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Romo EZ, Hong BV, Agus JK, Jin Y, Kang JW, Zivkovic AM. A low-dose prebiotic fiber supplement reduces lipopolysaccharide-binding protein concentrations in a subgroup of young, healthy adults consuming low-fiber diets. Nutr Res 2025; 133:138-147. [PMID: 39733508 PMCID: PMC12045461 DOI: 10.1016/j.nutres.2024.11.013] [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: 04/04/2024] [Revised: 11/19/2024] [Accepted: 11/30/2024] [Indexed: 12/31/2024]
Abstract
Although the beneficial effects of fiber supplementation on overall health and the gut microbiome are well-known, it is not clear whether fiber supplementation can also alter the concentrations of lipopolysaccharide-binding protein (LBP), a marker of intestinal permeability. A secondary analysis of a previously conducted study was performed. In the randomized-order, placebo-controlled, double-blinded, cross-over study 20 healthy, young participants consuming a low-fiber diet at baseline were administered a daily dose of 12 g of prebiotic fiber compared with a placebo over a period of 4 weeks with a 4-week washout between arms. In this secondary analysis, we hypothesized that the fiber supplement would reduce LBP concentration. We further hypothesized that lecithin cholesterol acyltransferase activity, a measure of high-density lipoprotein functional capacity, would be altered. Fiber supplementation did not significantly alter LBP concentration or lecithin cholesterol acyltransferase activity in the overall cohort. However, in a subgroup of individuals with elevated baseline LBP concentrations, fiber supplementation significantly reduced LBP from 9.27 ± 3.52 to 7.02 ± 2.32 µg/mL (P = .003). Exploratory analyses found positive correlations between microbial genes involved in lipopolysaccharide synthesis and conversely negative correlations with genes involved in antibiotic synthesis and LBP. Positive correlations between LBP and multiple sulfated molecules including sulfated bile acids and perfluorooctanesulfonate, and ibuprofen metabolites were also found. These findings highlight multiple environmental and lifestyle factors such as exposure to industrial chemicals and medication intake, in addition to diet, which may influence the association between the gut microbiome and gut barrier function.
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Affiliation(s)
- Eduardo Z Romo
- Department of Nutrition, University of California, Davis, CA, USA
| | - Brian V Hong
- Department of Nutrition, University of California, Davis, CA, USA
| | - Joanne K Agus
- Department of Nutrition, University of California, Davis, CA, USA
| | - Yanshan Jin
- Department of Nutrition, University of California, Davis, CA, USA
| | - Jea Woo Kang
- Department of Nutrition, University of California, Davis, CA, USA
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2
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Tanwar H, Gnanasekaran JM, Allison D, Chuang LS, He X, Aimetti M, Baima G, Costalonga M, Cross RK, Sears C, Mehandru S, Cho J, Colombel JF, Raufman JP, Thumbigere-Math V. Unravelling the Oral-Gut Axis: Interconnection Between Periodontitis and Inflammatory Bowel Disease, Current Challenges, and Future Perspective. J Crohns Colitis 2024; 18:1319-1341. [PMID: 38417137 PMCID: PMC11324343 DOI: 10.1093/ecco-jcc/jjae028] [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: 08/21/2023] [Revised: 12/04/2023] [Accepted: 02/27/2024] [Indexed: 03/01/2024]
Abstract
As the opposite ends of the orodigestive tract, the oral cavity and the intestine share anatomical, microbial, and immunological ties that have bidirectional health implications. A growing body of evidence suggests an interconnection between oral pathologies and inflammatory bowel disease [IBD], implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an 'oral-gut' axis, marked by a higher prevalence of periodontitis and other oral conditions in IBD patients and vice versa. We present an in-depth examination of the interconnection between oral pathologies and IBD, highlighting the shared microbiological and immunological pathways, and proposing a 'multi-hit' hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.
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Affiliation(s)
- Himanshi Tanwar
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | | | - Devon Allison
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Ling-shiang Chuang
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xuesong He
- Department of Microbiology, The Forsyth Institute, Cambridge, MA, USA
| | - Mario Aimetti
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Giacomo Baima
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Massimo Costalonga
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Raymond K Cross
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cynthia Sears
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judy Cho
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Pierre Raufman
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Vivek Thumbigere-Math
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
- National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA
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Du K, Liang Y, Song Z, Zheng C, Lai L, Zong K, Wang Y, Meng D. Monoterpenoid indole alkaloids from Melodinus axillaris W.T.Wang exhibit anti-inflammatory activities by inhibiting the NF-κB signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117771. [PMID: 38242218 DOI: 10.1016/j.jep.2024.117771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/07/2024] [Accepted: 01/11/2024] [Indexed: 01/21/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Melodinus axillaris W.T.Wang has been widely used as an important medicine in China. In the folk of China, its whole plant has been used for fractures, rheumatic heart disease, testitis, hernia, abdominal pain, and dyspepsia, etc. Despite its extensive use, there is a shortage of literature investigating the specific bioactive compounds and underlying mechanisms responsible for their anti-inflammatory effects. This knowledge gap serves as the primary impetus for conducting this study, which aims to shed light on the previously unexplored therapeutic potential of M. axillaris. AIM OF THE STUDY This study aims to investigate the material basis and potential mechanism of anti-inflammatory activity of M. axillaris. MATERIALS AND METHODS Compounds were isolated from the 95% ethanol extract of M. axillaris using a systematic phytochemical method. The structures were established by extensive spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, ECD calculation, and DP4+ analysis. The anti-inflammatory activities of ethanol extract and compounds from M. axillaris were tested by an inflammation model of LPS-stimulated RAW264.7 cells in vitro. Western blot analysis was employed to evaluate the expressions of COX-2, iNOS, and NF-κB signaling pathways, aiming to elucidate the underlying mechanisms. RESULTS Eleven undescribed monoterpenoid indole alkaloids (MIAs), axillines A-K (1-11), along with thirteen known analogs were isolated from M. axillaris. Compound 1 was the first representative of vincadine alkaloid with unprecedented 6/5/9/6/6 skeletons. Compounds 1-11 and ethanol extract showed significant anti-inflammatory effects in vitro. Among them, compound 2 had the best activity of inhibiting NO release (IC50 = 3.7 ± 0.9 μM). Additionally, subsequent Western blot analysis revealed that 2 could significantly inhibit the up-regulation of NF-κB signaling pathways, iNOS, and COX-2 in LPS-stimulated RAW264.7 cells, thereby demonstrating its anti-inflammatory activity. CONCLUSION This study provides support for the traditional use of M. axillaris in terms of its anti-inflammatory properties and highlights the potential of MIAs as promising candidates for further development as anti-inflammatory drugs.
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Affiliation(s)
- Kaicheng Du
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Yanan Liang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Zihao Song
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Changwei Zheng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Lantao Lai
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Kunqi Zong
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China
| | - Yumeng Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
| | - Dali Meng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
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Vuralli D, Ceren Akgor M, Gok Dagidir H, Gulbahar O, Yalinay M, Bolay H. Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation. J Headache Pain 2024; 25:23. [PMID: 38369488 PMCID: PMC10875763 DOI: 10.1186/s10194-024-01730-5] [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: 12/05/2023] [Accepted: 02/05/2024] [Indexed: 02/20/2024] Open
Abstract
OBJECTIVE Medication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation. MATERIALS AND METHODS The study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels. RESULTS Serum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores. CONCLUSION We have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH.
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Affiliation(s)
- Doga Vuralli
- Department of Neurology and Algology, Gazi University Faculty of Medicine, Ankara, Turkey
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey
- Neuropsychiatry Center, Gazi University, Ankara, Turkey
| | - Merve Ceren Akgor
- Department of Neurology and Algology, Gazi University Faculty of Medicine, Ankara, Turkey
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey
| | - Hale Gok Dagidir
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey
| | - Ozlem Gulbahar
- Department of Medical Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Meltem Yalinay
- Department of Clinical Microbiology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Hayrunnisa Bolay
- Department of Neurology and Algology, Gazi University Faculty of Medicine, Ankara, Turkey.
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Turkey.
- Neuropsychiatry Center, Gazi University, Ankara, Turkey.
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Hemgren C, Martinsson K, Rooney C, Wetterö J, Mankia K, Emery P, Kastbom A. Elevated Serum Levels of Zonulin Family Peptides in Anticitrullinated Protein Antibody-Positive At-Risk Individuals Without Arthritis. J Rheumatol 2024; 51:134-138. [PMID: 38302186 DOI: 10.3899/jrheum.2023-0160] [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] [Accepted: 11/01/2023] [Indexed: 02/03/2024]
Abstract
OBJECTIVE Recent advances imply that early events triggering rheumatoid arthritis (RA) occur at mucosal surfaces. We aimed to evaluate whether intestinal permeability is altered in patients at increased risk of RA, and/or predicts the development of clinical arthritis, by measuring serum zonulin family peptides (ZFP) levels, which are shown to reflect intestinal barrier integrity. METHODS Two independent prospective observational cohorts were studied, including subjects with musculoskeletal symptoms and anticitrullinated protein antibodies (ACPA), but without clinical arthritis at baseline. In Sweden, 82 such at-risk patients were compared to 100 age-matched healthy blood donors. In the UK, 307 at-risk patients were compared to 100 ACPA-negative symptomatic controls. ZFP was measured in baseline sera by enzyme-linked immunoassays. RESULTS In the Swedish at-risk cohort, ZFP levels were significantly increased in patients compared to controls (mean 41.4 vs 33.6 ng/mL, P < 0.001) and Cox regression analysis showed prognostic value of ZFP for arthritis development (hazard ratio [HZ] 1.04 per ng/mL ZFP increase, 95% CI 1.01-1.07, P = 0.02). Elevated ZFP levels among ACPA-positive at-risk patients compared to symptomatic ACPA-negative controls were confirmed in the UK at-risk cohort (mean 69.7 vs 36.0 ng/mL, P < 0.001), but baseline ZFP were not associated with arthritis development (HR 1.00 per ng/mL ZFP increase, 95% CI 1.00-1.01, P = 0.30). CONCLUSION Serum ZFP levels are elevated in ACPA-positive at-risk patients when compared to both healthy blood donors and symptomatic ACPA-negative controls. Thus, gut barrier function may be of importance in RA-associated autoimmunity. A possible prognostic value of serum ZFP merits further investigation, preferably in larger prospective cohorts.
