|
1
|
Wan X, Wang L, Wang Z, Wan C. Toll-like receptor 4 plays a vital role in irritable bowel syndrome: a scoping review. Front Immunol 2024; 15:1490653. [PMID: 39749341 PMCID: PMC11693509 DOI: 10.3389/fimmu.2024.1490653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Background Irritable bowel syndrome (IBS) is a common gastrointestinal disease. Recently, an increasing number of studies have shown that Toll-like receptor 4 (TLR4), widely distributed on the surface of a variety of epithelial cells (ECs) and immune sentinel cells in the gut, plays a vital role in developing IBS. Objectives We sought to synthesize the existing literature on TLR4 in IBS and inform further study. Methods We conducted a systematic search of the PubMed, Embase (Ovid), Scopus, Web of Science, MEDLINE, and Cochrane Library databases on June 8, 2024, and screened relevant literature. Critical information was extracted, including clinical significance, relevant molecular mechanisms, and therapeutic approaches targeting TLR4 and its pathways. Results Clinical data showed that aberrant TLR4 expression is associated with clinical manifestations such as pain and diarrhea in IBS. Aberrant expression of TLR4 is involved in pathological processes such as intestinal inflammation, barrier damage, visceral sensitization, and dysbiosis, which may be related to TLR4, NF-κB, pro-inflammatory effects, and CRF. Several studies have shown that many promising therapeutic options (i.e., acupuncture, herbs, probiotics, hormones, etc.) have been able to improve intestinal inflammation, visceral sensitization, intestinal barrier function, intestinal flora, defecation abnormalities, and depression by inhibiting TLR4 expression and related pathways. Conclusion TLR4 plays a crucial role in the development of IBS. Many promising therapeutic approaches alleviate IBS through TLR4 and its pathways. Strategies for targeting TLR4 in the future may provide new ideas for treating IBS.
Collapse
Affiliation(s)
- Xuemeng Wan
- Department of Pediatrics, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China
- National Health Commission Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
| | - Liyuan Wang
- Department of Pediatrics, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China
| | - Zhiling Wang
- Department of Pediatrics, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China
- National Health Commission Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
| | - Chaomin Wan
- Department of Pediatrics, West China Second University Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China
- National Health Commission Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
| |
Collapse
|
|
2
|
Barbaro MR, Cremon C, Marasco G, Savarino E, Guglielmetti S, Bonomini F, Palombo M, Fuschi D, Rotondo L, Mantegazza G, Duncan R, di Sabatino A, Valente S, Pasquinelli G, Vergnolle N, Stanghellini V, Collins SM, Barbara G. Molecular Mechanisms Underlying Loss of Vascular and Epithelial Integrity in Irritable Bowel Syndrome. Gastroenterology 2024; 167:1152-1166. [PMID: 39004156 DOI: 10.1053/j.gastro.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND & AIMS The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and includes epithelial barrier dysfunction, a key element at the interface between the gut lumen and the deeper intestinal layers. Beneath the epithelial barrier there is the vascular one representing the last barrier to avoid luminal antigen dissemination The aims of this study were to correlate morpho-functional aspects of epithelial and vascular barriers with symptom perception in IBS. METHODS Seventy-eight healthy subjects (controls) and 223 patients with IBS were enrolled in the study and phenotyped according to validated questionnaires. Sugar test was used to evaluate in vivo permeability. Immunohistochemistry, western blot, and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing the mucosal expression of plasmalemma vesicle-associated protein-1 and vascular endothelial cadherin. Caco-2 or human umbilical vein endothelial cell monolayers were incubated with soluble mediators released by mucosal biopsies to highlight the mechanisms involved in permeability alteration. Correlation analyses have been performed among experimental and clinical data. RESULTS The intestinal epithelial barrier was compromised in patients with IBS throughout the gastrointestinal tract. IBS-soluble mediators increased Caco-2 permeability via a downregulation of tight junction gene expression. Blood vessel density and vascular permeability were increased in the IBS colonic mucosa. IBS mucosal mediators increased permeability in human umbilical vein endothelial cell monolayers through the activation of protease-activated receptor-2 and histone deacetylase 11, resulting in vascular endothelial cadherin downregulation. Permeability changes correlated with intestinal and behavioral symptoms and health-related quality of life of patients with IBS. CONCLUSIONS Epithelial and vascular barriers are compromised in patients with IBS and contribute to clinical manifestations.
