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Zhan Y, Deng Q, Jia Y, Chen Z, Zhao X, Ling Y, Qiu Y, Wang X, Wang F, He M, Huang W, Shen J, Wen S. Pdia3 deficiency exacerbates intestinal injury by disrupting goblet and Paneth cell function during ischemia/reperfusion. Cell Signal 2025; 130:111682. [PMID: 39988288 DOI: 10.1016/j.cellsig.2025.111682] [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: 12/24/2024] [Revised: 01/27/2025] [Accepted: 02/18/2025] [Indexed: 02/25/2025]
Abstract
Intestinal ischemia/reperfusion (I/R) injury is a severe medical condition associated with high mortality rates due to its disruption of intestinal homeostasis and impairment of mucosal defenses. The intestinal epithelium, particularly goblet and Paneth cells, plays a critical role in maintaining gut barrier integrity. Protein disulfide isomerase A3 (PDIA3) is involved in protein folding within intestinal epithelial cells (IECs) and has been linked to the stress response during I/R injury. This study aims to explore the role of PDIA3 in preserving intestinal integrity and immune function during I/R injury. Our study employed both human and mouse models to investigate PDIA3's expression and function. The correlation between PDIA3 expression and disease severity was analyzed using statistical tests, including Pearson's correlation coefficient. An intestinal I/R model was established in intestinal epithelium-specific conditional knockout mice lacking the Pdia3 gene. Single-cell RNA sequencing, immunohistochemistry, and transcriptomic analysis were used to assess PDIA3 expression in various intestinal cell types and to evaluate its role in epithelial differentiation and immune responses. PDIA3 was found to be highly expressed in healthy IECs, especially in goblet and Paneth cells. Its expression was reduced in patients with mesenteric artery ischemia and Pdia3-deficient mice, leading to severe intestinal damage, including impaired goblet and Paneth cell function, reduced antimicrobial peptide production, and altered gut microbiota. Treatment with recombinant defensin α1, an antimicrobial peptide secreted by Paneth cells, significantly alleviated the adverse effects of Pdia3 deficiency, restoring gut microbiota balance and reducing inflammation in the intestinal I/R injury mice. Taken together, our findings suggest that Pdia3 plays a vital role in maintaining intestinal barrier function and immune defense. Its deficiency exacerbates I/R-induced intestinal damage by impairing epithelial differentiation, mucus production, and antimicrobial peptide secretion. Targeting Pdia3 and associated pathways offers promising therapeutic strategies for mitigating I/R injury and restoring intestinal homeostasis.
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Affiliation(s)
- Yaqing Zhan
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qiwen Deng
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yifan Jia
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhaorong Chen
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany
| | - Xu Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yihong Ling
- State Key Laboratory of Oncology in South, China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yuxin Qiu
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiwen Wang
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Fan Wang
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Muchen He
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenqi Huang
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Jiantong Shen
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Shihong Wen
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Department of Anesthesiology, Guangxi Hospital Division of the First Affiliated Hospital of Sun Yat-sen University, Nanning, China.
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García-Estrada J, Luquin S, Pesqueda-Cendejas K, Ruiz-Ballesteros AI, Campos-López B, Meza-Meza MR, Parra-Rojas I, González-Castañeda RE, Ramos-Lopez O, De la Cruz-Mosso U. Malnutrition in Substance Use Disorders: A Critical Issue in Their Treatment and Recovery. Healthcare (Basel) 2025; 13:868. [PMID: 40281819 PMCID: PMC12027436 DOI: 10.3390/healthcare13080868] [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: 01/21/2025] [Revised: 03/22/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Substance use disorders (SUDs) are widely prevalent in many countries, with the highest rates observed in nicotine and alcohol use, followed by opioid and cannabis use disorders. Within the field of SUDs, nutrition has become an increasingly important area of focus in both epidemiology and public health, as malnutrition is frequently observed among individuals affected by these disorders. Research indicates that people with SUDs are more likely to experience malnutrition than the general population; however, this issue remains an often-overlooked consequence that can impact disease progression and recovery outcomes. SUDs disrupt brain metabolism, leading to changes in brain function and disturbances in glucose, protein, and lipid metabolism. Evidence shows that individuals with certain SUDs often suffer from poor nutritional status, marked by high sugar consumption and insufficient intake of key micronutrients like iron, as well as vitamins D, C, A, and B-likely due to prioritizing drug use over adequate food intake. Importantly, diet can alter the metabolism and effects of drugs, potentially amplifying or diminishing their impact. While nutrition should play a central role in SUD treatment and rehabilitation, current research-both in animal models and human studies-on the role and benefits of specific nutrients in this context remains limited. This literature review aims to synthesize the available findings on the impact of malnutrition in human and murine models of SUDs, with the goal of identifying which nutrients may provide the most support for treatment and recovery.
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Affiliation(s)
- Joaquín García-Estrada
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
| | - Sonia Luquin
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
| | - Karen Pesqueda-Cendejas
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
| | - Adolfo I. Ruiz-Ballesteros
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
| | - Bertha Campos-López
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
| | - Mónica R. Meza-Meza
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
| | - Isela Parra-Rojas
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
- Laboratorio de Investigación en Obesidad y Diabetes, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo 39087, Mexico
- Red Iberoamericana de Colaboración Académica y Científica en Nutriómicas y Nutrición de Precisión (RINN22), 28049 Madrid, Spain
| | - Rocío Elizabeth González-Castañeda
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
| | - Omar Ramos-Lopez
- Red Iberoamericana de Colaboración Académica y Científica en Nutriómicas y Nutrición de Precisión (RINN22), 28049 Madrid, Spain
- Facultad de Medicina y Psicología, Universidad Autónoma de Baja California, Tijuana 22390, Mexico
| | - Ulises De la Cruz-Mosso
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (J.G.-E.); (S.L.); (K.P.-C.); (M.R.M.-M.); (R.E.G.-C.)
- Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Red de Inmunonutrición y Genómica Nutricional en las Enfermedades Autoinmunes, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (A.I.R.-B.); (I.P.-R.)
- Red Iberoamericana de Colaboración Académica y Científica en Nutriómicas y Nutrición de Precisión (RINN22), 28049 Madrid, Spain
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Yakut A. Gut microbiota in the development and progression of chronic liver diseases: Gut microbiota-liver axis. World J Hepatol 2025; 17:104167. [PMID: 40177197 PMCID: PMC11959663 DOI: 10.4254/wjh.v17.i3.104167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.
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Affiliation(s)
- Aysun Yakut
- Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, İstanbul 38000, Türkiye.
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Kreimeyer H, Llorente C, Schnabl B. Influence of Alcohol on the Intestinal Immune System. Alcohol Res 2025; 45:03. [PMID: 40151622 PMCID: PMC11913448 DOI: 10.35946/arcr.v45.1.03] [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] [Indexed: 03/29/2025] Open
Abstract
PURPOSE Alcohol misuse is associated with disruption of the microbial homeostasis (dysbiosis) and microbial overgrowth in the gut, gut barrier disruption, and translocation of microbes into the systemic circulation. It also induces changes in regulatory mechanisms of the gut, which is the largest peripheral immune organ. The gut-liver axis is important for health and disease, and alterations in the intestinal immune system contribute to alcohol-associated liver disease (ALD). Understanding these changes might help discover new targets for drugs and therapeutic approaches. SEARCH METHODS A systematic literature search was conducted in PubMed, Medline, and Embase of manuscripts published between January 2000 and November 2023 using the terms ("alcohol" or "ethanol") AND ("immune" or "immunol") AND ("intestine," "colon," or "gut"). Eligible manuscripts included studies and reviews that discussed the effects of ethanol on immune cells in the intestine. SEARCH RESULTS A total of 506 publications were found in the databases on November 20, 2023. After excluding duplicates and research not covering ALD (415 articles), 91 studies were reviewed. Also included were manuscripts covering specific immune cells in the context of ALD. DISCUSSION AND CONCLUSIONS Balancing immune tolerance vs. initiating an immune response challenges the intestinal immune system. Alcohol induces disruption of the intestinal barrier, which is accompanied by a thicker mucus layer and reduced anti-microbial peptides. This leads to longer attachment of bacteria to epithelial cells and consequently greater translocation into the circulation. Bacterial translocation activates the immune system, reducing the activity of regulatory T cells and inducing T helper 17 response via a variety of pathways. The role of innate immune cells, especially Type 3 innate lymphoid cells, and of specific B- and T-cell subsets in ALD remains elusive. Gut dysbiosis, translocation of viable bacteria and bacterial products into the circulation, and changes in the intestinal barrier have been linked to immune deficiency and infections in patients with cirrhosis. Modifying the intestinal immune system could reduce intestinal inflammation and alcohol-induced liver injury. Understanding the underlying pathophysiology can help to detect new targets for drugs and design therapeutic strategies.
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Affiliation(s)
- Henriette Kreimeyer
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California
- Department of Medicine, U.S. Department of Veterans Affairs San Diego Healthcare System, San Diego, California
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Xu J, Chen N, Li Z, Liu Y. Gut microbiome and liver diseases. FUNDAMENTAL RESEARCH 2025; 5:890-901. [PMID: 40242515 PMCID: PMC11997574 DOI: 10.1016/j.fmre.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 04/18/2025] Open
Abstract
Symbiotic microbiota plays a crucial role in the education, development, and maintenance of the host immune system, significantly contributing to overall health. Through the gut-liver axis, the gut microbiota and liver have a bidirectional relationship that is becoming increasingly evident as more research highlights the translocation of the gut microbiota and its metabolites. The focus of this narrative review is to examine and discuss the importance of the gut-liver axis and the enterohepatic barrier in maintaining overall health. Additionally, we emphasize the crucial role of the gut microbiome in liver diseases and explore potential therapeutic strategies for liver diseases by manipulating the microbiota.