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Affiliation(s)
- Cecilia Hemgren
- C. Hemgren, MD, Department of Internal Medicine, Division of Rheumatology, Ryhov Hospital, Jönköping, Sweden;
| | - Klara Martinsson
- K. Martinsson, PhD, J. Wetterö, PhD, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Christopher Rooney
- C. Rooney, MD, K. Mankia, MD, PhD, P. Emery, MD, PhD, Leeds NIHR Biomedical Research Centre, LTHT, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Jonas Wetterö
- K. Martinsson, PhD, J. Wetterö, PhD, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Kulveer Mankia
- C. Rooney, MD, K. Mankia, MD, PhD, P. Emery, MD, PhD, Leeds NIHR Biomedical Research Centre, LTHT, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Paul Emery
- C. Rooney, MD, K. Mankia, MD, PhD, P. Emery, MD, PhD, Leeds NIHR Biomedical Research Centre, LTHT, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Alf Kastbom
- A. Kastbom, MD, PhD, Department of Biomedical and Clinical Sciences, Linköping University, and Department of Rheumatology, Linköping University Hospital, Linköping, Sweden
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6
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Markovich Z, Abreu A, Sheng Y, Han SM, Xiao R. Deciphering internal and external factors influencing intestinal junctional complexes. Gut Microbes 2024; 16:2389320. [PMID: 39150987 PMCID: PMC11332634 DOI: 10.1080/19490976.2024.2389320] [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: 06/13/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/18/2024] Open
Abstract
The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional complexes, prevalent in inflammatory bowel diseases and irritable bowel syndrome, compromise barrier integrity and often lead to the notorious "leaky gut" syndrome. Critical to the maintenance of the intestinal barrier is a finely orchestrated network of intrinsic and extrinsic factors that modulate the expression, composition, and functionality of junctional complexes. This review navigates through the composition of key junctional complex components and the common methods used to assess intestinal permeability. It also explores the critical intracellular signaling pathways that modulate these junctional components. Lastly, we delve into the complex dynamics between the junctional complexes, microbial communities, and environmental chemicals in shaping the intestinal barrier function. Comprehending this intricate interplay holds paramount importance in unraveling the pathophysiology of gastrointestinal disorders. Furthermore, it lays the foundation for the development of precise therapeutic interventions targeting barrier dysfunction.
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Affiliation(s)
- Zachary Markovich
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA
- Graduate Program in Biomedical Sciences, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Smell and Taste, University of Florida, Gainesville, FL, USA
| | - Adriana Abreu
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Yi Sheng
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Sung Min Han
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Rui Xiao
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Smell and Taste, University of Florida, Gainesville, FL, USA
- Institute on Aging, University of Florida, Gainesville, FL, USA
- Genetics Institute, University of Florida, Gainesville, FL, USA
- UF Health Cancer Center, University of Florida, Gainesville, FL, USA
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7
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Dunleavy KA, Raffals LE, Camilleri M. Intestinal Barrier Dysfunction in Inflammatory Bowel Disease: Underpinning Pathogenesis and Therapeutics. Dig Dis Sci 2023; 68:4306-4320. [PMID: 37773554 PMCID: PMC10798146 DOI: 10.1007/s10620-023-08122-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/19/2023] [Indexed: 10/01/2023]
Abstract
The intestinal barrier is composed of several essential elements including luminal enzymes, bile acids, water layer, epithelial layer, and enterocyte layer. It acts as a dynamic interface between the luminal contents of food, commensal and pathogenic bacteria, and the gastrointestinal tract. The role of barrier dysfunction is of significant research interest in the development and targeted treatment of chronic inflammatory gastrointestinal conditions, such as inflammatory bowel disease. This review aims to examine the role of intestinal barrier dysfunction in the development of inflammatory bowel disease, the pathophysiology of increased barrier permeability in inflammatory bowel disease, and to explore potential treatment targets and clinical applications.
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Affiliation(s)
- Katie A Dunleavy
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA.
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA
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8
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Dağıdır HG, Topa E, Vuralli D, Bolay H. Medication overuse headache is associated with elevated lipopolysaccharide binding protein and pro-inflammatory molecules in the bloodstream. J Headache Pain 2023; 24:150. [PMID: 37940864 PMCID: PMC10631084 DOI: 10.1186/s10194-023-01672-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/25/2023] [Indexed: 11/10/2023] Open
Abstract
OBJECTIVE Medication overuse headache (MOH) is a secondary headache that accompanies chronic migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used analgesics worldwide and they are known to induce leaky gut. In this study, we aimed to investigate whether NSAID induced MOH is associated with altered circulating lipopolysaccharide binding protein (LBP) levels and inflammatory molecules. MATERIALS AND METHODS Piroxicam (10 mg/kg/day, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain behavior was evaluated by periorbital withdrawal thresholds, head-face grooming, freezing, and head shake behavior. Serum samples and brain tissues were collected to measure circulating LBP, tight junction protein occludin, adherens junction protein vascular endothelial (VE)-cadherin, calcitonin gene-related peptide (CGRP), IL-6 levels and brain high mobility group box-1 (HMGB1) and IL-17 levels. RESULTS Chronic piroxicam exposure resulted in decreased periorbital mechanical withdrawal thresholds, increased head-face grooming, freezing, and head shake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was positively correlated with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618) and head shakes (r = 0.921), and negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.740). CONCLUSION Elevated serum LBP, VE-cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation were shown in female rats with MOH. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules such as HMGB1, IL-6, IL-17 and CGRP may play a role in the development and maintenance of MOH. Interference with leaky gut and pro-inflammatory nociceptive molecules could also be a target for sustained management of MOH.
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Affiliation(s)
- Hale Gök Dağıdır
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Beşevler, Ankara, Türkiye
| | - Elif Topa
- Neuropsychiatry Center, Gazi University, Beşevler, Ankara, Türkiye
| | - Doga Vuralli
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Beşevler, Ankara, Türkiye
- Neuropsychiatry Center, Gazi University, Beşevler, Ankara, Türkiye
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Beşevler, Ankara, Türkiye
| | - Hayrunnisa Bolay
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Beşevler, Ankara, Türkiye.
- Neuropsychiatry Center, Gazi University, Beşevler, Ankara, Türkiye.
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Beşevler, Ankara, Türkiye.
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9
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Maher S, Geoghegan C, Brayden DJ. Safety of surfactant excipients in oral drug formulations. Adv Drug Deliv Rev 2023; 202:115086. [PMID: 37739041 DOI: 10.1016/j.addr.2023.115086] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
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Affiliation(s)
- Sam Maher
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.
| | - Caroline Geoghegan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland
| | - David J Brayden
- UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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10
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VURALLI D, DAĞIDIR HGÖK, TOPA EABBASOĞLU, BELEN HBOLAY. Leaky gut and inflammatory biomarkers in a medication overuse headache model in male rats. Turk J Med Sci 2023; 54:33-41. [PMID: 38812640 PMCID: PMC11031181 DOI: 10.55730/1300-0144.5763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 02/15/2024] [Accepted: 10/25/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim Medication overuse is common among chronic migraine patients and nonsteroidal antiinflammatory drugs (NSAIDs) are the most frequently overused drugs. The pathophysiological mechanisms underlying medication overuse headache (MOH) are not completely understood. Intestinal hyperpermeability and leaky gut are reported in patients using NSAIDs. The aim of the study is to investigate the role of leaky gut and inflammation in an MOH model MOH model in male rats. Methods The study was conducted in male Sprague Dawley rats. There were two experimental groups. The first group was the chronic NSAID group in which the rats received mefenamic acid (n = 8) for four weeks intraperitoneally (ip) and the second group was the vehicle group (n = 8) that received 5% dimethyl sulfoxide+sesame oil (ip) for 4 weeks. We assessed spontaneous pain-like behavior, periorbital mechanical withdrawal thresholds, and anxiety-like behavior using an elevated plus maze test. After behavioral testing, serum levels of occludin and lipopolysaccharide-binding protein (LBP) and brain levels of IL-17, IL-6, and high mobility group box 1 protein (HMGB1) were evaluated with ELISA.Results: Serum LBP and occludin levels and brain IL-17 and HMGB1 levels were significantly elevated in the chronic NSAID group compared to its vehicle (p = 0.006, p = 0.016, p = 0.016 and p = 0.016 respectively) while brain IL-6 levels were comparable (p = 0.67) between the groups. The chronic NSAID group showed pain-like and anxiety-like behavior in behavioral tests. Brain IL-17 level was positively correlated with number of head shakes (r = 0.64, p = 0.045), brain IL-6 level was negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.71, p = 0.049), and serum occludin level was positively correlated with grooming duration (r = 0.73, p = 0.032) in chronic NSAID group. Conclusion Elevated serum occludin and LBP levels and brain IL-17 and HMGB1 levels indicate a possible role of leaky gut and inflammation in an MOH model in male rats. Additionally, a significant correlation between pain behavior and markers of inflammation and intestinal hyperpermeability, supports the role of inflammation and leaky gut in MOH pathophysiology.