Collapse
Affiliation(s)
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Marasco
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology, and Gastroenterology of the University of Padova, Padova, Italy
| | - Simone Guglielmetti
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Francesca Bonomini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Marta Palombo
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Daniele Fuschi
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Rotondo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giacomo Mantegazza
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Robin Duncan
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Antonio di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine 1, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Sabrina Valente
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Gianandrea Pasquinelli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, Univ Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Stephen M Collins
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| |
Collapse
|
|
3
|
Jiang P, Yu F, Zhou X, Shi H, He Q, Song X. Dissecting causal links between gut microbiota, inflammatory cytokines, and DLBCL: a Mendelian randomization study. Blood Adv 2024; 8:2268-2278. [PMID: 38507680 PMCID: PMC11117010 DOI: 10.1182/bloodadvances.2023012246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/05/2024] [Accepted: 02/29/2024] [Indexed: 03/22/2024] Open
Abstract
ABSTRACT Causal relationships between gut microbiota, inflammatory cytokines, and diffuse large B-cell lymphoma (DLBCL) remain elusive. In addressing this gap, our Mendelian randomization (MR) study used data from the MiBioGen consortium encompassing 211 microbiota taxa (n = 18 340), genome-wide association study meta-analyses of 47 inflammatory cytokines, and DLBCL cases and controls from the FinnGen consortium (cases, n = 1010; controls, n = 287 137). Through bidirectional MR analyses, we examined the causal links between gut microbiota and DLBCL and used mediation analyses, including 2-step MR and multivariable MR (MVMR), to identify potential mediating inflammatory cytokines. Our findings revealed that 4 microbiota taxa were causally associated with DLBCL, and conversely, DLBCL influenced the abundance of 20 taxa. Specifically, in the 2-step MR analysis, both the genus Ruminococcaceae UCG-002 (odds ratio [OR], 1.427; 95% confidence interval [CI], 1.011-2.015; P = .043) and the inflammatory cytokine monokine induced by gamma (MIG) (OR, 1.244; 95% CI, 1.034-1.487; P = .020) were found to be causally associated with an increased risk of DLBCL. Additionally, a positive association was observed between genus Ruminococcaceae UCG-002 and MIG (OR, 1.275; 95% CI, 1.069-1.520; P = .007). Furthermore, MVMR analysis indicated that the association between genus Ruminococcaceae UCG-002 and DLBCL was mediated by MIG, contributing to 14.9% of the effect (P = .005). In conclusion, our MR study provides evidence that supports the causal relationship between genus Ruminococcaceae UCG-002 and DLBCL, with a potential mediating role played by the inflammatory cytokine MIG.
Collapse
Affiliation(s)
- Peiyao Jiang
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangfang Yu
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Zhou
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huizhong Shi
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiaomei He
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xianmin Song
- Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
4
|
Chen Y, Feng S, Li Y, Zhang C, Chao G, Zhang S. Gut microbiota and intestinal immunity-A crosstalk in irritable bowel syndrome. Immunology 2024; 172:1-20. [PMID: 38174581 DOI: 10.1111/imm.13749] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Irritable bowel syndrome (IBS), one of the most prevalent functional gastrointestinal disorders, is characterized by recurrent abdominal pain and abnormal defecation habits, resulting in a severe healthcare burden worldwide. The pathophysiological mechanisms of IBS are multi-factorially involved, including food antigens, visceral hypersensitivity reactions, and the brain-gut axis. Numerous studies have found that gut microbiota and intestinal mucosal immunity play an important role in the development of IBS in crosstalk with multiple mechanisms. Therefore, based on existing evidence, this paper elaborates that the damage and activation of intestinal mucosal immunity and the disturbance of gut microbiota are closely related to the progression of IBS. Combined with the application prospect, it also provides references for further in-depth exploration and clinical practice.