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Affiliation(s)
- Jun Xu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Ning Chen
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Zhou Li
- Beijing Key Laboratory of Micro-nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems Chinese Academy of Sciences, Beijing 101400, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
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Li W, Gao W, Yan S, Yang L, Zhu Q, Chu H. Gut Microbiota as Emerging Players in the Development of Alcohol-Related Liver Disease. Biomedicines 2024; 13:74. [PMID: 39857657 PMCID: PMC11761646 DOI: 10.3390/biomedicines13010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 12/23/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota's significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease.
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Affiliation(s)
- Wei Li
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Shengqi Yan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Qingjing Zhu
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
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Li S, Wang Y, Xie Z, Wang Y, Feng Z, Xu J, Yuan B, Zhang Y, Yang G, Wang J, Yuan Y. NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice. Clin Transl Med 2024; 14:e70099. [PMID: 39605303 PMCID: PMC11602754 DOI: 10.1002/ctm2.70099] [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: 09/18/2024] [Revised: 10/27/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Alcoholic liver disease (ALD) patients with bacterial infections usually exhibit high mortality rates. Infections frequently involve bacteria such as Vibrio vulnificus and Enterococcus faecalis. Nevertheless, the mechanisms predisposing ALD patients to bacterial infections and the role of the NLRP3 inflammasome in the intestinal epithelial barrier in ALD remain unclear. METHODS We established ALD mice models of WT, Nlrp3-/- and Gsdmd-/- through chronic alcohol consumption feeding and acute alcohol induction. We compared alterations in gut microbiota, ileitis, and adhesion protein expression, to analyze the role and potential mechanism of NLRP3 in the early onset of ALD. Concurrently, we examined the changes in inflammation and liver damage in the ileum of ALD and healthy mice following foodborne infection with V. vulnificus. RESULTS Compared with the control group, the expression levels of ZO-1, Claudin-1 and E-cadherin were reduced in the ileum of ALD mice, while those of NLRP3, caspase-1(p20), GSDMD-N and IL-1β were elevated. Nlrp3-/- and Gsdmd-/- ALD mice showed an increased gut bacterial load, decreased ileal expression of E-cadherin, more severe ileitis, pronounced liver damage, steatosis and higher plasma levels of FITC-dextran, D-LA and ZO-1 compared with WT mice. Notably, Nlrp3-/- ALD mice exhibited a higher presence of Deferribacterota and Enterobacteriaceae. Furthermore, ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. CONCLUSIONS This study indicated that NLRP3 activation in the ileum of ALD mice stabilizes the inflammation-related gut microbiota, preserves the intestinal epithelial barrier, and diminishes inflammation and liver injury. Furthermore, the compromised immune defence in ALD mice may contribute to their heightened susceptibility to bacterial pathogens. KEY POINTS Activation of the NLRP3-GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice. NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice. ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections.
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Affiliation(s)
- Shi‐Qing Li
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- State Key Laboratory of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Ya‐Ru Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- Hainan Medical Products AdministrationHainan Center for Drug InspectionHaikouChina
| | - Zhong‐Liang Xie
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Yan Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Zi‐Han Feng
- Department of Disease Control and PreventionThe No. 96609 Hospital of Chinese People's Liberation ArmyYinchuanNingxiaChina
| | - Jian‐Hao Xu
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Bing Yuan
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Yi‐Tong Zhang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Guan Yang
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Jing‐Lin Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Yuan Yuan
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
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Raya Tonetti F, Eguileor A, Mrdjen M, Pathak V, Travers J, Nagy LE, Llorente C. Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology 2024; 80:1342-1371. [PMID: 38691396 PMCID: PMC11801230 DOI: 10.1097/hep.0000000000000924] [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: 02/13/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.
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Affiliation(s)
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marko Mrdjen
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Vai Pathak
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jared Travers
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland OH
| | - Laura E Nagy
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Wallaeys C, Garcia-Gonzalez N, Timmermans S, Vandewalle J, Vanderhaeghen T, De Beul S, Dufoor H, Eggermont M, Moens E, Bosteels V, De Rycke R, Thery F, Impens F, Verbanck S, Lienenklaus S, Janssens S, Blumberg RS, Iwawaki T, Libert C. Paneth cell TNF signaling induces gut bacterial translocation and sepsis. Cell Host Microbe 2024; 32:1725-1743.e7. [PMID: 39243761 DOI: 10.1016/j.chom.2024.08.007] [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: 09/20/2023] [Revised: 06/20/2024] [Accepted: 08/12/2024] [Indexed: 09/09/2024]
Abstract
The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis.
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Affiliation(s)
- Charlotte Wallaeys
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Natalia Garcia-Gonzalez
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Steven Timmermans
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Jolien Vandewalle
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Tineke Vanderhaeghen
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Somara De Beul
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Hester Dufoor
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Melanie Eggermont
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Elise Moens
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium
| | - Victor Bosteels
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Laboratory for ER Stress and Inflammation, VIB-UniversityGent Center for Inflammation Research, Ghent 9052, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
| | - Riet De Rycke
- Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium; VIB Center for Inflammation Research and Bioimaging Core, VIB, Ghent 9052, Belgium
| | - Fabien Thery
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9052, Belgium
| | - Francis Impens
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent 9052, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9052, Belgium; VIB Proteomics Core, VIB, Ghent 9052, Belgium
| | - Serge Verbanck
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke 9820, Belgium
| | - Stefan Lienenklaus
- Institute of Laboratory Animal Science, Hannover Medical School, Hannover 30625, Germany
| | - Sophie Janssens
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Laboratory for ER Stress and Inflammation, VIB-UniversityGent Center for Inflammation Research, Ghent 9052, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
| | - Richard S Blumberg
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Takao Iwawaki
- Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan
| | - Claude Libert
- VIB Center for Inflammation Research, VIB, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium.
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10
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Sampah MES, Moore H, Ahmad R, Duess J, Lu P, Lopez C, Steinway S, Scheese D, Raouf Z, Tsuboi K, Ding J, Caputo C, McFarland M, Fulton WB, Wang S, Wang M, Prindle T, Gazit V, Rubin DC, Alaish S, Sodhi CP, Hackam DJ. Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation. Nat Commun 2024; 15:8613. [PMID: 39375337 PMCID: PMC11458589 DOI: 10.1038/s41467-024-52216-6] [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: 01/19/2024] [Accepted: 08/30/2024] [Indexed: 10/09/2024] Open
Abstract
Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.
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Affiliation(s)
- Maame Efua S Sampah
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Hannah Moore
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Raheel Ahmad
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Johannes Duess
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Peng Lu
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carla Lopez
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Steve Steinway
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel Scheese
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Zachariah Raouf
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Koichi Tsuboi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Jeffrey Ding
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Connor Caputo
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Madison McFarland
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William B Fulton
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sanxia Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Meghan Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas Prindle
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Vered Gazit
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Deborah C Rubin
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Samuel Alaish
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - David J Hackam
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, MD, USA.
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11
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Yan M, Man S, Ma L, Guo L, Huang L, Gao W. Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives. Clin Mol Hepatol 2024; 30:620-648. [PMID: 38988278 PMCID: PMC11540396 DOI: 10.3350/cmh.2024.0315] [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: 04/28/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/12/2024] Open
Abstract
Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin, China
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12
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Budianto IR, Kusmardi K, Maulana AM, Arumugam S, Afrin R, Soetikno V. Paneth-like cells disruption and intestinal dysbiosis in the development of enterocolitis in an iatrogenic rectosigmoid hypoganglionosis rat model. Front Surg 2024; 11:1407948. [PMID: 39315293 PMCID: PMC11417098 DOI: 10.3389/fsurg.2024.1407948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 08/16/2024] [Indexed: 09/25/2024] Open
Abstract
Background Hypoganglionosis resembles Hirschsprung disease (HSCR) which is characterized by severe constipation. Enterocolitis due to hypoganglionosis or Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of both diseases. This study investigated the role of Paneth-like cells (PLCs) and gut microbiota in the development of enterocolitis in an iatrogenic rectosigmoid hypoganglionosis rat model. Methods The rectosigmoid serosa of male Sprague-Dawley rats were exposed to 0.1% benzalkonium chloride (BAC). The rats were then sacrificed after 1, 3, 5, 8, and 12 weeks. A sham group was sacrificed on Week 12. With hematoxylin-eosin staining, the ganglionic cells were quantified, the degree of enterocolitis was analyzed, and the PLCs was identified. Intestinal barrier function was assessed for the anti-peripherin, occludin, and acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) ratio. qRT-PCR was used as reference for the evaluation of antimicrobial peptide (AMP) of PLCs using cryptdins, secretory Phospholipase A2, and lysozyme levels. 16S rRNA high-throughput sequencing on fecal samples was performed to analyze the changes in the intestinal microbiota diversity in each group. Results After 1 week of intervention, the ganglion cells were fewer in all sacrificial 0.1% BAC groups at varying times than those in the sham group. Occludin and peripherin were decreased, while the AChE/BChE ratio was increased. At Week 5 postintervention, the number of α-defensins-positive PLCs increased in the sigmoid colon tissues from BAC-treated rats. Conversely, PLCs-produced AMP decreased from Week 5 to Week 12. The sham group demonstrated increased Lactobacillus and decreased Bacteroides, while the 0.1% BAC group exhibited reciprocal changes, indicating dysbiosis. Enterocolitis occurred from Week 1 postintervention. Conclusion Application with BAC influences the disruption of PLCs in Week 5 postintervention, and dysbiosis exacerbate the occurrence of enterocolitis. Further research on Paneth cells involvement in HAEC development is warranted.