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Affiliation(s)
- Doğa VURALLI
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara,
Turkiye
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara,
Turkiye
- Neuropsychiatry Center, Gazi University, Ankara,
Turkiye
| | - Hale GÖK DAĞIDIR
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara,
Turkiye
| | | | - Hayrunnisa BOLAY BELEN
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara,
Turkiye
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara,
Turkiye
- Neuropsychiatry Center, Gazi University, Ankara,
Turkiye
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11
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Ceren Akgor M, Vuralli D, Sucu DH, Gokce S, Tasdelen B, Gultekin F, Bolay H. Distinct Food Triggers for Migraine, Medication Overuse Headache and Irritable Bowel Syndrome. J Clin Med 2023; 12:6488. [PMID: 37892628 PMCID: PMC10607881 DOI: 10.3390/jcm12206488] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is an under-diagnosed common health problem that impairs quality of life. Migraine and IBS are comorbid disorders that are triggered by foods. We aim to investigate IBS frequency in medication overuse headache (MOH) patients and identify food triggers and food avoidance behavior. METHODS Participants who completed the cross-sectional, observational and online survey were included (n = 1118). Demographic data, comorbid disorders, medications used, presence of headache, the diagnostic features of headache and IBS, migraine related subjective cognitive symptoms scale (MigSCog), consumption behavior of patients regarding 125 food/food additives and food triggers were asked about in the questionnaire. RESULTS Migraine and MOH diagnoses were made in 88% and 30.7% of the participants, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) were the main overused drug (89%) in MOH patients. IBS symptoms were present in 35.8% of non-headache sufferers, 52% of migraine patients and 65% of MOH patients. Specific food triggers for MOH patients were dopaminergic and frequently consumed as healthy foods such as banana, apple, cherry, apricot, watermelon, olive, ice cream and yogurt. MigSCog scores were significantly higher in episodic migraine and MOH patients when IBS symptoms coexisted. CONCLUSIONS The frequency of IBS was higher in MOH patients compared to migraine patients. Coexistence of IBS seems to be a confounding factor for cognitive functions. MOH specific triggers were mostly dopaminergic foods, whereas migraine specific food triggers were mostly histaminergic and processed foods. Personalized diets focusing on food triggers and interference with leaky gut must be integrated to MOH and migraine treatment to achieve sustainable management of these disorders.
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Affiliation(s)
- Merve Ceren Akgor
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara 06560, Türkiye; (M.C.A.); (D.V.); (S.G.)
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara 06560, Türkiye
| | - Doga Vuralli
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara 06560, Türkiye; (M.C.A.); (D.V.); (S.G.)
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara 06560, Türkiye
- Neuropsychiatry Center, Gazi University, Ankara 06560, Türkiye
| | - Damla Hazal Sucu
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Mersin University, Mersin 33343, Türkiye; (D.H.S.); (B.T.)
| | - Saliha Gokce
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara 06560, Türkiye; (M.C.A.); (D.V.); (S.G.)
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara 06560, Türkiye
| | - Bahar Tasdelen
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Mersin University, Mersin 33343, Türkiye; (D.H.S.); (B.T.)
| | - Fatih Gultekin
- Department of Medical Biochemistry, Lokman Hekim University, Ankara 06510, Türkiye;
| | - Hayrunnisa Bolay
- Department of Neurology and Algology, Faculty of Medicine, Gazi University, Ankara 06560, Türkiye; (M.C.A.); (D.V.); (S.G.)
- Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara 06560, Türkiye
- Neuropsychiatry Center, Gazi University, Ankara 06560, Türkiye
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12
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Tanwar H, Gnanasekaran JM, Allison D, Chuang LS, He X, Aimetti M, Baima G, Costalonga M, Cross RK, Sears C, Mehandru S, Cho J, Colombel JF, Raufman JP, Thumbigere-Math V. Unraveling the Link between Periodontitis and Inflammatory Bowel Disease: Challenges and Outlook. ARXIV 2023:arXiv:2308.10907v1. [PMID: 37645044 PMCID: PMC10462160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Periodontitis and Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions, characterized by microbial dysbiosis and hyper-immunoinflammatory responses. Growing evidence suggest an interconnection between periodontitis and IBD, implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an "Oral-Gut" axis, marked by a higher prevalence of periodontitis in IBD patients and vice versa. The specific mechanisms linking periodontitis and IBD remain to be fully elucidated, but emerging evidence points to the ectopic colonization of the gut by oral bacteria, which promote intestinal inflammation by activating host immune responses. This review presents an in-depth examination of the interconnection between periodontitis and IBD, highlighting the shared microbiological and immunological pathways, and proposing a "multi-hit" hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.
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Affiliation(s)
- Himanshi Tanwar
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | | | - Devon Allison
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Ling-shiang Chuang
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xuesong He
- Department of Microbiology, The Forsyth Institute, Cambridge, MA, USA
| | - Mario Aimetti
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Giacomo Baima
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Massimo Costalonga
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA
| | - Raymond K. Cross
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cynthia Sears
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judy Cho
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Pierre Raufman
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Vivek Thumbigere-Math
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
- National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA
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13
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Cohen-Mekelburg S, Van T, Wallace BI, Berinstein J, Yu X, Lewis J, Hou J, Dominitz JA, Waljee AK. Response to Squirell et al. Am J Gastroenterol 2023; 118:1462-1463. [PMID: 37534810 DOI: 10.14309/ajg.0000000000002276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Affiliation(s)
- Shirley Cohen-Mekelburg
- Division of Gastroenterology and Hepatology, University of Michigan Medicine, Ann Arbor, Michigan, USA
- VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - Tony Van
- VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - Beth I Wallace
- VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
- Division of Rheumatology, University of Michigan Medicine, Ann Arbor, Michigan, USA
| | - Jeffrey Berinstein
- Division of Gastroenterology and Hepatology, University of Michigan Medicine, Ann Arbor, Michigan, USA
| | - Xianshi Yu
- Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA
| | - James Lewis
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jason Hou
- Division of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- VA Houston Healthcare System, Houston, Texas, USA
| | - Jason A Dominitz
- VA Puget Sound Healthcare System, Seattle, Washington, USA
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, Washington, USA
| | - Akbar K Waljee
- Division of Gastroenterology and Hepatology, University of Michigan Medicine, Ann Arbor, Michigan, USA
- VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
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14
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Affiliation(s)
- Elizabeth Squirell
- Division of Gastroenterology, Department of Medicine, St Paul's Hospital, Vancouver, British Columbia, Canada
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15
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Brown GC, Camacho M, Williams‐Gray CH. The Endotoxin Hypothesis of Parkinson's Disease. Mov Disord 2023; 38:1143-1155. [PMID: 37157885 PMCID: PMC10947365 DOI: 10.1002/mds.29432] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 05/10/2023] Open
Abstract
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Guy C. Brown
- Department of BiochemistryUniversity of CambridgeCambridgeUK
| | - Marta Camacho
- Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
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16
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Bhatnagar A, Pemawat G. An overview on synthetic routes of anti-inflammatory active scaffolds including thiazole and thiazolidine cores. PHOSPHORUS SULFUR 2023. [DOI: 10.1080/10426507.2023.2189253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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Protective Effect of Irsogladine against Aspirin-Induced Mucosal Injury in Human Induced Pluripotent Stem Cell-Derived Small Intestine. Medicina (B Aires) 2022; 59:medicina59010092. [PMID: 36676718 PMCID: PMC9863323 DOI: 10.3390/medicina59010092] [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: 11/09/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Background and Objectives: Acetylsalicylic acid (ASA) is widely used for preventing cerebrovascular and cardiovascular diseases. Gastrointestinal (GI) tract injury is one of the major complications of aspirin use, potentially leading to severe GI bleeding. However, no drugs for preventing aspirin-induced small intestinal injury have been developed. The aim of this study was to establish a human experimental model for investigating aspirin-induced small intestinal mucosal injury. In addition, we evaluated the protective effect of Irsogladine against aspirin-induced small intestinal mucosal injury using human induced pluripotent stem cell-derived 2D monolayer crypt-villus structural small intestine (2D-hiPSC-SI). Materials and Methods: Human iPS cell-derived intestinal organoids were seeded and cultured in Air-liquid interface. The permeability of 2D-hiPSC-SI was evaluated using Lucifer yellow. Changes in structure and mucosal permeability of 2D-hiPSC-SI after addition of aspirin were confirmed over time, and changes in intestinal epithelium-related markers were evaluated by real-time qPCR and Immunofluorescence staining. The effect of Irsogladine on prevention of aspirin mucosal injury was examined by adding Irsogladine to the culture medium. Results: Cultured 2D-hiPSC-SI showed multi-lineage differentiation into small intestinal epithelium comprised of absorptive cells, goblet cells, enteroendocrine cells, and Paneth cells, which express CD10, MUC2, chromogranin A, and lysozyme, respectively. RNA in situ hybridization revealed intestinal stem cells that express Lgr5. ASA administration induced an increase in the mucosal permeability of 2D-hiPSC-SI. ASA-injured 2D-hiPSC-SI showed decreased mRNA expression of multi-lineage small intestinal cell markers as well as intestinal stem cell marker Lgr5. Administration of Irsogladine on the basal side of the 2D-hiPSC-SI resulted in significant increases in Mki67 and Muc2 mRNA expression by 2D-hiPSCs at 48 h compared with the control group. Administration of 400 µg/mL Irsogladine to the ASA-induced small intestinal injury model resulting in significantly decreased mucosal permeability of 2D-hiPSC-SI. In immunofluorescence staining, Irsogladine significantly increased the fluorescence intensity of MUC2 under normal conditions and administration of 400 µg/mL ASA. Conclusions: we established a novel ASA-induced small intestinal injury model using human iPSC-derived small intestine. Irsogladine maintains mucosal permeability and goblet cell differentiation against ASA-induced small intestinal injury.