Collapse
Affiliation(s)
- Yuxuan Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuyan Feng
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ying Li
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chi Zhang
- Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Guanqun Chao
- Department of General Practice, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, China
| | - Shuo Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
5
|
Monteiro CEDS, de Cerqueira Fiorio B, Silva FGO, de Fathima Felipe de Souza M, Franco ÁX, Lima MADS, Sales TMAL, Mendes TS, Havt A, Barbosa ALR, Resende ÂC, de Moura RS, de Souza MHLP, Soares PMG. A polyphenol-rich açaí seed extract protects against 5-fluorouracil-induced intestinal mucositis in mice through the TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway. Nutr Res 2024; 125:1-15. [PMID: 38428258 DOI: 10.1016/j.nutres.2024.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 03/03/2024]
Abstract
Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1β; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.
Collapse
Affiliation(s)
- Carlos Eduardo da Silva Monteiro
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Bárbara de Cerqueira Fiorio
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Francisca Géssica Oliveira Silva
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Maria de Fathima Felipe de Souza
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Álvaro Xavier Franco
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Marcos Aurélio de Sousa Lima
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Thiago Meneses Araujo Leite Sales
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Tiago Santos Mendes
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Alexandre Havt
- Laboratory of Molecular Toxinology, LTM, Federal University of Ceará, Fortaleza, CE, Brazil
| | - André Luiz Reis Barbosa
- LAFFEX- Laboratory of Experimental Physiopharmacology, Parnaiba Delta Federal University (UFDPAR), Parnaíba, PI, Brazil
| | - Ângela Castro Resende
- Department of Pharmacology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Roberto Soares de Moura
- Department of Pharmacology, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Pedro Marcos Gomes Soares
- LEFFAG- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
| |
Collapse
|
|
6
|
Imbrea AM, Balta I, Dumitrescu G, McCleery D, Pet I, Iancu T, Stef L, Corcionivoschi N, Liliana PC. Exploring the Contribution of Campylobacter jejuni to Post-Infectious Irritable Bowel Syndrome: A Literature Review. APPLIED SCIENCES 2024; 14:3373. [DOI: 10.3390/app14083373] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
This comprehensive review investigates the specific impact of the foodborne pathogen Campylobacter jejuni (C. jejuni) on gastrointestinal health, focusing on its connection to post-infectious irritable bowel syndrome (PI-IBS). This review examines the pathogen’s pathophysiology, clinical implications and epidemiological trends using recent research and data to highlight its prevalence and association with PI-IBS. A detailed literature analysis synthesizes current research to illuminate Campylobacter’s long-lasting effects on gut microbiota and intestinal function. It provides a detailed analysis of the literature to shed light on C. jejuni’s long-term impact on gut microbiota and intestinal function. The findings suggest the need for multifaceted prevention and treatment approaches considering individual, microbial and epidemiological factors, thus contributing to a more nuanced understanding of PI-IBS following C. jejuni infection.
