadis.2020.165901] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 07/14/2020] [Accepted: 07/17/2020] [Indexed: 12/22/2022]
Abstract
6-Formylindolo (3, 2-b) Carbazole (FICZ) is a ligand of aryl hydrocarbon receptor (AHR) which regulates Th17 release of IL-17 and IL-22 production. Earlier, we showed that ethanol combined with burn injury suppresses Th17 responses and disrupts intestinal barrier leading to increased gut bacterial growth and translocation. Since IL-22 is known for its role in intestinal barrier maintenance, we determined whether treatment of mice with FICZ restores T cell IL-22 release and protects intestine barrier following ethanol and burn injury. Wildtype and Rag1-/- mice were gavaged with ~2.9 g/kg ethanol or water, and given a ~12.5% total body surface area burn. Mice were given FICZ (5 μg) in resuscitation fluid. FICZ treatment of wildtype mice normalized IL-22 and IL-17 in lamina propria and spleen T cells, as well as increased CYP1A1 expression in spleen T cells. This was accompanied by improved gut motility, decreased copy number of small intestine total bacteria and Enterobacteriaceae, attenuation of intestinal tissue levels of IL-6, KC, IL-18, decreased apoptosis, and prevention of gut leakiness following ethanol and burn injury. However, FICZ treatment of Rag1-/- mice did not improve any of the parameters listed after ethanol and burn injury. Additional data generated using mice treated with recombinant IL-22 alone or in combination with anti-IL-18 antibody suggest that full protection of gut barrier integrity requires both IL-18 inhibition and IL-22 restoration following ethanol and burn injury. Together our findings suggest that AHR ligand FICZ may have better therapeutic potential for maintenance of gut barrier function after ethanol and burn injury.
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MESH Headings
- Animals
- Burns/drug therapy
- Burns/metabolism
- Carbazoles/therapeutic use
- Cytochrome P-450 CYP1A1/genetics
- Cytochrome P-450 CYP1A1/metabolism
- Cytokines/metabolism
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Ethanol/pharmacology
- Flow Cytometry
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Interleukin-17/metabolism
- Interleukins/metabolism
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/microbiology
- Intestine, Small/drug effects
- Intestine, Small/metabolism
- Intestine, Small/microbiology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mucous Membrane/drug effects
- Mucous Membrane/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Aryl Hydrocarbon/metabolism
- T-Lymphocytes/drug effects
- T-Lymphocytes/metabolism
- Interleukin-22
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Affiliation(s)
- Xiaoling Li
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Marisa E Luck
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Adam M Hammer
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Abigail R Cannon
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Burn & Shock Trauma Research Institute, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Department of Surgery, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA; Integrative Cell Biology Program, Stritch School of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, USA.
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38
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Morris NL, Cannon AR, Li X, Choudhry MA. Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury. J Leukoc Biol 2020; 109:1121-1130. [PMID: 32964503 DOI: 10.1002/jlb.3a0820-323rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/17/2020] [Accepted: 08/22/2020] [Indexed: 12/15/2022] Open
Abstract
Ethanol remains a confounder in postburn pathology, which is associated with an impaired intestinal barrier. Previously, we demonstrated that ethanol and burn injury reduce intestinal oxygen delivery (hypoxia) and alters microRNA (miR) expression in small intestinal epithelial cells. Hypoxia has been shown to influence expression of miRs and miR biogenesis components. Therefore, we examined whether hypoxia influences expression of miR biogenesis components (drosha, dicer, and argonaute-2 [ago-2]) and miRs (-7a and -150) and whether these changes impacted other parameters following ethanol and burn injury. Mice were gavaged with ethanol (∼2.9 g/kg) 4 h before receiving a ∼12.5% total body surface full thickness burn. Mice were resuscitated at the time of injury with normal saline with or without 5 mg/kg PX-478, a hypoxia-inducible factor-1α inhibitor. One day following injury mice were euthanized, and the expression of miRs and their biogenesis components as well as bacterial growth, tight junction proteins, intestinal transit, and permeability were assessed. Ethanol combined with burn injury significantly reduced expression of drosha, ago-2, miRs (-7a and -150), occludin, zonula occludens-1, claudin-4, zonula occludens-1, mucins-2 and -4, and intestinal transit compared to shams. Furthermore, there was an increase in intestinal permeability, total bacteria, and Enterobacteriaceae populations following the combined injury compared to shams. PX-478 treatment improved expression of drosha, ago-2, miRs (-7a and -150), occludin, claudin-4, zonula occludens-1, and mucin-2. PX-478 treatment also improved intestinal transit and reduced dysbiosis and permeability. These data suggest that PX-478 improves miR biogenesis and miR expression, and restores barrier integrity while reducing bacterial dysbiosis following ethanol and burn injury.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Current address: Department of Medicine, Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Georgia, USA
| | - Abigail R Cannon
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
| | - Xiaoling Li
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA.,Department of Microbiology and Immunology, Loyola University Chicago Health Sciences Campus, Maywood, Illinois, USA
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Blears E, Sommerhalder C, Toliver-Kinsky T, Finnerty CC, Herndon DN. Current problems in burn immunology. Curr Probl Surg 2020; 57:100779. [PMID: 32507131 DOI: 10.1016/j.cpsurg.2020.100779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 02/22/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Elizabeth Blears
- Department of Surgery, University of Texas Medical Branch, Galveston, TX
| | | | - Tracy Toliver-Kinsky
- Department of Anesthesiology, Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX.