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18
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Charoensappakit A, Sae-Khow K, Leelahavanichkul A. Gut Barrier Damage and Gut Translocation of Pathogen Molecules in Lupus, an Impact of Innate Immunity (Macrophages and Neutrophils) in Autoimmune Disease. Int J Mol Sci 2022; 23:ijms23158223. [PMID: 35897790 PMCID: PMC9367802 DOI: 10.3390/ijms23158223] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/25/2022] [Accepted: 07/25/2022] [Indexed: 02/08/2023] Open
Abstract
The gut barrier is a single cell layer that separates gut micro-organisms from the host, and gut permeability defects result in the translocation of microbial molecules from the gut into the blood. Despite the silent clinical manifestation, gut translocation of microbial molecules can induce systemic inflammation that might be an endogenous exacerbating factor of systemic lupus erythematosus. In contrast, circulatory immune-complex deposition and the effect of medications on the gut, an organ with an extremely large surface area, of patients with active lupus might cause gut translocation of microbial molecules, which worsens lupus severity. Likewise, the imbalance of gut microbiota may initiate lupus and/or interfere with gut integrity which results in microbial translocation and lupus exacerbation. Moreover, immune hyper-responsiveness of innate immune cells (macrophages and neutrophils) is demonstrated in a lupus model from the loss of inhibitory Fc gamma receptor IIb (FcgRIIb), which induces prominent responses through the cross-link between activating-FcgRs and innate immune receptors. The immune hyper-responsiveness can cause cell death, especially apoptosis and neutrophil extracellular traps (NETosis), which possibly exacerbates lupus, partly through the enhanced exposure of the self-antigens. Leaky gut monitoring and treatments (such as probiotics) might be beneficial in lupus. Here, we discuss the current information on leaky gut in lupus.
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Affiliation(s)
- Awirut Charoensappakit
- Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kritsanawan Sae-Khow
- Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Nephrology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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19
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Martel J, Chang SH, Ko YF, Hwang TL, Young JD, Ojcius DM. Gut barrier disruption and chronic disease. Trends Endocrinol Metab 2022; 33:247-265. [PMID: 35151560 DOI: 10.1016/j.tem.2022.01.002] [Citation(s) in RCA: 250] [Impact Index Per Article: 83.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 02/06/2023]
Abstract
The intestinal barrier protects the host against gut microbes, food antigens, and toxins present in the gastrointestinal tract. However, gut barrier integrity can be affected by intrinsic and extrinsic factors, including genetic predisposition, the Western diet, antibiotics, alcohol, circadian rhythm disruption, psychological stress, and aging. Chronic disruption of the gut barrier can lead to translocation of microbial components into the body, producing systemic, low-grade inflammation. While the association between gut barrier integrity and inflammation in intestinal diseases is well established, we review here recent studies indicating that the gut barrier and microbiota dysbiosis may contribute to the development of metabolic, autoimmune, and aging-related disorders. Emerging interventions to improve gut barrier integrity and microbiota composition are also described.
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Affiliation(s)
- Jan Martel
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Shih-Hsin Chang
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yun-Fei Ko
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung Biotechnology Corporation, Taipei, Taiwan; Biochemical Engineering Research Center, Ming Chi University of Technology, New Taipei City, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - John D Young
- Chang Gung Biotechnology Corporation, Taipei, Taiwan.
| | - David M Ojcius
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Biomedical Sciences, Arthur Dugoni School of Dentistry, University of the Pacific, San Francisco, CA, USA.
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20
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Pavlidis P, Joshi D, El Sherif Y, Warner B, Gulati S, Alexander J, Cross G, Dew T, Arqoub HA, Devlin J, Heneghan M, Dubois P, Bjarnason I, Powell N, Hayee B. Faecal calprotectin is a surrogate marker of biliary inflammation in primary sclerosing cholangitis associated inflammatory bowel disease. Frontline Gastroenterol 2022; 13:497-502. [PMID: 36250171 PMCID: PMC9555142 DOI: 10.1136/flgastro-2021-102053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 03/04/2022] [Indexed: 02/04/2023] Open
Abstract
Objective Faecal calprotectin (fCAL) is an established marker of intestinal inflammation in inflammatory bowel disease (IBD). Disproportionally high fCAL levels, for the severity of intestinal inflammation, have been previously observed in primary sclerosing cholangitis associated IBD (PSC-IBD). The aim of this study was to test the hypothesis that fCAL is a marker of biliary injury in PSC-IBD. Methods We used two cohorts: (1) post hoc analysis of a colonoscopic surveillance study allowing correlation of fCAL to endoscopic severity as measured by the ulcerative colitis endoscopic index of severity (UCEIS) in PSC-IBD (n=20) and ulcerative colitis (UC, n=20) and (2) prospective recruitment of patients attending for endoscopic retrograde cholangiopancreatography allowed the correlation of fCAL to biliary calprotectin (n=8). Results A strong correlation was seen between fCAL and UCEIS in UC (r=0.821, 95% CI (0.585 to 0.929), p<0.0001). In PSC-IBD, the correlation was weaker (r=0.596, 95% CI (0.195 to 0.8260), p=0.006). PSC-IBD patients with endoscopically quiescent colitis (UCEIS: 0-1) had higher fCAL than patients with UC (279 µg/g, IQR (68-601) vs 30 µg/g, IQR (14-107), p=0.015). This was associated with higher risk of biliary complications like need for antibiotics or instrumentation (HR 16.39, 95% CI (2.98 to 90.25)) rather than colitis flares (follow-up: 12 months). Calprotectin measured in faeces correlated positively with biliary calprotectin (r=0.898, p=0.0024). Conclusion fCAL is a surrogate marker for biliary inflammation in PSC-IBD. Trial registration number NCT02543021.
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Affiliation(s)
- Polychronis Pavlidis
- Experimental Immunobiology, King's College London, London, UK.,King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK
| | - Deepak Joshi
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK.,Institute of Liver Studies, King's College Hospital, London, UK
| | - Yasser El Sherif
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK.,Institute of Liver Studies, King's College Hospital, London, UK
| | - Ben Warner
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK.,Institute of Liver Studies, King's College Hospital, London, UK
| | - Shraddha Gulati
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK
| | | | - Gemma Cross
- Biomarker Discovery, Viapath, King's College Hospital, London, UK
| | - Tracy Dew
- Biomarker Discovery, Viapath, King's College Hospital, London, UK
| | - Hadil Abu Arqoub
- Pathology Department, Viapath, King's College Hospital, London, Algeria
| | - John Devlin
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK.,Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Patrick Dubois
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK
| | - Ingvar Bjarnason
- Department of Gastroenterology, King's College Hospital, London, UK
| | - Nick Powell
- Imperial College London Faculty of Medicine, London, UK
| | - Bu'Hussain Hayee
- King's Institute of Therapeutic Endoscopy, King's College Hospital, London, UK
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21
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Pharmacological Exploration of Phenolic Compound: Raspberry Ketone-Update 2020. PLANTS (BASEL, SWITZERLAND) 2021; 10:plants10071323. [PMID: 34209554 PMCID: PMC8309185 DOI: 10.3390/plants10071323] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023]
Abstract
Raspberry ketone (RK) is an aromatic phenolic compound naturally occurring in red raspberries, kiwifruit, peaches, and apples and reported for its potential therapeutic and nutraceutical properties. Studies in cells and rodents have suggested an important role for RK in hepatic/cardio/gastric protection and as an anti-hyperlipidemic, anti-obesity, depigmentation, and sexual maturation agent. Raspberry ketone-mediated activation of peroxisome proliferator-activated receptor-α (PPAR-α) stands out as one of its main modes of action. Although rodent studies have demonstrated the efficacious effects of RK, its mechanism remains largely unknown. In spite of a lack of reliable human research, RK is marketed as a health supplement, at very high doses. In this review, we provide a compilation of scientific research that has been conducted so far, assessing the therapeutic properties of RK in several disease conditions as well as inspiring future research before RK can be considered safe and efficacious with limited side effects as an alternative to modern medicines in the treatment of major lifestyle-based diseases.
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22
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Arslan A, Kaplan M, Duman H, Bayraktar A, Ertürk M, Henrick BM, Frese SA, Karav S. Bovine Colostrum and Its Potential for Human Health and Nutrition. Front Nutr 2021; 8:651721. [PMID: 34235166 PMCID: PMC8255475 DOI: 10.3389/fnut.2021.651721] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 05/27/2021] [Indexed: 01/17/2023] Open
Abstract
Colostrum is the first milk produced post-partum by mammals and is compositionally distinct from mature milk. Bovine colostrum has a long history of consumption by humans, and there have been a number of studies investigating its potential for applications in human nutrition and health. Extensive characterization of the constituent fractions has identified a wealth of potentially bioactive molecules, their potential for shaping neonatal development, and the potential for their application beyond the neonatal period. Proteins, fats, glycans, minerals, and vitamins are abundant in colostrum, and advances in dairy processing technologies have enabled the advancement of bovine colostrum from relative limitations of a fresh and unprocessed food to a variety of potential applications. In these forms, clinical studies have examined bovine colostrum as having the substantial potential to improve human health. This review discusses the macro-and micronutrient composition of colostrum as well as describing well-characterized bioactives found in bovine colostrum and their potential for human health. Current gaps in knowledge are also identified and future directions are considered in order to elevate the potential for bovine colostrum as a component of a healthy diet for a variety of relevant human populations.
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Affiliation(s)
- Ayşenur Arslan
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Merve Kaplan
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Hatice Duman
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, Turkey
| | - Ayşe Bayraktar
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, Turkey
- Uluova Dairy, Canakkale, Turkey
| | | | - Bethany M. Henrick
- Evolve Biosystems, Inc. Davis, CA, United States
- Department of Food Science and Technology, University of Nebraska Lincoln, Lincoln, NE, United States
| | - Steven A. Frese
- Department of Food Science and Technology, University of Nebraska Lincoln, Lincoln, NE, United States
- Department of Nutrition, University of Nevada Reno, Reno, NV, United States
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, Turkey
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23
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Hecquet S, Totoson P, Martin H, Prati C, Wendling D, Demougeot C, Verhoeven F. Intestinal permeability in spondyloarthritis and rheumatoid arthritis: A systematic review of the literature. Semin Arthritis Rheum 2021; 51:712-718. [PMID: 34139524 DOI: 10.1016/j.semarthrit.2021.04.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To describe the current methods usable to assess intestinal permeability in spondyloarthritis (SpA) and rheumatoid arthritis (RA), to analyze the available data on intestinal permeability in SpA and RA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability. METHODS A systematic review was conducted. Medline, Embase, and Cochrane Library databases were searched. Studies published in the last 40 years (January 1980-September 2020) with patients with SpA and/or RA assessing the intestinal permeability were selected. RESULTS A total of 2916 articles were collected, after discarding 1125 duplicate articles, we analyzed the titles and abstracts of 1791 studies. There were 459 articles that met the inclusion criteria and whose text was read. A total of 23 studies were included in the final analysis. Sample sizes ranged from 6 to 206 participants. In patients with spondyloarthritis, a large majority of studies reported an increase in intestinal permeability regardless of the method used. No increase in intestinal permeability was found in RA patients compared to healthy subject in half of the studies. NSAID treatment does not appear to influence intestinal permeability in SpA and seems to increase the intestinal permeability in RA patients as much as in healthy subjects. CONCLUSION The results of our review suggest the existence of increased intestinal permeability in SpA patients even in the absence of NSAIDs use and regardless of the method assessing the intestinal permeability. Studies in RA patients are more controversial.