Collapse
Affiliation(s)
- Ana-Maria Imbrea
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| | - Igori Balta
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| | - Gabi Dumitrescu
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| | - David McCleery
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast BT4 3SD, UK
| | - Ioan Pet
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| | - Tiberiu Iancu
- Faculty of Management and Rural Tourism, University of Life Sciences King Mihai I from Timisoara, 300645 Timisoara, Romania
| | - Lavinia Stef
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| | - Nicolae Corcionivoschi
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
- Bacteriology Branch, Veterinary Sciences Division, Agri-Food and Biosciences Institute, Belfast BT4 3SD, UK
- Academy of Romanian Scientists, Ilfov Street, No. 3, 050044 Bucharest, Romania
| | - Petculescu-Ciochina Liliana
- Faculty of Bioengineering of Animal Resources, University of Life Sciences King Michael I from Timisoara, 300645 Timisoara, Romania
| |
Collapse
|
|
7
|
Shah A, Lee YY, Suzuki H, Tan-Loh J, Siah KTH, Gwee KA, Fairlie T, Talley NJ, Ghoshal UC, Wang YP, Kim YS, Holtmann G. A pathophysiologic framework for the overlap of disorders of gut-brain interaction and the role of the gut microbiome. Gut Microbes 2024; 16:2413367. [PMID: 39482844 PMCID: PMC11540069 DOI: 10.1080/19490976.2024.2413367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/24/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Abstract
The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.
Collapse
Affiliation(s)
- Ayesha Shah
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Joash Tan-Loh
- Division of Gastroenterology Hepatology, Department of Internal Medicine, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Kok-Ann Gwee
- Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Thomas Fairlie
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| | - Nicholas J. Talley
- School of Medicine and Public Health, and Hunter Medical Research Institute, the University of Newcastle, Newcastle, Australia
| | - Uday C Ghoshal
- Institute of Gastrosciences & Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Yen-Po Wang
- Endoscopy centre for Diagnosis of Treatment, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yong Sung Kim
- Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea
- Good Breath Clinic, Gunpo, Korea
| | - Gerald Holtmann
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
| |
Collapse
|
|
8
|
Yuan Y, Wang X, Huang S, Wang H, Shen G. Low-level inflammation, immunity, and brain-gut axis in IBS: unraveling the complex relationships. Gut Microbes 2023; 15:2263209. [PMID: 37786296 PMCID: PMC10549202 DOI: 10.1080/19490976.2023.2263209] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023] Open
Abstract
Irritable bowel syndrome is a common functional gastrointestinal disorder, and it has been shown that the etiology of irritable bowel syndrome is a multifactorial complex of neurological, inflammatory, and immunological changes. There is growing evidence of low-grade chronic inflammation in irritable bowel patients. The peripheral action response of their intestinal immune factors is integrated into the central nervous system, while the microbiota interacts with the brain-gut axis contributing to the development of low-grade chronic inflammation. The objective of this review is to present a discussion about the impact of immune-brain-gut axis-inflammation interactions on irritable bowel syndrome, its clinical relevance in the course of irritable bowel syndrome disease, and possible therapeutic modalities.
Collapse
Affiliation(s)
- Yi Yuan
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Xiyang Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Shun Huang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Hao Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Guoming Shen
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
- Institute of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| |
Collapse
|
|
9
|
Liu XY, Wu SD. Fecal microbiota transplantation for treatment of irritable bowel syndrome: Current advances and future perspectives. Shijie Huaren Xiaohua Zazhi 2023; 31:922-932. [DOI: 10.11569/wcjd.v31.i22.922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/19/2023] [Indexed: 11/28/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a kind of functional gastroin-testinal disorder, characterized by recurrent abdominal pain and altered bowel habits. IBS adversely affects the quality of life of patients for the lack of effective treatment. The etiology of IBS remains poorly known. Previous studies suggested a possible role of gut dysbiosis in IBS pathogenesis. Fecal microbiota transplantation (FMT), which aims to reverse the gut dysbiosis, is a promising strategy in IBS management. In this review, we summarize the role of the gut microbiota in IBS pathogenesis from different aspects. We also review recent studies on efficacy evaluation of FMT in IBS. Besides, we discuss factors affecting the efficacy of FMT, hoping to provide a reference for future IBS treatment strategies targeting the gut microbiota.