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Affiliation(s)
- Iskandar Rahardjo Budianto
- Department of Surgery, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Kusmardi Kusmardi
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Andi Muh. Maulana
- Department of Anatomy, Faculty of Medicine, Universitas Muhammadiyah Purwokerto, Purwokerto, Indonesia
- Doctoral Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Somasundaram Arumugam
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Kolkata, Kolkata, India
| | - Rejina Afrin
- Department of Pharmacy, East West University, Dhaka, Bangladesh
| | - Vivian Soetikno
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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13
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Whitmore M, Tobin I, Burkardt A, Zhang G. Nutritional Modulation of Host Defense Peptide Synthesis: A Novel Host-Directed Antimicrobial Therapeutic Strategy? Adv Nutr 2024; 15:100277. [PMID: 39053604 PMCID: PMC11381887 DOI: 10.1016/j.advnut.2024.100277] [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: 02/28/2024] [Revised: 06/11/2024] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
The escalating threat of antimicrobial resistance underscores the imperative for innovative therapeutic strategies. Host defense peptides (HDPs), integral components of innate immunity, exhibit profound antimicrobial and immunomodulatory properties. Various dietary compounds, such as short-chain fatty acids, vitamins, minerals, sugars, amino acids, phytochemicals, bile acids, probiotics, and prebiotics have been identified to enhance the synthesis of endogenous HDPs without provoking inflammatory response or compromising barrier integrity. Additionally, different classes of these compounds synergize in augmenting HDP synthesis and disease resistance. Moreover, dietary supplementation of several HDP-inducing compounds or their combinations have demonstrated robust protection in rodents, rabbits, pigs, cattle, and chickens from experimental infections. However, the efficacy of these compounds in inducing HDP synthesis varies considerably among distinct compounds. Additionally, the regulation of HDP genes occurs in a gene-specific, cell type-specific, and species-specific manner. In this comprehensive review, we systematically summarized the modulation of HDP synthesis and the mechanism of action attributed to each major class of dietary compounds, including their synergistic combinations, across a spectrum of animal species including humans. We argue that the ability to enhance innate immunity and barrier function without triggering inflammation or microbial resistance positions the nutritional modulation of endogenous HDP synthesis as a promising host-directed approach for mitigating infectious diseases and antimicrobial resistance. These HDP-inducing compounds, particularly in combinations, harbor substantial clinical potential for further exploration in antimicrobial therapies for both human and other animals.
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Affiliation(s)
- Melanie Whitmore
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Isabel Tobin
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Amanda Burkardt
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, United States
| | - Guolong Zhang
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, United States.
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14
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Zhang M, Wang Y, Gan Y. The potential role of Akkermansia muciniphila in liver health. Future Microbiol 2024; 19:1081-1096. [PMID: 39109507 PMCID: PMC11323942 DOI: 10.2217/fmb-2023-0220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024] Open
Abstract
Akkermansia muciniphila (A. muciniphila) is a 'star strain' that has attracted much attention in recent years. A. muciniphila can effectively regulate host metabolism, significantly affect host immune function, and play an important role in balancing host health and disease. As one of the organs most closely related to the gut (the two can communicate through the hepatic portal vein and bile duct system), liver is widely affected by intestinal microorganisms. A growing body of evidence suggests that A. muciniphila may alleviate liver-related diseases by improving the intestinal barrier, energy metabolism and regulating inflammation through its protein components and metabolites. This paper systematically reviews the key roles of A. muciniphila and its derivatives in maintaining liver health and improving liver disease.
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Affiliation(s)
- Min Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 501 Haike Road, Shanghai, 201203, China
| | - Yang Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 501 Haike Road, Shanghai, 201203, China
| | - Yong Gan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 501 Haike Road, Shanghai, 201203, China
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15
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Guo W, Zhong W, He L, Wei X, Hao L, Dong H, Yue R, Sun X, Yin X, Zhao J, Zhang X, Zhou Z. Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice. Hepatol Commun 2024; 8:e0507. [PMID: 39082957 DOI: 10.1097/hc9.0000000000000507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/31/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. METHODS BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. RESULTS We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. CONCLUSIONS Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.
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Affiliation(s)
- Wei Guo
- Center for Translational Biomedical Research
| | - Wei Zhong
- Center for Translational Biomedical Research
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Liqing He
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Xiaoyuan Wei
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA
| | - Liuyi Hao
- Center for Translational Biomedical Research
| | - Haibo Dong
- Center for Translational Biomedical Research
| | - Ruichao Yue
- Center for Translational Biomedical Research
| | - Xinguo Sun
- Center for Translational Biomedical Research
| | - Xinmin Yin
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
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16
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Kuo CH, Wu LL, Chen HP, Yu J, Wu CY. Direct effects of alcohol on gut-epithelial barrier: Unraveling the disruption of physical and chemical barrier of the gut-epithelial barrier that compromises the host-microbiota interface upon alcohol exposure. J Gastroenterol Hepatol 2024; 39:1247-1255. [PMID: 38509796 DOI: 10.1111/jgh.16539] [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: 10/12/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/22/2024]
Abstract
The development of alcohol-associated diseases is multifactorial, mechanism of which involves metabolic alteration, dysregulated immune response, and a perturbed intestinal host-environment interface. Emerging evidence has pinpointed the critical role of the intestinal host-microbiota interaction in alcohol-induced injuries, suggesting its contribution to disease initiation and development. To maintain homeostasis in the gut, the intestinal mucosa serves as the first-line defense against exogenous factors in the gastrointestinal tract, including dietary contents and the commensal microbiota. The gut-epithelial barrier comprises a physical barrier lined with a single layer of intestinal epithelial cells and a chemical barrier with mucus trapping host regulatory factors and gut commensal bacteria. In this article, we review recent studies pertaining to the disrupted gut-epithelial barrier upon alcohol exposure and examine how alcohol and its metabolism can affect the regulatory ability of intestinal epithelium.
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Affiliation(s)
- Cheng-Hao Kuo
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Li-Ling Wu
- Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiao-Ping Chen
- Institute of Biomedical Informatics, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Yu
- Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ying Wu
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biomedical Informatics, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
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17
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Suresh P, Sun X, Zhou Z, Zhang Q. Spatial Proteomics Reveals Alcohol-Induced Damages to the Crypts and Villi of the Mouse Small Intestine. J Proteome Res 2024; 23:1801-1809. [PMID: 38655769 PMCID: PMC11077582 DOI: 10.1021/acs.jproteome.4c00037] [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: 01/18/2024] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 04/26/2024]
Abstract
Alcohol consumption perturbs the gut immune barrier and ultimately results in alcoholic liver diseases, but little is known about how immune-related cells in the gut are perturbed in this process. In this study, we employed laser capture microdissection and a label-free proteomics approach to investigate the consequences of alcohol exposure to the proteomes of crypts and villi in the proximal small intestine. Intestinal tissues from alcohol-fed and pair-fed mice were microdissected to selectively capture cells in the crypts and villi regions, followed by one-pot protein digestion and data-independent LC-MS/MS analysis. We successfully identified over 3000 proteins from each of the crypt or villi regions equivalent to ∼3000 cells. Analysis of alcohol-treated tissues indicated an enhanced alcohol metabolism and reduced levels of α-defensins in crypts, alongside increased lipid metabolism and apoptosis in villi. Immunofluorescence imaging further corroborated the proteomic findings. Our work provides a detailed profiling of the proteomic changes in the compartments of the mouse small intestine and aids in molecular-level understanding of alcohol-induced tissue damage.
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Affiliation(s)
- Patil
Shivprasad Suresh
- Center
for Translational Biomedical Research, University
of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States
| | - Xinguo Sun
- Center
for Translational Biomedical Research, University
of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States
| | - Zhanxiang Zhou
- Center
for Translational Biomedical Research, University
of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States
- Department
of Nutrition, University of North Carolina
at Greensboro, Greensboro, North Carolina 27402, United States
| | - Qibin Zhang
- Center
for Translational Biomedical Research, University
of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States
- Department
of Chemistry & Biochemistry, University
of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States
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18
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Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
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Ding Q, Guo R, Hao L, Song Q, Fu A, Lai S, Xu T, Zhuge H, Chang K, Chen Y, Wei H, Ren D, Sun Z, Song Z, Dou X, Li S. Hepatic TRPC3 loss contributes to chronic alcohol consumption-induced hepatic steatosis and liver injury in mice. LIFE METABOLISM 2024; 3:load050. [PMID: 39871879 PMCID: PMC11749259 DOI: 10.1093/lifemeta/load050] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 11/08/2023] [Accepted: 12/14/2023] [Indexed: 01/29/2025]
Abstract
Emerging evidence discloses the involvement of calcium channel protein in the pathological process of liver diseases. Transient receptor potential cation channel subfamily C member 3 (TRPC3), a ubiquitously expressed non-selective cation channel protein, controls proliferation, inflammation, and immune response via operating calcium influx in various organs. However, our understanding on the biofunction of hepatic TRPC3 is still limited. The present study aims to clarify the role and potential mechanism(s) of TRPC3 in alcohol-associated liver disease (ALD). We recently found that TRPC3 expression plays an important role in the disease process of ALD. Alcohol exposure led to a significant reduction of hepatic TRPC3 in patients with alcohol-related hepatitis (AH) and ALD models. Antioxidants (N-acetylcysteine and mitoquinone) intervention improved alcohol-induced suppression of TRPC3 via a miR-339-5p-involved mechanism. TRPC3 loss robustly aggravated the alcohol-induced hepatic steatosis and liver injury in mouse liver; this was associated with the suppression of Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) and dysregulation of genes related to lipid metabolism. TRPC3 loss also enhanced hepatic inflammation and early fibrosis-like change in mice. Replenishing hepatic TRPC3 effectively reversed chronic alcohol-induced detrimental alterations in ALD mice. Briefly, chronic alcohol exposure-induced TRPC3 reduction contributes to the pathological development of ALD via suppression of the CAMKK2/AMPK pathway. Oxidative stress-stimulated miR-339-5p upregulation contributes to alcohol-reduced TRPC3. TRPC3 is the requisite and a potential target to defend alcohol consumption-caused ALD.