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Affiliation(s)
- Sophie Hecquet
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France; Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France
| | - Perle Totoson
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Hélène Martin
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Clément Prati
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France; Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France
| | - Daniel Wendling
- Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France; EA 4266 « Agents Pathogènes et Inflammation », EPILAB, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Céline Demougeot
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France.
| | - Frank Verhoeven
- PEPITE EA4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France; Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France
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24
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Zaiss MM, Joyce Wu HJ, Mauro D, Schett G, Ciccia F. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol 2021; 17:224-237. [PMID: 33674813 DOI: 10.1038/s41584-021-00585-3] [Citation(s) in RCA: 204] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.
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Affiliation(s)
- Mario M Zaiss
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Hsin-Jung Joyce Wu
- Department of Immunobiology, Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Daniele Mauro
- Dipartimento di Medicina di Precisione, University della Campania L. Vanvitelli, Naples, Italy
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.,Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Francesco Ciccia
- Dipartimento di Medicina di Precisione, University della Campania L. Vanvitelli, Naples, Italy.
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25
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Silva AR, Bernardo MA, Mesquita MF, Vaz Patto J, Moreira P, Padrão P, Silva ML. Dysbiosis, Small Intestinal Bacterial Overgrowth, and Chronic Diseases. ADVANCES IN MEDICAL DIAGNOSIS, TREATMENT, AND CARE 2021:334-362. [DOI: 10.4018/978-1-7998-4808-0.ch015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Dysbiosis is characterized by an alteration in quantity and quality of intestinal microbiota composition. In the presence of dysbiosis, enterocytes will have difficulty in maintaining the integrity of the mucosal barrier, leading to increased intestinal permeability. These events are recognised to be linked to several chronic diseases. One of the consequences of dysbiosis is the manifestation of small intestinal bacterial overgrowth (SIBO), which is associated to a variety of chronic diseases. Single food nutrients and bioactive molecules, food additives, pre- and probiotics, and different dietary patterns may change the composition of the intestinal microbiota. Low FODMAPs diet has been a reference in SIBO treatment. This chapter intends to describe how the intestinal microbiota, dysbiosis, and SIBO can be related; to define dysbiosis food and nutrients influence; and to offer some nutritional therapy strategies for applying the low FODMAPs protocol, enabling better adherence by patients in order to increase their wellbeing.
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Affiliation(s)
- Ana Rita Silva
- Centro de Investigação Interdisciplinar Egas Moniz, Portugal
| | | | | | | | - Pedro Moreira
- Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Portugal
| | - Patrícia Padrão
- Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Portugal
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26
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Mitchell JA, Kirkby NS, Ahmetaj-Shala B, Armstrong PC, Crescente M, Ferreira P, Lopes Pires ME, Vaja R, Warner TD. Cyclooxygenases and the cardiovascular system. Pharmacol Ther 2021; 217:107624. [DOI: 10.1016/j.pharmthera.2020.107624] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
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Oxidative and/or Inflammatory Thrust Induced by Silver Nanoparticles in Rabbits: Effect of Vitamin E or NSAID Administration on Semen Parameters. Mediators Inflamm 2020; 2020:6664062. [PMID: 33424436 PMCID: PMC7781726 DOI: 10.1155/2020/6664062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 11/18/2022] Open
Abstract
The aim of this research was to evaluate the inflammatory and/or oxidative damage related to silver nanoparticles (AgNPs), which are responsible for negative effects on sperm physiology and metabolism. Thirty New Zealand White rabbit bucks were divided into 5 experimental groups (6 animals/group): Control, treated with 0.9% NaCl; AgNP, treated with a 5 mM AgNP solution; LPS, treated with 50 g/kg b.w. E. coli LPS; AgNPs + NSAID, treated with an anti-inflammatory drug at 0.2 mg/kg b.w. and 5 mM AgNPs; and AgNPs + Vit E, treated with 0.18 mg/kg b.w. vitamin E and 5 mM AgNPs. Sperm quality and oxidative and inflammatory status were assessed at different times (0-60 days). Two statistical models were built: the first evaluated the effects of AgNPs and LPS (vs. Control), whereas the second evaluated the protective effect of an NSAID and vitamin E against AgNP-induced damage. Three principal component analyses were performed: sperm traits (motility, volume), oxidative status (antioxidants, oxidative metabolites, and redox reactions), and cytokines (TNF-α, IL-8, and IL-6). A negative effect on reproductive traits resulted after NP administration. In particular, an inflammatory/oxidative response took place in the reproductive tract during the first 2-3 wks of AgNP administration (cytokine and oxidative metabolite generation); the inflammatory/oxidative thrust impaired the status of rabbit tissues (seminal plasma, sperm, and blood), inducing a response (increased antioxidant enzymes and redox reactions) at 4-7 wks; oxidative stress, if not totally counteracted, likely induced toxicity in the late phases of AgNP administration (8-9 wks). In conclusion, exposure to silver nanoparticles produced a similar but more persistent effect than that of LPS on rabbit reproductive tissues: AgNP administration triggered a proinflammatory response linked to oxidative thrust, worsening many sperm parameters. However, only anti-inflammatory treatment counteracted the negative effects of AgNPs, whereas vitamin E seemed to act as an adjuvant, attenuating the oxidative cascade.
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28
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New R. Oral Delivery of Biologics via the Intestine. Pharmaceutics 2020; 13:E18. [PMID: 33374222 PMCID: PMC7824380 DOI: 10.3390/pharmaceutics13010018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/17/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023] Open
Abstract
Biologics are currently one of the most promising avenues for therapeutic interventions in conditions such as metabolic disease, ageing and inflammatory disorders, and for chronic ailments, oral delivery of such medicines has for years been recognised as an important goal. Despite decades of intensive research, oral delivery of biologics is only just starting to prove feasible. There has been much talk about the barriers to uptake of biologics, and indeed, one function of the intestine is to prevent, in one way or another, passage of unwanted materials across the gut, and yet, grams of biological agents both large and small pass across the intestinal cell wall every day. This review first describes the functioning of the gut under normal circumstances, then identifies the principle biological mechanisms which have been harnessed successfully, to date, to achieve oral uptake, outlining the pros and cons of each approach. Examples with different biologics are given, and information on result of the latest clinical trials is provided, where available.
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Affiliation(s)
- Roger New
- Proxima Concepts Ltd., London NW1 0NH, UK;
- Faculty of Science and Technology, Middlesex University, London NW4 4BT, UK
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29
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Therapeutic and Preventive Effects of Olea europaea Extract on Indomethacin-Induced Small Intestinal Injury Model in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6669813. [PMID: 33424990 PMCID: PMC7773470 DOI: 10.1155/2020/6669813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 12/18/2022]
Abstract
Background Olea europaea (known as olive fruit) has anti-inflammatory and antioxidant activities and many potential health benefits including gastric inflammation reduction has been shown previously. This study aimed to investigate the preventive and therapeutic effects of O. europaea extract on the early histological changes in indomethacin-induced small intestinal injury model with the plasma D-lactate concentration being measured as a tool for determination of intestinal permeability. Methods In this experimental study, two separate protective and therapeutic protocols were designed. In both experiments, male Wistar rats were randomly divided into 4 groups and either pretreated with 0, 100, 200, or 400 mg/kg/day of O. europaea extract or received the treatment after administration of indomethacin. Their small intestines were examined to compare the histological changes. The intestinal injury severity was evaluated according to the presence of eosinophils, plasma cell infiltration, edema, congestion, and hyperplasia of the crypt using a histological scoring system. Also, measured were the presence of neutrophils, decreased villus length-to-crypt depth ratio, and destructed villus architecture. The plasma concentration of D-lactate was measured as well. Results The therapeutic use of O. europaea decreased the eosinophil, edema, congestion, and crypt hyperplasia scores compared to the control group. Although no significant difference was seen between groups of the preventive experiment in plasma cell infiltration score, villus length-to-crypt depth ratio, neutrophil infiltration, and percentage of destructed villus architecture, treatment with O. europaea caused a reduction in edema, eosinophil, congestion, and crypt hyperplasia score. In both experiments, no significant difference was seen between groups for villus length-to-crypt depth ratio, neutrophil infiltration, and percentage of destructed villus architecture. Plasma D-lactate concentration was decreased in all O. europaea-treated groups compared to the control group in the therapeutic and preventive experiments (p < 0.01, one-way ANOVA followed by the Dunnett test). Conclusion O. europaea extract can be used to decrease some side effects of indomethacin on intestinal tissue and enhances the gastrointestinal function. O. europaea extract could be considered as a potential herbal supplement in the treatment of intestinal morphological injuries.