Collapse
Affiliation(s)
- Xin-Yi Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Sheng-Di Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| |
Collapse
|
|
10
|
Marginean CM, Popescu M, Drocas AI, Cazacu SM, Mitrut R, Marginean IC, Iacob GA, Popescu MS, Docea AO, Mitrut P. Gut–Brain Axis, Microbiota and Probiotics—Current Knowledge on Their Role in Irritable Bowel Syndrome: A Review. GASTROINTESTINAL DISORDERS 2023; 5:517-535. [DOI: 10.3390/gidisord5040043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Irritable bowel syndrome (IBS) is a common digestive disorder with a significant impact on both individuals and society in terms of quality of life and healthcare costs. A growing body of research has identified various communication pathways between the microbiota and the brain in relation to motility disorders, with the gut–brain axis being key to the pathogenesis of IBS. Multiple factors contribute to the pathogenetic pathways in IBS, including immune mechanisms, psychosocial factors, increased oxidative stress and pro-inflammatory cytokine release, as well as genetic and hormonal factors. Increased permeability of the normal intestinal barrier allows bacterial products to access the lamina propria, providing a mechanism for perpetuating chronic inflammation and characteristic symptoms. The microbiota influences inflammatory processes in IBS by altering the balance between pro-inflammatory factors and host defence. Probiotics modulate the pathophysiological mechanisms involved in IBS by influencing the composition of the microbiota and improving intestinal motility disorders, visceral hypersensitivity, immune function of the intestinal epithelium, metabolic processes in the intestinal lumen, dysfunction of the microbiota-GBA, and are recognised as effective and safe in IBS therapy. Our study aimed to provide a comprehensive overview of the relationship between the gut–brain axis, microbiota, and IBS, based on current information.
Collapse
Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Andrei Ioan Drocas
- Department of Urology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Sergiu Marian Cazacu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitrut
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marian Sorin Popescu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitrut
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| |
Collapse
|
|
11
|
Napolitano M, Fasulo E, Ungaro F, Massimino L, Sinagra E, Danese S, Mandarino FV. Gut Dysbiosis in Irritable Bowel Syndrome: A Narrative Review on Correlation with Disease Subtypes and Novel Therapeutic Implications. Microorganisms 2023; 11:2369. [PMID: 37894027 PMCID: PMC10609453 DOI: 10.3390/microorganisms11102369] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. It can be subclassified in different subtypes according to the main clinical manifestation: constipation, diarrhea, mixed, and unclassified. Over the past decade, the role of gut microbiota in IBS has garnered significant attention in the scientific community. Emerging research spotlights the intricate involvement of microbiota dysbiosis in IBS pathogenesis. Studies have demonstrated reduced microbial diversity and stability and specific microbial alterations for each disease subgroup. Microbiota-targeted treatments, such as antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and even diet, offer exciting prospects for managing IBS. However, definitive conclusions are hindered by the heterogeneity of these studies. Further research should focus on elucidating the mechanisms, developing microbiome-based diagnostics, and enabling personalized therapies tailored to an individual's microbiome profile. This review takes a deep dive into the microscopic world inhabiting our guts, and its implications for IBS. Our aim is to elucidate the complex interplay between gut microbiota and each IBS subtype, exploring novel microbiota-targeted treatments and providing a comprehensive overview of the current state of knowledge.
Collapse
Affiliation(s)
- Maria Napolitano
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
| | - Ernesto Fasulo
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
| | - Federica Ungaro
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
- Division of Immunology, Transplantation and Infectious Disease, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Luca Massimino
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
- Division of Immunology, Transplantation and Infectious Disease, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Emanuele Sinagra
- Gastroenterology & Endoscopy Unit, Fondazione Istituto G. Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy;
| | - Silvio Danese
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Francesco Vito Mandarino
- Department of Gastroenterology and Gastrointestinal Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (E.F.); (F.U.); (L.M.); (S.D.); (F.V.M.)