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Affiliation(s)
- Qinchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
- College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Liuyi Hao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Qing Song
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, United States
| | - Ai Fu
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Shanglei Lai
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Tiantian Xu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Hui Zhuge
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Kaixin Chang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yanli Chen
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Haibin Wei
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Daxi Ren
- College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, United States
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
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20
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Jiang DQY, Guo TL. Interaction between Per- and Polyfluorinated Substances (PFAS) and Acetaminophen in Disease Exacerbation-Focusing on Autism and the Gut-Liver-Brain Axis. TOXICS 2024; 12:39. [PMID: 38250995 PMCID: PMC10818890 DOI: 10.3390/toxics12010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/05/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024]
Abstract
This review presents a new perspective on the exacerbation of autism spectrum disorder (ASD) by per- and polyfluoroalkyl substances (PFAS) through the gut-liver-brain axis. We have summarized evidence reported on the involvement of the gut microbiome and liver inflammation that led to the onset and exacerbation of ASD symptoms. As PFAS are toxicants that particularly target liver, this review has comprehensively explored the possible interaction between PFAS and acetaminophen, another liver toxicant, as the chemicals of interest for future toxicology research. Our hypothesis is that, at acute dosages, acetaminophen has the ability to aggravate the impaired conditions of the PFAS-exposed liver, which would further exacerbate neurological symptoms such as lack of social communication and interest, and repetitive behaviors using mechanisms related to the gut-liver-brain axis. This review discusses their potential interactions in terms of the gut-liver-brain axis and signaling pathways that may contribute to neurological diseases.
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Affiliation(s)
| | - Tai Liang Guo
- Department of Veterinary Biomedical Sciences, University of Georgia, Athens, GA 30602, USA;
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21
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Kumar MS. Paneth cell: The missing link between obesity, MASH and portal hypertension. Clin Res Hepatol Gastroenterol 2024; 48:102259. [PMID: 38070827 DOI: 10.1016/j.clinre.2023.102259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023]
Abstract
Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible, but stages of liver disease before the development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities that influences the pathophysiology of portal hypertension. This review provides evidence supporting that, Paneth cells[PCs] in the intestinal epithelium, which remained enigmatic for a century, are the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability, which are the potential triggers of systemic inflammation. Thus, it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.
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Affiliation(s)
- Minu Sajeev Kumar
- Department of Gastroenterology, Government Medical College, Thiruvanathapuram, India.
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22
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Sparfel L, Ratodiarivony S, Boutet-Robinet E, Ellero-Simatos S, Jolivet-Gougeon A. Akkermansia muciniphila and Alcohol-Related Liver Diseases. A Systematic Review. Mol Nutr Food Res 2024; 68:e2300510. [PMID: 38059838 DOI: 10.1002/mnfr.202300510] [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: 07/18/2023] [Revised: 10/03/2023] [Indexed: 12/08/2023]
Abstract
SCOPE Akkermansia muciniphila (A. muciniphila) are Gram negative commensal bacteria, degrading mucin in the intestinal mucosa, modulating intestinal permeability and inflammation in the digestive tract, liver, and blood. Some components can promote the relative abundance of A. muciniphila in the gut microbiota, but lower levels of A. muciniphila are more commonly found in people with obesity, diabetes, metabolic syndromes, or inflammatory digestive diseases. Over-intake of ethanol can also induce a decrease of A. muciniphila, associated with dysregulation of microbial metabolite production, impaired intestinal permeability, induction of chronic inflammation, and production of cytokines. METHODS AND RESULTS Using a PRISMA search strategy, a review is performed on the bacteriological characteristics of A. muciniphila, the factors capable of modulating its relative abundance in the digestive tract and its probiotic use in alcohol-related liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, hepatic transplantation, partial hepatectomy). CONCLUSION Several studies have shown that supplementation with A. muciniphila can improve ethanol-related hepatic pathologies, and highlight the interest in using this bacterial species as a probiotic.
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Affiliation(s)
- Lydie Sparfel
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, F-35000, France
| | - Sandy Ratodiarivony
- Univ Rennes, Bacterial Regulatory RNAs and Medicine (BRM), UMR_S 1230, Rennes, F-35000, France
| | - Elisa Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300, Toulouse, France
| | - Anne Jolivet-Gougeon
- Univ Rennes, Bacterial Regulatory RNAs and Medicine (BRM), UMR_S 1230, Rennes, F-35000, France
- Teaching Hospital, CHU Rennes, 2 rue Henri Le Guilloux 35033, Rennes, F-35000, France
- INSERM, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer), U1241, INSERM 1241, Rennes, F-35000, France
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23
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Yue R, Wei X, Hao L, Dong H, Guo W, Sun X, Zhao J, Zhou Z, Zhong W. Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice. Front Immunol 2023; 14:1289356. [PMID: 37908362 PMCID: PMC10613651 DOI: 10.3389/fimmu.2023.1289356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Background The hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated. Methods Intestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity. Results After alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3γ and α-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced Akkermansia, IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using in vitro cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3. Conclusion Our study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.
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Affiliation(s)
- Ruichao Yue
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Xiaoyuan Wei
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United States
| | - Liuyi Hao
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Haibo Dong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Wei Guo
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Xinguo Sun
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United States
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, United States
| | - Wei Zhong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United States
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, United States
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24
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Hao L, Zhong W, Woo J, Wei X, Ma H, Dong H, Guo W, Sun X, Yue R, Zhao J, Zhang Q, Zhou Z. Conventional type 1 dendritic cells protect against gut barrier disruption via maintaining Akkermansia muciniphila in alcoholic steatohepatitis. Hepatology 2023; 78:896-910. [PMID: 36626632 PMCID: PMC11140646 DOI: 10.1097/hep.0000000000000019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 10/07/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Alcohol-perturbed gut immune homeostasis is associated with the development of alcoholic liver disease (ALD). However, the role of intestinal dendritic cells (DCs) in ALD progression is still unknown. This study aimed to investigate the cellular and molecular mechanisms through which intestinal DCs respond to alcohol exposure and contribute to the pathogenesis of ALD. APPROACH AND RESULTS After 8 weeks of alcohol consumption, the number of basic leucine zipper transcription factor ATF-like 3 ( Batf3 )-dependent conventional type 1 DCs (cDC1s) was dramatically decreased in the intestine but not the liver. cDC1 deficient Batf3 knockout mice along with wild-type mice were subjected to chronic-binge ethanol feeding to determine the role of intestinal cDC1s reduction in ALD. cDC1s deficiency exacerbated alcohol-induced gut barrier disruption, bacterial endotoxin translocation into the circulation, and liver injury. Adoptive transfer of cDC1s to alcohol-fed mice ameliorated alcohol-mediated gut barrier dysfunction and liver injury. Further studies revealed that intestinal cDC1s serve as a positive regulator of Akkermansia muciniphila ( A. muciniphila ). Oral administration of A. muciniphila markedly reversed alcoholic steatohepatitis in mice. Mechanistic studies revealed that cDC1s depletion exacerbated alcohol-downregulated intestinal antimicrobial peptides which play a crucial role in maintaining A. muciniphila abundance, by disrupting the IL-12-interferon gamma signaling pathway. Lastly, we identified that intestinal cDC1s were required for the protective role of Lactobacillus reuteri in alcoholic steatohepatitis. CONCLUSIONS This study demonstrated that cDC1s protect alcohol-induced liver injury by maintaining A. muciniphila abundance in mice. Targeting cDC1s may serve as a promising therapeutic approach for treating ALD.
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Affiliation(s)
- Liuyi Hao
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Wei Zhong
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
- Department of Nutrition, Kannapolis, North Carolina, USA
| | - Jongmin Woo
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Xiaoyuan Wei
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, USA
| | - Hao Ma
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA
| | - Haibo Dong
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Wei Guo
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Xinguo Sun
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Ruichao Yue
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, USA
| | - Qibin Zhang
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Kannapolis, North Carolina, USA
- Department of Nutrition, Kannapolis, North Carolina, USA
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25
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Maccioni L, Fu Y, Horsmans Y, Leclercq I, Stärkel P, Kunos G, Gao B. Alcohol-associated bowel disease: new insights into pathogenesis. EGASTROENTEROLOGY 2023; 1:e100013. [PMID: 37662449 PMCID: PMC10472976 DOI: 10.1136/egastro-2023-100013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 02/01/2023] [Indexed: 09/05/2023]
Abstract
Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine, but the underlying mechanisms are not fully understood. In this review, we discuss the effects of alcohol on small and large intestinal functions, such as leaky gut, dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions, commonly referred to as alcohol-associated bowel disease (ABD). To date, detailed mechanistic insights into ABD are lacking. Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract. Ethanol metabolism generates acetaldehyde and acetate, which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract. The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD, including cancer, is discussed. We also highlight some gaps in knowledge existing in the field of ABD. Finally, we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.