| | - Celeste C Finnerty
- Department of Surgery, University of Texas Medical Branch, Galveston, TX; Shriners Hospitals for Children, Galveston, TX
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40
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Keir ME, Yi T, Lu TT, Ghilardi N. The role of IL-22 in intestinal health and disease. J Exp Med 2020; 217:e20192195. [PMID: 32997932 PMCID: PMC7062536 DOI: 10.1084/jem.20192195] [Citation(s) in RCA: 288] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 12/24/2022] Open
Abstract
The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.
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Affiliation(s)
- Mary E. Keir
- Biomarker Discovery, Genentech, South San Francisco, CA
| | - Tangsheng Yi
- Department of Immunology, Genentech, South San Francisco, CA
| | - Timothy T. Lu
- Early Clinical Development, Genentech, South San Francisco, CA
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41
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Tripathi D, Radhakrishnan RK, Sivangala Thandi R, Paidipally P, Devalraju KP, Neela VSK, McAllister MK, Samten B, Valluri VL, Vankayalapati R. IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis. PLoS Pathog 2019; 15:e1008140. [PMID: 31809521 PMCID: PMC6919622 DOI: 10.1371/journal.ppat.1008140] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 12/18/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.
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Affiliation(s)
- Deepak Tripathi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Rajesh Kumar Radhakrishnan
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Ramya Sivangala Thandi
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Padmaja Paidipally
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Kamakshi Prudhula Devalraju
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Venkata Sanjeev Kumar Neela
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Madeline Kay McAllister
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Buka Samten
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
| | - Vijaya Lakshmi Valluri
- Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India
| | - Ramakrishna Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Science Center, Tyler, Texas, TX, United States of America
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42
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Walker EM, Slisarenko N, Gerrets GL, Kissinger PJ, Didier ES, Kuroda MJ, Veazey RS, Jazwinski SM, Rout N. Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells. GeroScience 2019; 41:739-757. [PMID: 31713098 PMCID: PMC6925095 DOI: 10.1007/s11357-019-00099-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 08/29/2019] [Indexed: 02/06/2023] Open
Abstract
The development of chronic inflammation, called inflammaging, contributes to the pathogenesis of age-related diseases. Although it is known that both B and T lymphocyte compartments of the adaptive immune system deteriorate with advancing age, the impact of aging on immune functions of Th17-type CD161-expressing innate immune cells and their role in inflammaging remain incompletely understood. Here, utilizing the nonhuman primate model of rhesus macaques, we report that a dysregulated Th17-type effector function of CD161+ immune cells is associated with leaky gut and inflammatory phenotype of aging. Higher plasma levels of inflammatory cytokines IL-6, TNF-α, IL-1β, GM-CSF, IL-12, and Eotaxin correlated with elevated markers of gut permeability including LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and sCD14 in aging macaques. Further, older macaques displayed significantly lower frequencies of circulating Th17-type immune cells comprised of CD161+ T cell subsets, NK cells, and innate lymphoid cells. Corresponding with the increased markers of gut permeability, production of the type-17 cytokines IL-17 and IL-22 was impaired in CD161+ T cell subsets and NK cells, along with a skewing towards IFN-γ cytokine production. These findings suggest that reduced frequencies of CD161+ immune cells along with a specific loss in Th17-type effector functions contribute to impaired gut barrier integrity and systemic inflammation in aging macaques. Modulating type-17 immune cell functions via cytokine therapy or dietary interventions towards reducing chronic inflammation in inflammaging individuals may have the potential to prevent or delay age-related chronic diseases and improve immune responses in the elderly population.