| |
Collapse
|
|
12
|
Singh SV, Ganguly R, Jaiswal K, Yadav AK, Kumar R, Pandey AK. Molecular signalling during cross talk between gut brain axis regulation and progression of irritable bowel syndrome: A comprehensive review. World J Clin Cases 2023; 11:4458-4476. [PMID: 37469740 PMCID: PMC10353503 DOI: 10.12998/wjcc.v11.i19.4458] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 05/09/2023] [Accepted: 06/06/2023] [Indexed: 06/30/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder which alters gastrointestinal (GI) functions, thus leading to compromised health status. Pathophysiology of IBS is not fully understood, whereas abnormal gut brain axis (GBA) has been identified as a major etiological factor. Recent studies are suggestive for visceral hyper-sensitivity, altered gut motility and dysfunctional autonomous nervous system as the main clinical abnormalities in IBS patients. Bidirectional signalling interactions among these abnormalities are derived through various exogenous and endogenous factors, such as microbiota population and diversity, microbial metabolites, dietary uptake, and psychological abnormalities. Strategic efforts focused to study these interactions including probiotics, antibiotics and fecal transplantations in normal and germ-free animals are clearly suggestive for the pivotal role of gut microbiota in IBS etiology. Additionally, neurotransmitters act as communication tools between enteric microbiota and brain functions, where serotonin (5-hydroxytryptamine) plays a key role in pathophysiology of IBS. It regulates GI motility, pain sense and inflammatory responses particular to mucosal and brain activity. In the absence of a better understanding of various interconnected crosstalks in GBA, more scientific efforts are required in the search of novel and targeted therapies for the management of IBS. In this review, we have summarized the gut microbial composition, interconnected signalling pathways and their regulators, available therapeutics, and the gaps needed to fill for a better management of IBS.
Collapse
Affiliation(s)
- Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Risha Ganguly
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Kritika Jaiswal
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Aditya Kumar Yadav
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| |
Collapse
|
|
13
|
Bora G, Atkinson SN, Pan A, Sood M, Salzman N, Karrento K. Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: A pilot study. J Dig Dis 2023; 24:348-358. [PMID: 37448237 DOI: 10.1111/1751-2980.13203] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 05/07/2023] [Accepted: 07/11/2023] [Indexed: 07/15/2023]
Abstract
OBJECTIVES Percutaneous electrical nerve field stimulation (PENFS) has documented efficacy for irritable bowel syndrome (IBS) via plausible vagal neuromodulation effects. The vagus nerve may affect gut microbiome composition via brain-gut-microbiome signaling. We aimed to investigate gut microbiome alterations by PENFS therapy in adolescent IBS patients. METHODS A prospective study of females with IBS aged 11-18 years receiving PENFS therapy for 4 weeks with pre- and post-intervention stool sampling was conducted. Outcome surveys completed pre-therapy, weekly, and post-therapy included IBS-Severity Scoring System (IBS-SSS), Visceral Sensitivity Index (VSI), Functional Disability Inventory (FDI), and the global symptom response scale (SRS). Bacterial DNA was extracted from stool samples followed by 16S rRNA amplification and sequencing. QIIME 2 (version 2022.2) was used for analyses of α and β diversity and differential abundance by group. RESULTS Twenty females aged 15.6 ± 1.62 years were included. IBS-SSS, VSI, and FDI scores decreased significantly after PENFS therapy (P < 0.0001, P = 0.0003, P = 0.0004, respectively). No intra- or interindividual microbiome changes were noted pre- versus post-therapy or between responders and non-responders. When response was defined by 50-point IBS-SSS score reduction, α diversity was higher in responders compared with non-responders at week 4 (P = 0.033). There was higher abundance of Blautia in excellent responders versus non-responders. CONCLUSIONS There were no substantial microbial diversity alterations with PENFS. Subjects with excellent therapeutic response showed an enrichment of relative abundance of Blautia, which may indicate that patients with specific microbial signature have a more favorable response to PENFS.