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Affiliation(s)
- Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yves Horsmans
- Department of Hepato-Gastroenterology, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Isabelle Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium
| | - Peter Stärkel
- Department of Hepato-Gastroenterology, Cliniques universitaires Saint-Luc, Brussels, Belgium
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Brussels, Belgium
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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26
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Hrynkiewicz R, Niedźwiedzka-Rystwej P. Etiology of viral induced acute liver failure and defensins as potential therapeutic agents in ALF treatment. Front Immunol 2023; 14:1153528. [PMID: 37153560 PMCID: PMC10160486 DOI: 10.3389/fimmu.2023.1153528] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 04/12/2023] [Indexed: 05/09/2023] Open
Abstract
Acute liver failure (ALF) is a rare and severe disease, which, despite continuous advances in medicine, is still characterized by high mortality (65-85%). Very often, a liver transplant is the only effective treatment for ALF. Despite the implementation of prophylactic vaccinations in the world, the viral background of ALF is still a problem and leads to many deaths. Depending on the cause of ALF, it is sometimes possible to reverse this condition with appropriate therapies, which is why the search for effective antiviral agents seems to be a very desirable direction of research. Defensins, which are our natural antimicrobial peptides, have a very high potential to be used as therapeutic agents for infectious liver diseases. Previous studies on the expression of human defensins have shown that increased expression of human α and β-defensins in HCV and HBV infections is associated with a better response to treatment. Unfortunately, conducting clinical trials for ALF is very difficult due to the severity of the disease and the low incidence, therefore animal models are important for the development of new therapeutic strategies. One of the best animal models that has real reference to research on acute liver failure (ALF) is rabbit hemorrhagic disease in rabbits caused by the Lagovirus europaeus virus. So far, there have been no studies on the potential of defensins in rabbits infected with Lagovirus europaeus virus.
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27
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Cui C, Wang X, Li L, Wei H, Peng J. Multifaceted involvements of Paneth cells in various diseases within intestine and systemically. Front Immunol 2023; 14:1115552. [PMID: 36993974 PMCID: PMC10040535 DOI: 10.3389/fimmu.2023.1115552] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn’s disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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28
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Zinc-glutathione in Chinese Baijiu prevents alcohol-associated liver injury. Heliyon 2023; 9:e13722. [PMID: 36873153 PMCID: PMC9975285 DOI: 10.1016/j.heliyon.2023.e13722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Zinc depletion is associated with alcohol-associated liver injury. We tested the hypothesis that increasing zinc availability along with alcohol consumption prevents alcohol-associated liver injury. Zinc-glutathione (ZnGSH) was synthesized and directly added to Chinese Baijiu. Mice were administered a single gastric dose of 6 g/kg ethanol in Chinese Baijiu with or without ZnGSH. ZnGSH in Chinese Baijiu did not change the likeness of the drinkers but significantly reduced the recovery time from drunkenness along with elimination of high-dose mortality. ZnGSH in Chinese Baijiu decreased serum AST and ALT, suppressed steatosis and necrosis, and increased zinc and GSH concentrations in the liver. It also increased alcohol dehydrogenase and aldehyde dehydrogenase in the liver, stomach, and intestine and reduced acetaldehyde in the liver. Thus, ZnGSH in Chinese Baijiu prevents alcohol-associated liver injury by increasing alcohol metabolism timely with alcohol consumption, providing an alternative approach to the management of alcohol-associated drinking.
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29
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Shimizu Y, Yamamura R, Yokoi Y, Ayabe T, Ukawa S, Nakamura K, Okada E, Imae A, Nakagawa T, Tamakoshi A, Nakamura K. Shorter sleep time relates to lower human defensin 5 secretion and compositional disturbance of the intestinal microbiota accompanied by decreased short-chain fatty acid production. Gut Microbes 2023; 15:2190306. [PMID: 36945116 PMCID: PMC10038026 DOI: 10.1080/19490976.2023.2190306] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
Sleep is essential for our health. Short sleep is known to increase disease risks via imbalance of intestinal microbiota, dysbiosis. However, mechanisms by which short sleep induces dysbiosis remain unknown. Small intestinal Paneth cell regulates the intestinal microbiota by secreting antimicrobial peptides including α-defensin, human defensin 5 (HD5). Disruption of circadian rhythm mediating sleep-wake cycle induces Paneth cell failure. We aim to clarify effects of short sleep on HD5 secretion and the intestinal microbiota. Fecal samples and self-reported sleep time were obtained from 35 healthy middle-aged Japanese (41 to 60-year-old). Shorter sleep time was associated with lower fecal HD5 concentration (r = 0.354, p = 0.037), lower centered log ratio (CLR)-transformed abundance of short-chain fatty acid (SCFA) producers in the intestinal microbiota such as [Ruminococcus] gnavus group (r = 0.504, p = 0.002) and Butyricicoccus (r = 0.484, p = 0.003), and lower fecal SCFA concentration. Furthermore, fecal HD5 positively correlated with the abundance of these genera and SCFA concentration. These findings suggest that short sleep relates to disturbance of the intestinal microbiota via decreased HD5 secretion.
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Affiliation(s)
- Yu Shimizu
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Ryodai Yamamura
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan
| | - Yuki Yokoi
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Tokiyoshi Ayabe
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
| | - Shigekazu Ukawa
- Department of Social Welfare Science and Clinical Psychology, Osaka Metropolitan University Graduate School of Human Life and Ecology, Osaka, Japan
| | - Koshi Nakamura
- Department of Public Health and Hygiene, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Emiko Okada
- Department of Nutritional Epidemiology and Shokuiku, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | | | | | - Akiko Tamakoshi
- Department of Public Health, Faculty of Medicine, Hokkaido University, Hokkaido, Japan
| | - Kiminori Nakamura
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Hokkaido, Japan
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30
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Wallaeys C, Garcia‐Gonzalez N, Libert C. Paneth cells as the cornerstones of intestinal and organismal health: a primer. EMBO Mol Med 2022; 15:e16427. [PMID: 36573340 PMCID: PMC9906427 DOI: 10.15252/emmm.202216427] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 12/28/2022] Open
Abstract
Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells.
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Affiliation(s)
- Charlotte Wallaeys
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Natalia Garcia‐Gonzalez
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Claude Libert
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
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31
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Woo J, Schoenfeld M, Sun X, Iraguha T, Zhou Z, Zhang Q. Mouse Paneth Cell-Enriched Proteome Enabled by Laser Capture Microdissection. J Proteome Res 2022; 21:2435-2442. [PMID: 36153828 PMCID: PMC9671084 DOI: 10.1021/acs.jproteome.2c00311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Paneth cells are antimicrobial peptide-secreting cells located at the base of the crypts of the small intestine. The proteome of Paneth cells is not well defined because of their coexistence with stem cells, making it difficult to culture Paneth cells alone in vitro. Using a simplified toluidine blue O method for staining mouse intestinal tissue, laser capture microdissection (LCM) to isolate cells from the crypt region, and surfactant-assisted one-pot protein digestion, we identified more than 1300 proteins from crypts equivalent to 18,000 cells. Compared with the proteomes of villi and smooth muscle regions, the crypt proteome is highly enriched in defensins, lysozymes, and other antimicrobial peptides that are characteristic of Paneth cells. The sensitivity of the LCM-based proteomics approach was also assessed using a smaller number of cell equivalent tissues: a comparable proteomic coverage can be achieved with 3600 cells. This work is the first proteomics study of intestinal tissue enriched with Paneth cells. The simplified workflow enables profiling of Paneth cell-associated pathological changes at the proteome level directly from frozen intestinal tissue. It may also be useful for proteomics studies of other spatially resolved cell types from other tissues.
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Affiliation(s)
- Jongmin Woo
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
| | - Madeline Schoenfeld
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
| | - Xinguo Sun
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
| | - Thierry Iraguha
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
- Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402
| | - Qibin Zhang
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081
- Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402
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32
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Toll-like receptor 4-mediated endoplasmic reticulum stress induces intestinal paneth cell damage in mice following CLP-induced sepsis. Sci Rep 2022; 12:15256. [PMID: 36088483 PMCID: PMC9464222 DOI: 10.1038/s41598-022-19614-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/31/2022] [Indexed: 11/14/2022] Open
Abstract
A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.
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Abstract
We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our
in vivo
research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder.