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Affiliation(s)
- Edith M Walker
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA, USA
| | - Nadia Slisarenko
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA, USA
| | - Giovanni L Gerrets
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA, USA
| | - Patricia J Kissinger
- School of Public Health & Tropical Medicine, Tulane University, New Orleans, LA, USA
| | - Elizabeth S Didier
- Center for Comparative Medicine and California National Primate Research Center, University of California Davis, Davis, CA, USA
| | - Marcelo J Kuroda
- Center for Comparative Medicine and California National Primate Research Center, University of California Davis, Davis, CA, USA
| | - Ronald S Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, USA
| | | | - Namita Rout
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA, USA.
- Tulane Center for Aging, Tulane University, New Orleans, LA, USA.
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43
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Litwinowicz K, Choroszy M, Waszczuk E. Changes in the composition of the human intestinal microbiome in alcohol use disorder: a systematic review. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2019; 46:4-12. [DOI: 10.1080/00952990.2019.1669629] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Kamil Litwinowicz
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Marcin Choroszy
- Department of Microbiology, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Waszczuk
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland
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44
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Ramakrishnan SK, Zhang H, Ma X, Jung I, Schwartz AJ, Triner D, Devenport SN, Das NK, Xue X, Zeng MY, Hu Y, Mortensen RM, Greenson JK, Cascalho M, Wobus CE, Colacino JA, Nunez G, Rui L, Shah YM. Intestinal non-canonical NFκB signaling shapes the local and systemic immune response. Nat Commun 2019; 10:660. [PMID: 30737385 PMCID: PMC6368617 DOI: 10.1038/s41467-019-08581-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 01/21/2019] [Indexed: 12/13/2022] Open
Abstract
Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The function of M-cells in systemic inflammatory responses are still unclear. Here we show that epithelial non-canonical NFkB signaling mediated by NFkB-inducing kinase (NIK) is highly active in intestinal lymphoid follicles, and is required for M-cell maintenance. Intestinal NIK signaling modulates M-cell differentiation and elicits both local and systemic IL-17A and IgA production. Importantly, intestinal NIK signaling is active in mouse models of colitis and patients with inflammatory bowel diseases; meanwhile, constitutive NIK signaling increases the susceptibility to inflammatory injury by inducing ectopic M-cell differentiation and a chronic increase of IL-17A. Our work thus defines an important function of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis.
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Affiliation(s)
| | - Huabing Zhang
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Xiaoya Ma
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Inkyung Jung
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Andrew J Schwartz
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Daniel Triner
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Samantha N Devenport
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Nupur K Das
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Xiang Xue
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Melody Y Zeng
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yinling Hu
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Richard M Mortensen
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Marilia Cascalho
- Transplantation Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Christiane E Wobus
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Justin A Colacino
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Gabriel Nunez
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
- Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Liangyou Rui
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yatrik M Shah
- Department of Molecular & Integrative Physiology, University of Michigan, Michigan, MI, 48109, USA.
- Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
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45
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Abstract
Pulmonary respiration inevitably exposes the mucosal surface of the lung to potentially noxious stimuli, including pathogens, allergens, and particulates, each of which can trigger pulmonary damage and inflammation. As inflammation resolves, B and T lymphocytes often aggregate around large bronchi to form inducible Bronchus-Associated Lymphoid Tissue (iBALT). iBALT formation can be initiated by a diverse array of molecular pathways that converge on the activation and differentiation of chemokine-expressing stromal cells that serve as the scaffolding for iBALT and facilitate the recruitment, retention, and organization of leukocytes. Like conventional lymphoid organs, iBALT recruits naïve lymphocytes from the blood, exposes them to local antigens, in this case from the airways, and supports their activation and differentiation into effector cells. The activity of iBALT is demonstrably beneficial for the clearance of respiratory pathogens; however, it is less clear whether it dampens or exacerbates inflammatory responses to non-infectious agents. Here, we review the evidence regarding the role of iBALT in pulmonary immunity and propose that the final outcome depends on the context of the disease.