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30
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Cheudjeu A. Correlation of D-xylose with severity and morbidity-related factors of COVID-19 and possible therapeutic use of D-xylose and antibiotics for COVID-19. Life Sci 2020; 260:118335. [PMID: 32846167 PMCID: PMC7443215 DOI: 10.1016/j.lfs.2020.118335] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 01/08/2023]
Abstract
The SARS-Cov-2 pandemic that currently affects the entire world has been shown to be especially dangerous in the elderly (≥65 years) and in smokers, with notably strong comorbidity in patients already suffering from chronic diseases, such as Type 2 diabetes, cancers, chronic respiratory diseases, obesity, and hypertension. Inflammation of the lungs is the main factor leading to respiratory distress in patients with chronic respiratory disease and in patients with severe COVID-19. Several studies have shown that inflammation of the lungs in general and Type 2 diabetes are accompanied by the degradation of glycosaminoglycans (GAGs), especially heparan sulfate (HS). Several studies have also shown the importance of countering the degradation of HS in lung infections and Type 2 diabetes. D-xylose, which is the initiating element for different sulfate GAG chains (especially HS), has shown regeneration properties for GAGs. D-xylose and xylitol have demonstrated anti-inflammatory, antiglycemic, antiviral, and antibacterial properties in lung infections, alone or in combination with antibiotics. Considering the existing research on COVID-19 and related to D-xylose/xylitol, this review offers a perspective on why the association between D-xylose and antibiotics may contribute to significantly reducing the duration of treatment of COVID-19 patients and why some anti-inflammatory drugs may increase the severity of COVID-19. A strong correlation with scurvy, based on gender, age, ethnicity, smoking status, and obesity status, is also reviewed. Related to this, the effects of treatment with plants such as Artemisia are also addressed. CHEMICAL COMPOUNDS: D-xylose; xylitol; l-ascorbic Acid; D-glucuronic acid; N-acetylglucosamine; D-N-acetylglucosamine; N-acetylgalactosamine; galactose.
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31
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Wu WK, Ivanova EA, Orekhov AN. Gut microbiome: A possible common therapeutic target for treatment of atherosclerosis and cancer. Semin Cancer Biol 2020; 70:85-97. [PMID: 32610150 DOI: 10.1016/j.semcancer.2020.06.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023]
Abstract
Human gut microbiota is a dynamic and variable system that can change over time and in response to different diets and treatments. There is currently no doubt that gut microbiota can provide interesting therapeutic opportunities, since it can metabolize biologically active molecules, drugs, and their precursors, and control their bioavailability. Moreover, it can produce both beneficial and dangerous metabolites that influence host's health. In this review, we summarize the current knowledge on the involvement of gut microbiota in two chronic human pathologies that represent the greatest challenges of modern medicine: atherosclerosis and cancer. Interesting parallels are observed between the mechanisms and possible treatment approaches of these pathologies. Some of the common effects of therapeutic agents targeting both pathologies, such as anti-inflammatory activity, are partially mediated by the gut microbiota. We will discuss the effects of common drugs (metformin, statins and aspirin) and various nutraceuticals on gut microbiota and outline the pathways of microbial involvement in mediating the pleiotropic beneficial effects of these agents in atherosclerosis and cancer.
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Affiliation(s)
- Wei-Kai Wu
- Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | | | - Alexander N Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia; Institute of Human Morphology, 117418, Moscow, Russia.
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32
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Erdrich S, Hawrelak JA, Myers SP, Harnett JE. Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review. BMC Musculoskelet Disord 2020; 21:181. [PMID: 32192466 PMCID: PMC7083062 DOI: 10.1186/s12891-020-03201-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The association between fibromyalgia and irritable bowel syndrome is well-established. Alterations in the composition and diversity of the gut microbiome in irritable bowel syndrome have been reported, however, this association is poorly understood in fibromyalgia. Our aim was to summarise the research reporting on the gastrointestinal microbiome and its biomarkers in people with fibromyalgia. METHODS A systematic review of published original research reporting on the gastrointestinal microbiota and its biomarkers in adults with a diagnosis of fibromyalgia was undertaken. RESULTS From 4771 studies, 11 met our inclusion criteria and were separated into four main groups: papers reporting Helicobacter pylori; other gut bacterial markers; metabolomics and other biomarkers, which included intestinal permeability and small intestinal bacterial overgrowth. CONCLUSION The results suggest there is a paucity of quality research in this area, with indications that the gut microbiota may play a role in fibromyalgia within the emerging field of the gut-musculoskeletal axis. Further investigations into the relationship between the gut microbiota, gut dysfunction and fibromyalgia are warranted.
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Affiliation(s)
- Sharon Erdrich
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
| | - Jason A Hawrelak
- College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Stephen P Myers
- NatMed Research Unit, Division of Research, Southern Cross University, Lismore, New South Wales, Australia
| | - Joanna E Harnett
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia
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Maseda D, Ricciotti E. NSAID-Gut Microbiota Interactions. Front Pharmacol 2020; 11:1153. [PMID: 32848762 PMCID: PMC7426480 DOI: 10.3389/fphar.2020.01153] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAID)s relieve pain, inflammation, and fever by inhibiting the activity of cyclooxygenase isozymes (COX-1 and COX-2). Despite their clinical efficacy, NSAIDs can cause gastrointestinal (GI) and cardiovascular (CV) complications. Moreover, NSAID use is characterized by a remarkable individual variability in the extent of COX isozyme inhibition, therapeutic efficacy, and incidence of adverse effects. The interaction between the gut microbiota and host has emerged as a key player in modulating host physiology, gut microbiota-related disorders, and metabolism of xenobiotics. Indeed, host-gut microbiota dynamic interactions influence NSAID disposition, therapeutic efficacy, and toxicity. The gut microbiota can directly cause chemical modifications of the NSAID or can indirectly influence its absorption or metabolism by regulating host metabolic enzymes or processes, which may have consequences for drug pharmacokinetic and pharmacodynamic properties. NSAID itself can directly impact the composition and function of the gut microbiota or indirectly alter the physiological properties or functions of the host which may, in turn, precipitate in dysbiosis. Thus, the complex interconnectedness between host-gut microbiota and drug may contribute to the variability in NSAID response and ultimately influence the outcome of NSAID therapy. Herein, we review the interplay between host-gut microbiota and NSAID and its consequences for both drug efficacy and toxicity, mainly in the GI tract. In addition, we highlight progress towards microbiota-based intervention to reduce NSAID-induced enteropathy.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Emanuela Ricciotti,
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34
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Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 2019; 68:1516-1526. [PMID: 31076401 PMCID: PMC6790068 DOI: 10.1136/gutjnl-2019-318427] [Citation(s) in RCA: 628] [Impact Index Per Article: 104.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022]
Abstract
The objectives of this review on 'leaky gut' for clinicians are to discuss the components of the intestinal barrier, the diverse measurements of intestinal permeability, their perturbation in non-inflammatory 'stressed states' and the impact of treatment with dietary factors. Information on 'healthy' or 'leaky' gut in the public domain requires confirmation before endorsing dietary exclusions, replacement with non-irritating foods (such as fermented foods) or use of supplements to repair the damage. The intestinal barrier includes surface mucus, epithelial layer and immune defences. Epithelial permeability results from increased paracellular transport, apoptosis or transcellular permeability. Barrier function can be tested in vivo using orally administered probe molecules or in vitro using mucosal biopsies from humans, exposing the colonic mucosa from rats or mice or cell layers to extracts of colonic mucosa or stool from human patients. Assessment of intestinal barrier requires measurements beyond the epithelial layer. 'Stress' disorders such as endurance exercise, non-steroidal anti-inflammatory drugs administration, pregnancy and surfactants (such as bile acids and dietary factors such as emulsifiers) increase permeability. Dietary factors can reverse intestinal leakiness and mucosal damage in the 'stress' disorders. Whereas inflammatory or ulcerating intestinal diseases result in leaky gut, no such disease can be cured by simply normalising intestinal barrier function. It is still unproven that restoring barrier function can ameliorate clinical manifestations in GI or systemic diseases. Clinicians should be aware of the potential of barrier dysfunction in GI diseases and of the barrier as a target for future therapy.
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Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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35
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Camilleri M, Lyle BJ, Madsen KL, Sonnenburg J, Verbeke K, Wu GD. Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations. Am J Physiol Gastrointest Liver Physiol 2019; 317:G17-G39. [PMID: 31125257 PMCID: PMC6689735 DOI: 10.1152/ajpgi.00063.2019] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.
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Affiliation(s)
- Michael Camilleri
- 1Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Barbara J. Lyle
- 2International Life Sciences Institute North America, Washington, DC,3School of Professional Studies, Northwestern University, Evanston, Illinois
| | - Karen L. Madsen
- 4Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Justin Sonnenburg
- 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California
| | - Kristin Verbeke
- 6Translational Research in Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Gary D. Wu
- 7Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Scherf KA, Lindenau AC, Valentini L, Collado MC, García-Mantrana I, Christensen M, Tomsitz D, Kugler C, Biedermann T, Brockow K. Cofactors of wheat-dependent exercise-induced anaphylaxis do not increase highly individual gliadin absorption in healthy volunteers. Clin Transl Allergy 2019; 9:19. [PMID: 30962874 PMCID: PMC6432753 DOI: 10.1186/s13601-019-0260-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Background In wheat-dependent exercise-induced anaphylaxis (WDEIA), cofactors such as exercise, acetylsalicylic acid (ASA), alcohol or unfavorable climatic conditions are required to elicit a reaction to wheat products. The mechanism of action of these cofactors is unknown, but an increase of gliadin absorption has been speculated. Our objectives were to study gliadin absorption with and without cofactors and to correlate plasma gliadin levels with factors influencing protein absorption in healthy volunteers.
Methods Twelve healthy probands (six males, six females; aged 20–56 years) ingested 32 g of gluten without any cofactor or in combination with cofactors aerobic and anaerobic exercise, ASA, alcohol and pantoprazole. Gliadin serum levels were measured up to 120 min afterwards and the intestinal barrier function protein zonulin in stool was collected before and after the procedure; both were measured by ELISA. Stool microbiota profile was obtained by 16S gene sequencing.