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34
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Chen L, Zhu Y, Hou X, Yang L, Chu H. The Role of Gut Bacteria and Fungi in Alcohol-Associated Liver Disease. Front Med (Lausanne) 2022; 9:840752. [PMID: 35308525 PMCID: PMC8927088 DOI: 10.3389/fmed.2022.840752] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis and liver cancer caused by alcohol-associated liver disease (ALD) are serious threats to people's health. In addition to hepatic cell apoptosis and liver inflammation caused by oxidative stress during alcohol metabolism, intestinal microbiota disorders are also involved in the onset and development of ALD. Ethanol and its' oxidative and non-oxidative metabolites, together with dysbiosis-caused-inflammation, destroys the intestinal barrier. Changes of several microbial metabolites, such as bile acids, short-chain fatty acids, and amino acid, are closely associated with gut dysbiosis in ALD. The alcohol-caused dysbiosis can further influence intestinal barrier-related proteins, such as mucin2, bile acid-related receptors, and aryl hydrocarbon receptor (AhR), and these abnormal changes also participate in the injury of the intestinal barrier and hepatic steatosis. Gut-derived bacteria, fungi, and their toxins, such as lipopolysaccharide (LPS) and β-glucan translocate into the liver through the damaged intestinal barrier and promote the progression of inflammation and fibrosis of ALD. Thus, the prevention of alcohol-induced disruption of intestinal permeability has a beneficial effect on ALD. Currently, multiple therapeutic treatments have been applied to restore the gut microbiota of patients with ALD. Fecal microbial transplantation, probiotics, antibiotics, and many other elements has already shown their ability of restoring the gut microbiota. Targeted approaches, such as using bacteriophages to remove cytolytic Enterococcus faecalis, and supplement with Lactobacillus, Bifidobacterium, or boulardii are also powerful therapeutic options for ALD.
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Affiliation(s)
- Liuying Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixin Zhu
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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35
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Jiang Y, Xi Y, Li Y, Zuo Z, Zeng C, Fan J, Zhang D, Tao H, Guo Y. Ethanol promoting the upregulation of C-X-C Motif Chemokine Ligand 1（CXCL1） and C-X-C Motif Chemokine Ligand 6（CXCL6） in models of early alcoholic liver disease. Bioengineered 2022; 13:4688-4701. [PMID: 35156518 PMCID: PMC8973977 DOI: 10.1080/21655979.2022.2030557] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Alcoholic liver disease (ALD) denotes a series of liver diseases caused by ethanol. Recently, immune-related genes (IRGs) play increasingly crucial role in diseases. However, it’s unclear the role of IRGs in ALD. Bioinformatic analysis was used to discern the core immune-related differential genes (IRDGs) in the present study. Subsequently, Cell Counting Kit-8 say, oil red O staining, and triglyceride detection were employed to explore optimal experimental conditions of establishing hepatocellular models of early ALD. Ultimately, real-time reverse transcription-PCR and immunohistochemistry/immunocytochemistry methods were adopted to verify the expressions of mRNA and proteins of core IRDGs, respectively. C-X-C Motif Chemokine Ligand 1 (Cxcl1) and Cxcl6 were regarded as core IRDGs via integrated bioinformatics analysis. Besides, Lieber Decarli Ethanol feeding and 200 mM and 300 mM ethanol stimulating L02 cells for 36 h can both successfully hepatocellular model. In ethanol groups, the levels of CXCL1 and CXCL6 mRNA were significantly upregulated than pair-fed groups (P < 0.0001). Also, immunohistochemistry revealed that positive particles of CXCL1 and CXCL6 in mice model of early ALD were obviously more than control groups (P < 0.0001). Besides, in L02 hepatocytes stimulated by ethanol, CXCL1 and CXCL6 mRNA were over-expressed, compared with normal L02 cells (P < 0.0001). Meanwhile, immunocytochemistry indicated that CXCL1 and CXCL6 proteins in hepatocellular model of early ALD were higher than normal L02 hepatocytes stimulus (P < 0.0001). Ethanol promoted the upregulation of Cxcl1 and Cxcl6 mRNA and proteins in models of early ALD, denoting their potentiality of acting as biomarkers of ALD.
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Affiliation(s)
- Yao Jiang
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yuge Xi
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yiqin Li
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Zhihua Zuo
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chuyi Zeng
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jia Fan
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Dan Zhang
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Hualin Tao
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yongcan Guo
- Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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36
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Poplawska M, Dutta D, Jayaram M, Chong NS, Salifu M, Lim SH. Genes modulating intestinal permeability and microbial community are dysregulated in sickle cell disease. Ann Hematol 2022; 101:1009-1013. [PMID: 35166891 DOI: 10.1007/s00277-022-04794-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/08/2022] [Indexed: 01/06/2023]
Abstract
Based on previous studies showing abnormalities in the intestinal pathophysiology characterized by disruption in the gut barrier functions, and alteration in the intestinal microbial load and composition, we set out in the study to examine the expression of genes that might be involved in mediating these changes in Townes sickle cell disease (SCD) mice at 6 months old compared to non-SCD control mice. Using qPCR on total RNA isolated from the intestine, we found downregulation of the TJ genes JAM-A, Occludin, and ZO-1 in both the small intestine and colon. E-Cadherin and MUC2 were also downregulated. In contrast, gene encoding claudin-2 that mediates increase permeability to water and ions was upregulated in the small intestine. Claudin-2 upregulation is usually also associated with ongoing inflammation. Intestinal epithelium also includes Paneth cells that produce antimicrobial peptides (AMPs) that regulate intestinal microbial community. We also found that the expression of the genes encoding the AMPs defensin-α4 was reduced in the small intestine and colon and defensin-α1 in the colon in the SCD mice. Our findings are novel and provide direction for further studies into the characteristics and mechanisms of the intestinal pathophysiologic changes observed in SCD.
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Affiliation(s)
- Maria Poplawska
- Division of Hematology and Oncology, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, MSC #20, Brooklyn, NY, 11203, USA
| | - Dibyendu Dutta
- Division of Hematology and Oncology, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, MSC #20, Brooklyn, NY, 11203, USA.
| | - Manjunath Jayaram
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN, USA
| | - Ngee S Chong
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN, USA
| | - Moro Salifu
- Division of Hematology and Oncology, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, MSC #20, Brooklyn, NY, 11203, USA
| | - Seah H Lim
- Division of Hematology and Oncology, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, MSC #20, Brooklyn, NY, 11203, USA.
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37
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Warner JB, Larsen IS, Hardesty JE, Song YL, Warner DR, McClain CJ, Sun R, Deng Z, Jensen BAH, Kirpich IA. Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice. Front Physiol 2022; 12:812882. [PMID: 35153819 PMCID: PMC8829467 DOI: 10.3389/fphys.2021.812882] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.
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Affiliation(s)
- Jeffrey B. Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Ida S. Larsen
- Québec Heart and Lung Institute (IUCPQ), Faculty of Medicine, Laval University, Québec city, QC, Canada
| | - Josiah E. Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Ying L. Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Dennis R. Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Craig J. McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States
- Robley Rex Veterans Medical Center, Louisville, KY, United States
| | - Rui Sun
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - Zhongbin Deng
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
- Department of Surgery, University of Louisville, Louisville, KY, United States
| | - Benjamin A. H. Jensen
- Québec Heart and Lung Institute (IUCPQ), Faculty of Medicine, Laval University, Québec city, QC, Canada
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Irina A. Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United States
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United States
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Fujimoto Y, Kaji K, Nishimura N, Enomoto M, Murata K, Takeda S, Takaya H, Kawaratani H, Moriya K, Namisaki T, Akahane T, Yoshiji H. Dual therapy with zinc acetate and rifaximin prevents from ethanol-induced liver fibrosis by maintaining intestinal barrier integrity. World J Gastroenterol 2021; 27:8323-8342. [PMID: 35068872 PMCID: PMC8717023 DOI: 10.3748/wjg.v27.i48.8323] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/06/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic overload of gut-derived lipopolysaccharide dictates the progression of alcoholic liver disease (ALD) by inducing oxidative stress and activating Kupffer cells and hepatic stellate cells through toll-like receptor 4 signaling. Therefore, targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of ALD. Zinc acetate and rifaximin, which is a nonabsorbable antibiotic, had been clinically used for patients with cirrhosis, particularly those with hepatic encephalopathy, and had been known to improve intestinal barrier dysfunction. However, only few studies focused on their efficacies in preventing the ALD-related fibrosis development. AIM To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD model. METHODS To induce ALD-related liver fibrosis, female C57BL/6J mice were fed a 2.5% (v/v) ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbon tetrachloride (CCl4) injection twice weekly (1 mL/kg) for 8 wk. Zinc acetate (100 mg/L) and/or rifaximin (100 mg/L) were orally administered during experimental period. Hepatic steatosis, inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular analyses. Moreover, the direct effects of both agents on Caco-2 barrier function were assessed by in vitro assays. RESULTS In the ethanol plus CCl4-treated mice, combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and Nox4. This combination significantly inhibited the Kupffer cells expansion and the proinflammatory response with blunted hepatic exposure of lipopolysaccharide and the toll-like receptor 4/nuclear factor kB pathway. Consequently, liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2, -9, -13, and Timp1. Both agents improved the atrophic changes and permeability in the ileum, with restoration of tight junction proteins (TJPs) by decreasing the expressions of tumor necrosis factor α and myosin light chain kinase. In the in vitro assay, both agents directly reinforced ethanol or lipopolysaccharide-stimulated paracellular permeability and upregulated TJPs in Caco-2 cells. CONCLUSION Dual therapy with zinc acetate and rifaximin may serve as a strategy to prevent ALD-related fibrosis by maintaining intestinal barrier integrity.
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Affiliation(s)
- Yuki Fujimoto
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Masahide Enomoto
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Koji Murata
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Soichi Takeda
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara 6348521, Nara, Japan
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39
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Duan Y, Chu H, Brandl K, Jiang L, Zeng S, Meshgin N, Papachristoforou E, Argemi J, Mendes BG, Wang Y, Su H, Sun W, Llorente C, Hendrikx T, Liu X, Hosseini M, Kisseleva T, Brenner DA, Bataller R, Ramachandran P, Karin M, Fu W, Schnabl B. CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease. Nat Commun 2021; 12:7172. [PMID: 34887405 PMCID: PMC8660815 DOI: 10.1038/s41467-021-27385-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 11/15/2021] [Indexed: 12/19/2022] Open
Abstract
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.