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46
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Correlation of the expression of inflammatory factors with expression of apoptosis-related genes Bax and Bcl-2, in burned rats. Exp Ther Med 2018; 17:1790-1796. [PMID: 30783451 PMCID: PMC6364214 DOI: 10.3892/etm.2018.7118] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 12/03/2018] [Indexed: 12/25/2022] Open
Abstract
Correlation of the expression of inflammatory factors with expression of apoptosis-related genes, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax), in burned rats was investigated. Forty healthy Sprague-Dawley rats were selected and randomly divided into SHAM group (n=10), I° burn group (n=10), II° burn group (n=10) and III° burn group (n=10). Changes in tumor necrosis factor-α (TNF-α), Bax messenger ribonucleic acid (mRNA), Bcl-2 mRNA, Bax protein and Bcl-2 protein expression levels were detected. The correlation of TNF-α, Bax and Bcl-2 with the degree of burn in rats was observed, and the correlation of TNF-α with Bax and Bcl-2 was also analyzed. Moreover, Bax mRNA and Bcl-2 mRNA were detected via reverse transcription-quantitative polymerase chain reaction, and TNF-α, Bax protein and Bcl-2 protein were detected via enzyme-linked immunosorbent assay. In burn groups, TNF-α, Bax mRNA and Bax protein levels were significantly increased at each time point compared with those at the previous time point (P<0.05), but Bcl-2 mRNA and protein levels were significantly decreased compared with those at the previous time point (P<0.05). At the same time point, TNF-α, Bax mRNA, Bcl-2 mRNA, Bax protein and Bcl-2 protein expression levels had statistically significant differences between any given two groups (P<0.05). The TNF-α expression level was positively correlated with Bax expression levels and negatively correlated with Bcl-2 expression levels. Additionally, TNF-α, Bax mRNA and Bax protein had positive correlations with the degree of burn and time after burn, while Bcl-2 mRNA and Bcl-2 protein had negative correlations with the degree of burn and time after burn. Continuous monitoring of changes in the TNF-α level can be used as a means to evaluate the degree of burn and apoptosis, and to prevent the deepening of burn wounds, thus facilitating the early clinical evaluation of prognosis.
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47
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Jose S, Mukherjee A, Abhyankar MM, Leng L, Bucala R, Sharma D, Madan R. Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection. Anaerobe 2018; 53:56-63. [PMID: 29944928 PMCID: PMC6309669 DOI: 10.1016/j.anaerobe.2018.06.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 12/16/2022]
Abstract
Clostridium difficile is an important cause of nosocomial diarrhea in the western world. Toxins (A, B, and binary toxins) generated by C. difficile bacteria damage intestinal epithelial cells. Hallmarks of host response to C. difficile infection (CDI) include upregulation of inflammatory mediators and tissue infiltration by immune cells. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that is known to enhance the host immune response to infectious pathogens. Additionally, MIF can adversely impact host survival to numerous infections. The role of MIF in the pathogenesis of CDI remains poorly understood. Here, we show that patients with CDI had significantly higher circulating MIF compared to patients who had diarrhea but tested negative for C. difficile (non-CDI controls). Similarly, in a mouse model, C. difficile challenge significantly increased levels of plasma and tissue MIF. Antibody-mediated depletion of MIF decreased C. difficile-induced inflammatory responses, clinical disease, and mortality. Together, these results uncover a potential role for MIF in exacerbating CDI and suggest that use of anti-MIF antibodies may represent a therapeutic strategy to curb host inflammatory responses and improve disease outcomes in CDI.
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Affiliation(s)
- Shinsmon Jose
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Anindita Mukherjee
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Mayuresh M Abhyankar
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Lin Leng
- Departments of Internal Medicine, Yale University, New Haven, CT, USA
| | - Richard Bucala
- Departments of Internal Medicine, Yale University, New Haven, CT, USA
| | - Divya Sharma
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Rajat Madan
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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48
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Hou Q, Ye L, Liu H, Huang L, Yang Q, Turner JR, Yu Q. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 2018; 25:1657-1670. [PMID: 29459771 PMCID: PMC6143595 DOI: 10.1038/s41418-018-0070-2] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 01/19/2018] [Accepted: 01/22/2018] [Indexed: 02/06/2023] Open
Abstract
The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa. We found that only live L. reuteri D8 was effective in protecting the morphology of intestinal organoids and normal proliferation of epithelial stained with EdU under TNF-α treatment, which was also further verified in mice experiments. L. reuteri D8 colonized in the intestinal mucosa and ameliorated intestinal mucosa damage caused by DSS treatment, including improvement of body weight, colon length, pathological change, and proliferation level. The repair process stimulated by L. reuteri D8 was also accompanied with increased numbers of Lgr5+ and lysozyme+ cells both in intestinal organoids and mice intestine. Furthermore, we demonstrated that D8 metabolite indole-3-aldehyde stimulated LPLs to secret IL-22 through aryl hydrocarbon receptor (AhR) and then induced phosphorylation of STAT3 to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa. Our findings indicate L. reuteri protects intestinal barrier and activates intestinal epithelial proliferation, which sheds light on treatment approaches for intestinal inflammation based on ISCs with probiotics Lactobacillus and daily probiotic consumption in heath foods.