Results Within 15 min after gluten intake, gliadin concentrations in blood serum increased from baseline in all subjects reaching highly variable peak levels after 15–90 min. Addition of cofactors did not lead to substantially higher gliadin levels, although variability of levels was higher with differences between individuals (p < 0.001) and increased levels at later time points. Zonulin levels in stool were associated neither with addition of cofactors nor with peak gliadin concentrations. There were no differences in gut microbiota between the different interventions, although the composition of microbiota (p < 0.001) and the redundancy discriminant analysis (p < 0.007) differed in probands with low versus high stool zonulin levels. Conclusion The adsorption of gliadin in the gut in healthy volunteers is less dependent on cofactors than has been hypothesized. Patients with WDEIA may have a predisposition needed for the additional effect of cofactors, e.g., hyperresponsive or damaged intestinal epithelium. Alternatively, other mechanisms, such as cofactor-induced blood flow redistribution, increased activity of tissue transglutaminase, or increases in plasma osmolality and acidosis inducing basophil and mast cell histamine release may play the major role in WDEIA.
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Affiliation(s)
- Katharina Anne Scherf
- 1Leibniz-Institute for Food Systems Biology, Technical University of Munich, Lise-Meitner-Strasse 34, 85354 Freising, Germany
| | - Ann-Christin Lindenau
- 2Department of Agriculture and Food Sciences, Section of Dietetics, University of Applied Sciences Neubrandenburg, Brodaer Str. 2, 17033 Neubrandenburg, Germany
| | - Luzia Valentini
- 2Department of Agriculture and Food Sciences, Section of Dietetics, University of Applied Sciences Neubrandenburg, Brodaer Str. 2, 17033 Neubrandenburg, Germany
| | - Maria Carmen Collado
- 3Department of Biotechnology, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Av. Catedrático Agustín Escardino 7, 46980 Valencia, Spain
| | - Izaskun García-Mantrana
- 3Department of Biotechnology, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Av. Catedrático Agustín Escardino 7, 46980 Valencia, Spain
| | - Morten Christensen
- 4Department of Dermatology and Allergy Centre, Odense Research Center for Anaphylaxis (ORCA), Odense University Hospital, 5000 Odense, Denmark
| | - Dirk Tomsitz
- 5Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany
| | - Claudia Kugler
- 5Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany
| | - Tilo Biedermann
- 5Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany
| | - Knut Brockow
- 5Department of Dermatology and Allergy Biederstein, Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany
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Coates MD, Vrana KE, Ruiz-Velasco V. The influence of voltage-gated sodium channels on human gastrointestinal nociception. Neurogastroenterol Motil 2019; 31:e13460. [PMID: 30216585 DOI: 10.1111/nmo.13460] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 08/01/2018] [Accepted: 08/07/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Abdominal pain is a frequent and persistent problem in the most common gastrointestinal disorders, including irritable bowel syndrome and inflammatory bowel disease. Pain adversely impacts quality of life, incurs significant healthcare expenditures, and remains a challenging issue to manage with few safe therapeutic options currently available. It is imperative that new methods are developed for identifying and treating this symptom. A variety of peripherally active neuroendocrine signaling elements have the capability to influence gastrointestinal pain perception. A large and growing body of evidence suggests that voltage-gated sodium channels (VGSCs) play a critical role in the development and modulation of nociceptive signaling associated with the gut. Several VGSC isoforms demonstrate significant promise as potential targets for improved diagnosis and treatment of gut-based disorders associated with hyper- and hyposensitivity to abdominal pain. PURPOSE In this article, we critically review key investigations that have evaluated the potential role that VGSCs play in visceral nociception and discuss recent advances related to this topic. Specifically, we discuss the following: (a) what is known about the structure and basic function of VGSCs, (b) the role that each VGSC plays in gut nociception, particularly as it relates to human physiology, and (c) potential diagnostic and therapeutic uses of VGSCs to manage disorders associated with chronic abdominal pain.
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Affiliation(s)
- Matthew D Coates
- Division of Gastroenterology & Hepatology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania
| | - Kent E Vrana
- Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania
| | - Victor Ruiz-Velasco
- Department of Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, Pennsylvania
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Shimada S, Tanigawa T, Watanabe T, Nakata A, Sugimura N, Itani S, Higashimori A, Nadatani Y, Otani K, Taira K, Hosomi S, Nagami Y, Tanaka F, Kamata N, Yamagami H, Shiba M, Fujiwara Y. Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage. PLoS One 2019; 14:e0211436. [PMID: 30785904 PMCID: PMC6382145 DOI: 10.1371/journal.pone.0211436] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/14/2019] [Indexed: 12/15/2022] Open
Abstract
Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.
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Affiliation(s)
- Sunao Shimada
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
- SAMURAI GI Research Centre, Osaka City University Graduate School of Medicine, Osaka, Japan
- * E-mail:
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
- SAMURAI GI Research Centre, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akinobu Nakata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Naoki Sugimura
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shigehiro Itani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akira Higashimori
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
- SAMURAI GI Research Centre, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hirokazu Yamagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masatsugu Shiba
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
- SAMURAI GI Research Centre, Osaka City University Graduate School of Medicine, Osaka, Japan
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Sandborn WJ, Bhandari BR, Randall C, Younes ZH, Romanczyk T, Xin Y, Wendt E, Chai H, McKevitt M, Zhao S, Sundy JS, Keshav S, Danese S. Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease. J Crohns Colitis 2018; 12:1021-1029. [PMID: 29767728 PMCID: PMC6113706 DOI: 10.1093/ecco-jcc/jjy049] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/09/2018] [Accepted: 05/13/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIMS Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. METHODS Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. RESULTS Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. CONCLUSIONS Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.
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Affiliation(s)
- William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,Corresponding author: William J. Sandborn, Professor of Medicine and Adjunct Professor of Surgery; Chief, Division of Gastroenterology; Vice Chair for Clinical Operations, Department of Medicine; Director, UCSD IBD Center, 9500 Gilman Drive, MC 0956, La Jolla, CA 92093, USA. Tel.: [858] 657-5331; fax [858] 657-5022;
| | | | - Charles Randall
- Gastroenterology Research America and University of Texas, San Antonio, TX, USA
| | | | | | - Yan Xin
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Hao Chai
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Sally Zhao
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Satish Keshav
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Silvio Danese
- Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Rozzano, Italy
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Alves TFR, Barros CT, Baldo D, Amaral VA, Sever M, Santos C, Severino P, Chaud MV. Preparation, Characterization and ex vivo Intestinal Permeability Studies of Ibuprofen Solid Dispersion. J DISPER SCI TECHNOL 2018. [DOI: 10.1080/01932691.2018.1472014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
| | - Cecília Torqueti Barros
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
| | - Denicezar Baldo
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
| | - Venâncio Alves Amaral
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
| | - Mirella Sever
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
| | - Carolina Santos
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
| | | | - Marco Vinicius Chaud
- Laboratory of Biomaterials and Nanotechnology, Univerity of Sorocaba, Sorocaba, São Paulo, Brazil
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Endoscopic and Pathologic Resolution of Chronic Nonsteroidal Anti-Inflammatory Drug-Induced Diaphragm-Like Colonic Strictures and Ulceration. Case Rep Gastrointest Med 2018; 2018:7824081. [PMID: 29955401 PMCID: PMC6000850 DOI: 10.1155/2018/7824081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 04/19/2018] [Indexed: 11/17/2022] Open
Abstract
The chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) has steadily increased and, as a result, adverse effects have become more common. Isolated case reports have documented diaphragm-like colonic strictures and ulceration as the result of NSAID use. We report a unique case of this rare side effect with documented endoscopic and histologic healing of multiple proximal diaphragm-like colonic strictures and ulceration months after simple discontinuation of NSAID therapy.
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Jia L, Chopp M, Wang L, Lu X, Szalad A, Zhang ZG. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy. FASEB J 2018; 32:fj201800597R. [PMID: 29932869 PMCID: PMC6219828 DOI: 10.1096/fj.201800597r] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/12/2018] [Indexed: 02/07/2023]
Abstract
Schwann cells actively interact with axons of dorsal root ganglia (DRG) neurons. Exosomes mediate intercellular communication by transferring their biomaterials, including microRNAs (miRs) into recipient cells. We hypothesized that exosomes derived from Schwann cells stimulated by high glucose (HG) exosomes accelerate development of diabetic peripheral neuropathy and that exosomal cargo miRs contribute to this process. We found that HG exosomes contained high levels of miR-28, -31a, and -130a compared to exosomes derived from non-HG-stimulated Schwann cells. In vitro, treatment of distal axons with HG exosomes resulted in reduction of axonal growth, which was associated with elevation of miR-28, -31a, and -130a and reduction of their target proteins of DNA methyltransferase-3α, NUMB (an endocytic adaptor protein), synaptosome associated protein 25, and growth-associated protein-43 in axons. In vivo, administration of HG exosomes to sciatic nerves of diabetic db/db mice at 7 wk of age promoted occurrence of peripheral neuropathy characterized by impairment of nerve conduction velocity and induction of mechanic and thermal hypoesthesia, which was associated with substantial decreases in intraepidermal nerve fibers. Our findings demonstrate a functional role of exosomes derived from HG-stimulated Schwann cells in mediating development of diabetic peripheral neuropathy.-Jia, L., Chopp, M., Wang, L., Lu, X., Szalad, A., Zhang, Z. G. Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy.
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Affiliation(s)
- Longfei Jia
- Inovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
- Department of Physics, Oakland University, Rochester, Michigan, USA
| | - Lei Wang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Xuerong Lu
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Alexandra Szalad
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA; and
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Edogawa S, Peters SA, Jenkins GD, Gurunathan SV, Sundt WJ, Johnson S, Lennon RJ, Dyer RB, Camilleri M, Kashyap PC, Farrugia G, Chen J, Singh RJ, Grover M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota. FASEB J 2018; 32:fj201800560R. [PMID: 29897814 PMCID: PMC6219825 DOI: 10.1096/fj.201800560r] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022]
Abstract
Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was to determine sex-based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty-three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex-specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex-based differences in intestinal barrier function and microbiome should be considered in future studies.-Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota.