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MESH Headings
- Animals
- Bacterial Translocation
- Complement C3b/immunology
- Enterococcus faecalis/immunology
- Enterococcus faecalis/physiology
- Ethanol/adverse effects
- Female
- Gastrointestinal Tract/microbiology
- Gram-Positive Bacterial Infections/genetics
- Gram-Positive Bacterial Infections/immunology
- Gram-Positive Bacterial Infections/microbiology
- Humans
- Liver/drug effects
- Liver/immunology
- Liver/microbiology
- Liver Diseases, Alcoholic/etiology
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/immunology
- Liver Diseases, Alcoholic/microbiology
- Macrophages/immunology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Complement/deficiency
- Receptors, Complement/genetics
- Receptors, Complement/immunology
- Receptors, Complement 3b/genetics
- Receptors, Complement 3b/immunology
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Affiliation(s)
- Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Huikuan Chu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, China
| | - Katharina Brandl
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lu Jiang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Suling Zeng
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Nairika Meshgin
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Eleni Papachristoforou
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
- Hepatology Program, Centro de Investigacion Medica Aplicada (CIMA), Liver Unit, Clinica Universidad de Navarra (CUN), Instituto de Investigacion de Navarra (IdisNA), University of Navarra, Pamplona, Spain
| | - Beatriz G Mendes
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yanhan Wang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Hua Su
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Weizhong Sun
- 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
| | - Tim Hendrikx
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Xiao Liu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Surgery, University of California San Diego, La Jolla, CA, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA, USA
| | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Prakash Ramachandran
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, UK
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Wenxian Fu
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Department of Cancer Immunology, Genentech, South San Francisco, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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Skalny AV, Aschner M, Lei XG, Gritsenko VA, Santamaria A, Alekseenko SI, Prakash NT, Chang JS, Sizova EA, Chao JCJ, Aaseth J, Tinkov AA. Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues. Int J Mol Sci 2021; 22:13074. [PMID: 34884881 PMCID: PMC8658153 DOI: 10.3390/ijms222313074] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 12/17/2022] Open
Abstract
The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity disorder, as well as fetal alcohol syndrome and obesity. In view of both Zn and gut microbiota, as well as their interaction in the regulation of the physiological functions of the host organism, addressing these targets through the use of Zn-enriched probiotics may be considered an effective strategy for health management.
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Affiliation(s)
- Anatoly V. Skalny
- Laboratory of Molecular Dietetics, World-Class Research Center, Digital Biodesign and Personalized Healthcare, IM Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia; (A.V.S.); (M.A.); (J.A.)
- Department of Bioelementology, K.G. Razumovsky Moscow State University of Technologies and Management, 109004 Moscow, Russia
| | - Michael Aschner
- Laboratory of Molecular Dietetics, World-Class Research Center, Digital Biodesign and Personalized Healthcare, IM Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia; (A.V.S.); (M.A.); (J.A.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA;
| | - Viktor A. Gritsenko
- Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences, 460000 Orenburg, Russia;
| | - Abel Santamaria
- Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, Mexico;
| | - Svetlana I. Alekseenko
- Saint-Petersburg Research Institute of Ear, Throat, Nose and Speech, 190013 St. Petersburg, Russia;
- Department of Otorhinolaryngology, I.I. Mechnikov North-Western State Medical University, 195067 St. Petersburg, Russia
- K.A. Raukhfus Children’s City Multidisciplinary Clinical Center for High Medical Technologies, 191036 St. Petersburg, Russia
| | - Nagaraja Tejo Prakash
- School of Energy and Environment, Thapar Institute Engineering and Technology, Patiala 147004, Punjab, India;
| | - Jung-Su Chang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan; (J.-S.C.); (J.C.J.C.)
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
| | - Elena A. Sizova
- Federal Research Centre of Biological Systems and Agro-technologies of the Russian Academy of Sciences, 460000 Orenburg, Russia;
| | - Jane C. J. Chao
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan; (J.-S.C.); (J.C.J.C.)
- Nutrition Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Jan Aaseth
- Laboratory of Molecular Dietetics, World-Class Research Center, Digital Biodesign and Personalized Healthcare, IM Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia; (A.V.S.); (M.A.); (J.A.)
- Research Department, Innlandet Hospital Trust, 2380 Brumunddal, Norway
| | - Alexey A. Tinkov
- Laboratory of Molecular Dietetics, World-Class Research Center, Digital Biodesign and Personalized Healthcare, IM Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia; (A.V.S.); (M.A.); (J.A.)
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Sovetskaya Str. 14, 150000 Yaroslavl, Russia
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Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation. Cells 2021; 10:cells10123333. [PMID: 34943840 PMCID: PMC8699208 DOI: 10.3390/cells10123333] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022] Open
Abstract
Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp–/– mice. Neutrophil infiltration was lessened in the liver of Camp–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.
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Guo W, Zhong W, Hao L, Sun X, Zhou Z. Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease. Cells 2021; 10:2730. [PMID: 34685712 PMCID: PMC8535060 DOI: 10.3390/cells10102730] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/18/2022] Open
Abstract
Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.
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Affiliation(s)
- Wei Guo
- Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; (W.G.); (W.Z.); (L.H.); (X.S.)
| | - Wei Zhong
- Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; (W.G.); (W.Z.); (L.H.); (X.S.)
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA
| | - Liuyi Hao
- Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; (W.G.); (W.Z.); (L.H.); (X.S.)
| | - Xinguo Sun
- Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; (W.G.); (W.Z.); (L.H.); (X.S.)
| | - Zhanxiang Zhou
- Centers for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; (W.G.); (W.Z.); (L.H.); (X.S.)
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA
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Abstract
Malnutrition is common in alcohol-associated hepatitis (AH); almost all patients with severe AH have some component of malnutrition. The classic phenotype of malnutrition in AH is sarcopenia, but this has become more difficult to discern clinically as patients have become more obese. Patients with AH are often drinking 10 to 15 standard drinks per day. This substantial alcohol consumption becomes a major source of calories, but these are considered "empty" calories that contain little nutritional value. Malnutrition is associated with liver complications, such as hepatic encephalopathy, and worse liver outcomes. Nutrition support can improve nutrition status and reduce complications.
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Affiliation(s)
- Craig J. McClain
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY;,UofL Alcohol Research Center, University of Louisville, Louisville, KY;,Department of Medicine, University of Louisville, Louisville, KY;,Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY;,Robely Rex Veterans Affairs Medical Center, Louisville, KY 40207
| | - Cristian D. Rios
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY
| | - Sally Condon
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY
| | - Luis S. Marsano
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY;,Department of Medicine, University of Louisville, Louisville, KY
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Guo W, Zhong W, Hao L, Dong H, Sun X, Yue R, Li T, Zhou Z. Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver Disease. Cell Mol Gastroenterol Hepatol 2021; 12:1599-1615. [PMID: 34284164 PMCID: PMC8536789 DOI: 10.1016/j.jcmgh.2021.07.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. METHODS Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. RESULTS Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. CONCLUSIONS This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.
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Affiliation(s)
- Wei Guo
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Wei Zhong
- Center for Translational Biomedical Research, Kannapolis, North Carolina,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Liuyi Hao
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Haibo Dong
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Xinguo Sun
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Ruichao Yue
- Center for Translational Biomedical Research, Kannapolis, North Carolina
| | - Tianjiao Li
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Kannapolis, North Carolina,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina,Correspondence Address correspondence to: Zhanxiang Zhou, PhD, Center for Translational Biomedical Research, University of North Carolina at Greensboro, 600 Laureate Way, Suite 2203, Kannapolis, North Carolina 28081.fax: (704) 250-5809.
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45
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Hao L, Zhong W, Sun X, Zhou Z. TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice. Front Pharmacol 2021; 12:709002. [PMID: 34262465 PMCID: PMC8273378 DOI: 10.3389/fphar.2021.709002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 06/11/2021] [Indexed: 12/12/2022] Open
Abstract
Toll-Like Receptor 9 (TLR9) elicits cellular response to nucleic acids derived from pathogens or dead cells. Previous studies have shown that TLR9-driven response may lead to differential impact on the pathogenesis of liver diseases. This study aimed to determine how TLR9 may contribute to chronic alcohol exposure-induced liver pathogenesis. We observed that TLR9 KO mice were more susceptible to alcohol-induced liver injury, which was evidenced by higher serum ALT/AST levels and more lipid accumulation in alcohol-fed TLR9 KO mice than wild-type mice. Alcohol-induced oxidative stress and mitochondrial dysfunction were also exacerbated by TLR9 KO. We found that chronic alcohol exposure-induced hepatic CHOP and ATF6 activation were enhanced in TLR9 KO mice. By using primary hepatocytes and AML-12 cells, we confirmed that TLR9 activation by CpG ODN administration significantly ameliorated acetaldehyde-induced cell injury via suppressing ATF6-CHOP signaling. By using STAT3 knockdown AML12 cells, we showed that TLR9-mediated STAT3 activation inhibited ATF6-CHOP signaling cascade and thereby protecting against acetaldehyde-induced mitochondrial dysfunction and cell injury. Interestingly, we found that TLR9 KO mice ameliorate chronic alcohol exposure-induced CXCL1 induction and neutrophils infiltration in the liver. Furthermore, hepatocyte lack of STAT3 significantly ameliorated CpG ODN and LPS-increased CXCL1 levels in hepatocytes. Overall, our data demonstrate that TLR9 signaling in hepatocytes counteracts alcohol-induced hepatotoxicity but worsens proinflammatory response.