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Affiliation(s)
- Qihang Hou
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China
| | - Lulu Ye
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China
| | - Haofei Liu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China
| | - Lulu Huang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China
| | - Qian Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China
| | - J R Turner
- Department of Pathology, The University of Chicago, Chicago, IL, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine,Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA
| | - Qinghua Yu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China.
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49
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Budda SA, Zenewicz LA. IL-22 deficiency increases CD4 T cell responses to mucosal immunization. Vaccine 2018; 36:3694-3700. [PMID: 29739717 PMCID: PMC11078027 DOI: 10.1016/j.vaccine.2018.05.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 04/27/2018] [Accepted: 05/02/2018] [Indexed: 01/09/2023]
Abstract
Mucosal vaccines are a promising platform for combatting infectious diseases for which we still lack effective preventative measures. Optimizing these vaccines to generate the best protective immune responses with the least complicated immunization regimen is imperative. Mucosal barriers are the first line of defense against many pathogens and, as such, we looked to their biology for strategies to improve vaccine delivery. Interleukin-22 (IL-22) is a key cytokine in both healthy and inflamed mucosal tissues. IL-22 promotes epithelial cell proliferation and inhibits apoptosis, upregulates mucin and antimicrobial peptides, all of which promote mucosal barrier integrity. In this study, we find that IL-22 impairs the development of a T cell response during mucosal immunization. Compared to wild-type control mice, IL-22 deficient mice had increased antigen-specific CD4 T cell responses to intrarectal immunization using a protein and cholera toxin adjuvant vaccine. When immunized systemically with the same protein antigen adsorbed to alum, no differences in the CD4 T cell response between wild-type and IL-22 deficient mice were detected. This suggests that transiently inhibiting IL-22 during mucosal vaccination could enhance T cell responses. The broad-applicability of this proposed approach would allow for improvement of many existing mucosal vaccine regimens and have positive implications in the development of more efficacious mucosal vaccines.
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Affiliation(s)
- Scott A Budda
- Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Lauren A Zenewicz
- Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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50
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Hulsebus HJ, Curtis BJ, Molina PE, Afshar M, Boule LA, Morris N, Keshavarzian A, Kolls JK, Yeligar SM, Price ME, Wyatt TA, Choudhry MA, Kovacs EJ. Summary of the 2017 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 2018; 69:51-56. [PMID: 29654985 PMCID: PMC5930121 DOI: 10.1016/j.alcohol.2017.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 10/20/2017] [Accepted: 10/23/2017] [Indexed: 02/08/2023]
Abstract
On June 24, 2017, the 22nd annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Research Society on Alcoholism (RSA) Scientific Meeting in Denver, Colorado. The 2017 meeting focused broadly on mechanisms that link alcohol to tissue injury and inflammation, and how this research can be translated to improve human health. Two plenary sessions composed the meeting, which first explored the association between alcohol and trauma/tissue injury, and finished with a discussion of alcohol and mucosal inflammation. The presentations encompassed diverse areas of alcohol research, from effects on the brain, to airway and pulmonary systems, to gut barrier disruption. The discussions also thoughtfully highlighted how current laboratory and clinical research can be used to prevent or treat alcohol-related morbidity and mortality.
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Affiliation(s)
- Holly J. Hulsebus
- Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Brenda J. Curtis
- Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Patricia E. Molina
- Department of Physiology and Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Majid Afshar
- Division of Pulmonary and Critical Care Medicine, Loyola University Chicago, Maywood, IL, USA,Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Lisbeth A. Boule
- Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Niya Morris
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Ali Keshavarzian
- Department of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
| | - Jay K. Kolls
- Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, LA, USA
| | - Samantha M. Yeligar
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University and Atlanta Veterans Affairs Medical Center, Decatur, GA, USA
| | - Michael E. Price
- Department of Internal Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Todd A. Wyatt
- Department of Internal Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mashkoor A. Choudhry
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Elizabeth J. Kovacs
- Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA,Corresponding author: Elizabeth J. Kovacs, Ph.D., 12700 East 19th Ave, Research Complex 2, Mailstop #8620, Aurora, CO, 80045. Phone: 303-724-8243.
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