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Affiliation(s)
- Shoko Edogawa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephanie A. Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory D. Jenkins
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Wendy J. Sundt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephen Johnson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryan J. Lennon
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Roy B. Dyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Purna C. Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jun Chen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravinder J. Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Grattagliano I, Ubaldi E, Portincasa P. Drug-induced enterocolitis: Prevention and management in primary care. J Dig Dis 2018; 19:127-135. [PMID: 29417737 DOI: 10.1111/1751-2980.12585] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/11/2022]
Abstract
Drug-induced enterocolitis is a condition diagnosed with increasing frequency. It includes a variety of morphological and functional alterations of the small and large intestine as a consequence of exposure to pharmacological active compounds. A number of factors play a key role in this condition or participate in the onset of enterocolitis, which is the result of an interplay between the effect of the drug molecule and the tolerance of the bowel to damaging insults. The patient's age, gender, dose of drug, time of exposure, pharmaceutical preparation, drug-drug and drug-food interactions, gut barrier integrity, underlying intestinal conditions, and gut microbiota composition are all involved in the occurrence and extent of the injury. This review approaches the topic from the viewpoint of primary care, and focuses on epidemiology, mechanisms of damage, protective systems and diagnostic tools. Although the first-line therapeutic measure is the discontinuation of the drug, some options for prevention and treatment are discussed.
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Affiliation(s)
| | - Enzo Ubaldi
- Italian College of General Practitioners and Primary Care, Florence, Italy
| | - Piero Portincasa
- Division of Internal Medicine, Clinica Medica "A. Murri", Department of Biomedical Sciences & Human Oncology, University Medical School of Bari, Bari, Italy
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Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. Gastroenterology 2018; 154:500-514. [PMID: 29221664 DOI: 10.1053/j.gastro.2017.10.049] [Citation(s) in RCA: 297] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.
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Affiliation(s)
- Ingvar Bjarnason
- Department of Gastroenterology, King's College Hospital, London, United Kingdom.
| | - Carmelo Scarpignato
- Department of Clinical and Experimental Medicine, University of Parma, Italy
| | - Erik Holmgren
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Michael Olszewski
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Kim D Rainsford
- Biomedical Sciences, Biomedical Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
| | - Angel Lanas
- Department of Gastroenterology, University of Zaragoza School of Medicine, IIS Aragón, CIBERehd, Zaragoza, Spain
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Bhatt AP, Gunasekara DB, Speer J, Reed MI, Peña AN, Midkiff BR, Magness ST, Bultman SJ, Allbritton NL, Redinbo MR. Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells. ACS Infect Dis 2018; 4:46-52. [PMID: 29094594 DOI: 10.1021/acsinfecdis.7b00139] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The intestinal epithelium provides a critical barrier that separates the gut microbiota from host tissues. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious analgesics and antipyretics and are among the most frequently used drugs worldwide. In addition to gastric damage, NSAIDs are toxic to the intestinal epithelium, causing erosions, perforations, and longitudinal ulcers in the gut. Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment. We found that physiologically relevant doses of the NSAID diclofenac (DCF) are cytotoxic because they uncouple mitochondrial oxidative phosphorylation and generate reactive oxygen species. We also find that DCF induces intestinal barrier permeability, facilitating the translocation of compounds from the luminal to the basolateral side of the intestinal epithelium. The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions.
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Affiliation(s)
- Aadra P. Bhatt
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
| | - Dulan B. Gunasekara
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
| | - Jennifer Speer
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
| | - Mark I. Reed
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
| | - Alexis N. Peña
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
| | - Bentley R. Midkiff
- Translational Pathology Laboratory, Lineberger
Comprehensive Cancer Center, University of North Carolina, 160
North Medical Drive, Chapel Hill, North Carolina 27599-7525, United States
| | - Scott T. Magness
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, United States, and North Carolina State University, Raleigh, North Carolina 27607, United States
- Departments of Medicine, Cell Biology and
Physiology, University of North Carolina, 111 Mason Farm Road, Chapel Hill, North Carolina 27599-7032, United States
| | - Scott J. Bultman
- Department of Genetics, University of North Carolina, 120 Mason Farm Road, Chapel
Hill, North Carolina 27599-7264, United States
- Lineberger
Comprehensive Cancer Center, University of North Carolina, 450
West Drive, Chapel Hill, North Carolina 27599, United States
| | - Nancy L. Allbritton
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, United States, and North Carolina State University, Raleigh, North Carolina 27607, United States
- Lineberger
Comprehensive Cancer Center, University of North Carolina, 450
West Drive, Chapel Hill, North Carolina 27599, United States
| | - Matthew R. Redinbo
- Department of Chemistry, University of North Carolina, 250 Bell Tower Drive, Chapel
Hill, North Carolina 27599-3290, United States
- Lineberger
Comprehensive Cancer Center, University of North Carolina, 450
West Drive, Chapel Hill, North Carolina 27599, United States
- Departments of Biochemistry and Biophysics,
and Microbiology and Immunology, and the Integrated Program for Biological
and Genome Science, University of North Carolina, 250 Bell Tower
Drive, Chapel Hill, North
Carolina 27599-3290, United States
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Abstract
The rapidly declining prevalence of Helicobacter pylori infection and widespread use of potent anti-secretory drugs means peptic ulcer disease has become substantially less prevalent than it was two decades ago. Management has, however, become more challenging than ever because of the threat of increasing antimicrobial resistance worldwide and widespread use of complex anti-thrombotic therapy in the ageing population. Peptic ulcers not associated with H pylori infection or the use of non-steroidal anti-inflammatory drugs are now also imposing substantial diagnostic and therapeutic challenges. This Seminar aims to provide a balanced overview of the latest advances in the pathogenetic mechanisms of peptic ulcers, guidelines on therapies targeting H pylori infection, approaches to treatment of peptic ulcer complications associated with anti-inflammatory analgesics and anti-thrombotic agents, and the unmet needs in terms of our knowledge and management of this increasingly challenging condition.
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Affiliation(s)
- Angel Lanas
- Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, University of Zaragoza, IIS Aragón, CIBEREHD, Zaragoza, Spain.
| | - Francis K L Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
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48
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Chitul A, Voiosu AM, Marinescu M, Caraiola S, Nicolau A, Badea GC, Pârvu MI, Ionescu RA, Mateescu BR, Voiosu MR, Băicuş CR, Rimbaş M. Different effects of anti-TNF-alpha biologic drugs on the small bowel macroscopic inflammation in patients with ankylosing spondylitis. ACTA ACUST UNITED AC 2017; 55:44-52. [PMID: 28103201 DOI: 10.1515/rjim-2017-0001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Considering the ability of anti-TNF alpha drugs to lower the burden intestinal inflammation in patients with inflammatory bowel disease (IBD), and the similarity between IBD and ankylosing spondylitis (AS) regarding inflammatory intestinal involvement, we aimed to investigate the impact of anti-TNF alpha biologic therapy on subclinical intestinal inflammation in AS patients. METHODS Between January 2008 and December 2013, 38 AS patients and 23 controls were enrolled in the study and investigated with small bowel videocapsule endoscopy examination and ileocolonoscopy. Each tertile of the small bowel (proximal, mid and distal) was assessed by calculating the Lewis score based on the image stream. RESULTS The Lewis scores were significantly higher in the AS group compared to controls (580.9 ± 818 vs. 81 ± 121, p<0.001). 16 patients (42.1%) were on anti-TNF alpha therapy (Adalimumab (n = 5), Infliximab (n = 5) or Etanercept (n = 6)).31.3% of them used NSAIDs simultaneously, compared with 77.3% of the other patients (p<0.01). Their Lewis scores were lower compared to the other patients for the entire small bowel (306 ± 164 vs. 790 ± 1038, p = 0.015), its proximal and distal tertiles (238 ± 154 vs. 560 ± 543, p = 0.021, and 140 ± 189 vs. 300 ± 220, p = 0.027, respectively). The Lewis score was also lower in patients receiving Adalimumab/Infliximab compared to those on Etanercept for the entire bowel and its distal tertile (262 ± 165 vs. 380 ± 148, p = 0.069 and 62 ± 101 vs. 273 ± 236, p = 0.060, respectively). CONCLUSION Anti-TNF alpha therapy in patients with AS reduces the subclinical intestinal inflammation, but the magnitude seems to depend upon the class anti-TNF alpha agent used (Clinical Trials. gov NCT00768950).
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49
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Audet GN, Dineen SM, Stewart DA, Plamper ML, Pathmasiri WW, McRitchie SL, Sumner SJ, Leon LR. Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke. J Appl Physiol (1985) 2017; 123:544-557. [PMID: 28596269 DOI: 10.1152/japplphysiol.00242.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/06/2017] [Accepted: 06/07/2017] [Indexed: 01/16/2023] Open
Abstract
It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (Tc) of male, C57BL/6J mice (n = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4°C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (Tc,Max)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to Tc,Max, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at Tc,Max, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury.NEW & NOTEWORTHY This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity.
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Affiliation(s)
- Gerald N Audet
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts;
| | - Shauna M Dineen
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Delisha A Stewart
- National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core, RTI International, Research Triangle Park, North Carolina; and
| | - Mark L Plamper
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Wimal W Pathmasiri
- National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core, RTI International, Research Triangle Park, North Carolina; and
| | - Susan L McRitchie
- National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core, RTI International, Research Triangle Park, North Carolina; and
| | - Susan J Sumner
- National Institutes of Health Eastern Regional Comprehensive Metabolomics Resource Core, University of North Carolina at Chapel Hill Nutrition Research Institute, Kannapolis, North Carolina
| | - Lisa R Leon
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
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50
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Joseph J, Depp C, Shih PAB, Cadenhead KS, Schmid-Schönbein G. Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Front Neurosci 2017; 11:155. [PMID: 28396623 PMCID: PMC5366345 DOI: 10.3389/fnins.2017.00155] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/10/2017] [Indexed: 12/14/2022] Open
Abstract
Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia.
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Affiliation(s)
- Jamie Joseph
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
| | - Colin Depp
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
- Department of Psychology, VA San Diego Healthcare SystemSan Diego, CA, USA
| | - Pei-an B. Shih
- Department of Psychiatry, University of CaliforniaSan Diego, La Jolla, CA, USA
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