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Affiliation(s)
- Liuyi Hao
- Center for Translational Biomedical Research, The University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Wei Zhong
- Center for Translational Biomedical Research, The University of North Carolina at Greensboro, Kannapolis, NC, United States.,Department of Nutrition, The University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Xinguo Sun
- Center for Translational Biomedical Research, The University of North Carolina at Greensboro, Kannapolis, NC, United States
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, The University of North Carolina at Greensboro, Kannapolis, NC, United States.,Department of Nutrition, The University of North Carolina at Greensboro, Kannapolis, NC, United States
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Suzuki K, Nakamura K, Shimizu Y, Yokoi Y, Ohira S, Hagiwara M, Wang Y, Song Y, Aizawa T, Ayabe T. Decrease of α-defensin impairs intestinal metabolite homeostasis via dysbiosis in mouse chronic social defeat stress model. Sci Rep 2021; 11:9915. [PMID: 33972646 PMCID: PMC8110768 DOI: 10.1038/s41598-021-89308-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Psychological stress has been reported to relate to dysbiosis, imbalance of the intestinal microbiota composition, and contribute to the onset and exacerbation of depression, though, underlying mechanisms of psychological stress-related dysbiosis have been unknown. It has been previously established that α-defensins, which are effector peptides of innate enteric immunity produced by Paneth cells in the small intestine, play an important role in regulation of the intestinal microbiota. However, the relationship between disruption of intestinal ecosystem and α-defensin under psychological stress is yet to be determined. Here we show using chronic social defeat stress (CSDS), a mouse depression model that (1) the exposure to CSDS significantly reduces α-defensin secretion by Paneth cells and (2) induces dysbiosis and significant composition changes in the intestinal metabolites. Furthermore, (3) they are recovered by administration of α-defensin. These results indicate that α-defensin plays an important role in maintaining homeostasis of the intestinal ecosystem under psychological stress, providing novel insights into the onset mechanism of stress-induced depression, and may further contribute to discovery of treatment targets for depression.
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Affiliation(s)
- Kosuke Suzuki
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Sapporo, Japan
| | - Kiminori Nakamura
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Sapporo, Japan.,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 001-0021, Japan
| | - Yu Shimizu
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 001-0021, Japan
| | - Yuki Yokoi
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 001-0021, Japan
| | - Shuya Ohira
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Sapporo, Japan
| | - Mizu Hagiwara
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Sapporo, Japan
| | - Yi Wang
- Laboratory of Protein Science, Department of Advanced Transdisciplinary Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Yuchi Song
- Laboratory of Protein Science, Department of Advanced Transdisciplinary Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Tomoyasu Aizawa
- Laboratory of Protein Science, Department of Advanced Transdisciplinary Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.,Global Station for Soft Matter, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
| | - Tokiyoshi Ayabe
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Sapporo, Japan. .,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 001-0021, Japan.
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Yue R, Wei X, Zhao J, Zhou Z, Zhong W. Essential Role of IFN-γ in Regulating Gut Antimicrobial Peptides and Microbiota to Protect Against Alcohol-Induced Bacterial Translocation and Hepatic Inflammation in Mice. Front Physiol 2021; 11:629141. [PMID: 33536944 PMCID: PMC7848155 DOI: 10.3389/fphys.2020.629141] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022] Open
Abstract
The mechanisms by which alcohol provokes bacterial translocation in the development of alcoholic liver disease (ALD) remain incompletely defined. Our previous study demonstrates that impaired gut epithelial antimicrobial defense is critically involved in the pathogenesis of ALD. The study was set to determine the mechanisms of how alcohol inhibits the antimicrobial ability of intestinal epithelial cells (IECs) and to explore possible solutions to this issue. C57BL/6J mice were fed either alcohol or isocaloric dextrin liquid diet for 8 weeks, and intestinal IFN-γ-signal transducer and activator of transcription (STAT) signaling was analyzed. We found that chronic alcohol exposure led to a significant reduction in intestinal IFN-γ levels compared to a control; the protein levels of phosphorylated STAT1 (p-STAT1) and p-STAT3 were both declined by alcohol. We then tested the effects of IFN-γ-STAT signaling on regulating antimicrobial peptides (AMPs), gut microbiota, and disease progression of ALD in a mouse model of chronic alcohol feeding, time-course acute IFN-γ treatment, and in vivo and in vitro IEC-specific STAT1 or STAT3 knockout mouse models, respectively. Administration of IFN-γ activated intestinal STAT1 and STAT3, upregulated the expression of Reg3 and α-defensins, orchestrated gut microbiota, and reversed alcohol-induced intestinal ZO-1 disruption and systemic endotoxin elevation as well as hepatic inflammation. Meanwhile, acute IFN-γ treatment time-dependently induced AMP expression and α-defensin activation. We then dissected the roles of STAT1 and STAT3 in this progress. Lack of IEC-specific STAT3 inhibited IFN-γ-induced expression of Reg3 and α-defensins and hindered activation of α-defensins via inactivating matrix metallopeptidase 7 (MMP7), whereas lack of IEC-specific STAT1 impaired IFN-γ-stimulated expression of α-defensins and the IEC marker, sodium-hydrogen exchanger 3. Lastly, we found that interleukin (IL)-18, a known IFN-γ inducer, was also reduced by alcohol in mice. IL-18 treatment to alcohol-fed mice normalized gut IFN-γ levels and ameliorated organ damages in both the intestine and liver. Taken together, the study reveals that IFN-γ is critically involved in the regulation of AMPs through regulation of STAT1 and STAT3; impaired IFN-γ-STAT signaling provides an explanation for alcohol-induced gut antimicrobial dysfunction and microbial dysbiosis. Therefore, IFN-γ remains a promising host defense-enhancing cytokine with unexplored clinical potential in ALD therapy.
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Affiliation(s)
- Ruichao Yue
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
| | - Xiaoyuan Wei
- Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR, United States
| | - Jiangchao Zhao
- Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR, United States
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
| | - Wei Zhong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, United States
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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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49
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Ding JH, Jin Z, Yang XX, Lou J, Shan WX, Hu YX, Du Q, Liao QS, Xie R, Xu JY. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J Gastroenterol 2020; 26:6141-6162. [PMID: 33177790 PMCID: PMC7596643 DOI: 10.3748/wjg.v26.i40.6141] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/29/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gut-brain axis is a bidirectional information interaction system between the central nervous system (CNS) and the gastrointestinal tract, in which gut microbiota plays a key role. The gut microbiota forms a complex network with the enteric nervous system, the autonomic nervous system, and the neuroendocrine and neuroimmunity of the CNS, which is called the microbiota-gut-brain axis. Due to the close anatomical and functional interaction of the gut-liver axis, the microbiota-gut-liver-brain axis has attracted increased attention in recent years. The microbiota-gut-liver-brain axis mediates the occurrence and development of many diseases, and it offers a direction for the research of disease treatment. In this review, we mainly discuss the role of the gut microbiota in the irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and hepatic encephalopathy via the gut-liver-brain axis, and the focus is to clarify the potential mechanisms and treatment of digestive diseases based on the further understanding of the microbiota-gut- liver-brain axis.
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Affiliation(s)
- Jian-Hong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Xiao-Xu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Wei-Xi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Yan-Xia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Qiu-Shi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
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50
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Li F, Zhao C, Shao T, Liu Y, Gu Z, Jiang M, Li H, Zhang L, Gillevet PM, Puri P, Deng ZB, Chen SY, Barve S, Gobejishvili L, Vatsalya V, McClain CJ, Feng W. Cathelicidin-related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation. J Pathol 2020; 252:371-383. [PMID: 33245573 DOI: 10.1002/path.5531] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 07/05/2020] [Accepted: 08/06/2020] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp-/-) and wild-type (WT) mice were subjected to binge-on-chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum/plasma and hepatic tissue samples from human subjects with alcohol use disorder and/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)-1β levels. Although Camp-/- mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL-1β in alcohol use disorder patients with ALD and were increased in Camp-/- mice fed alcohol. In vitro studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL-1β concentrations and rescued the liver from alcohol-induced damage in both WT and Camp-/- mice. In summary, CRAMP exhibited a protective role against binge-on-chronic alcohol-induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Fengyuan Li
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Cuiqing Zhao
- Department of Medicine, University of Louisville, Louisville, KY, USA.,College of Animal Science and Technology, Key Lab of Preventive Veterinary Medicine in Jilin Province, Jilin Agricultural Science and Technology University, Jilin, PR China
| | - Tuo Shao
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Yunhuan Liu
- Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Zelin Gu
- Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Mengwei Jiang
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Huimin Li
- Department of Medicine, University of Louisville, Louisville, KY, USA.,School of Pharmaceutical Sciences, Jiujiang University, Jiujiang, PR China
| | - Lihua Zhang
- Department of Medicine, University of Louisville, Louisville, KY, USA
| | | | - Puneet Puri
- Section of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.,McGuire VA Medical Center, Richmond, VA, USA
| | - Zhong-Bin Deng
- Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Shao-Yu Chen
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA
| | - Shirish Barve
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Leila Gobejishvili
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Vatsalya Vatsalya
- Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA.,Robley Rex VA Medical Center, Louisville, KY, USA
| | - Wenke Feng
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.,Department of Medicine, University of Louisville, Louisville, KY, USA.,Alcohol Research Center, University of Louisville, Louisville, KY, USA.,Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY, USA
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