Collapse
Affiliation(s)
- Geetanjali Bora
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Samantha N Atkinson
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Amy Pan
- Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Divison of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Manu Sood
- Division of Pediatric Gastroenterology, Department of Pediatrics, University of Illinois College of Medicine Peoria, Peoria, Illinois, USA
| | - Nita Salzman
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Katja Karrento
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
14
|
Zhao Y, Zou DW. Gut microbiota and irritable bowel syndrome. J Dig Dis 2023; 24:312-320. [PMID: 37458142 DOI: 10.1111/1751-2980.13204] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/11/2023] [Accepted: 07/13/2023] [Indexed: 07/18/2023]
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that poses a significant health concern. Although its etiology remains unknown, there is growing evidence that gut dysbiosis is involved in the development and exacerbation of IBS. Previous studies have reported altered microbial diversity, abundance, and composition in IBS patients when compared to controls. However, whether dysbiosis or aberrant changes in the intestinal microbiota can be used as a hallmark of IBS remains inconclusive. We reviewed the literatures on changes in and roles of intestinal microbiota in relation to IBS and discussed various gut microbiota manipulation strategies. Gut microbiota may affect IBS development by regulating the mucosal immune system, brain-gut-microbiome interaction, and intestinal barrier function. The advent of high-throughput multi-omics provides important insights into the pathogenesis of IBS and promotes the development of individualized treatment for IBS. Despite advances in currently available microbiota-directed therapies, large-scale, well-organized, and long-term randomized controlled trials are highly warranted to assess their clinical effects. Overall, gut microbiota alterations play a critical role in the pathophysiology of IBS, and modulation of microbiota has a significant therapeutic potential that requires to be further verified.
Collapse
Affiliation(s)
- Ye Zhao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duo Wu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
15
|
Ghoshal UC, Sachdeva S, Pratap N, Karyampudi A, Mustafa U, Abraham P, Bhatt CB, Chakravartty K, Chaudhuri S, Goyal O, Makharia GK, Panigrahi MK, Parida PK, Patwari S, Sainani R, Sadasivan S, Srinivas M, Upadhyay R, Venkataraman J. Indian consensus statements on irritable bowel syndrome in adults: A guideline by the Indian Neurogastroenterology and Motility Association and jointly supported by the Indian Society of Gastroenterology. Indian J Gastroenterol 2023; 42:249-273. [PMID: 36961659 PMCID: PMC10036984 DOI: 10.1007/s12664-022-01333-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 03/25/2023]
Abstract
The Indian Neurogastroenterology and Motility Association (INMA), earlier named the Indian Motility and Functional Diseases Association developed this evidence-based practice guidelines for the management of irritable bowel syndrome (IBS). A modified Delphi process was used to develop this consensus containing 28 statements, which were concerning diagnostic criteria, epidemiology, etiopathogenesis and comorbidities, investigations, lifestyle modifications and treatments. Owing to the Coronavirus disease-19 (COVID-19) pandemic, lockdowns and mobility restrictions, web-based meetings and electronic voting were the major tools used to develop this consensus. A statement was regarded as accepted when the sum of "completely accepted" and "accepted with minor reservation" voted responses were 80% or higher. Finally, the consensus was achieved on all 28 statements. The consensus team members are of the view that this work may find use in teaching, patient care, and research on IBS in India and other nations.
Collapse
Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India.
| | - Sanjeev Sachdeva
- Department of Gastroenterology, GB Pant Hospital, New Delhi, 110 002, India
| | - Nitesh Pratap
- Department of Gastroenterology, KIMS Hospital, Secunderabad, 500 003, India
| | - Arun Karyampudi
- Department of Gastroenterology, GSL Medical College and General Hospital, Rajahmundry , 533 296, India
| | - Uzma Mustafa
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Philip Abraham
- Department of Gastroenterology, P. D. Hinduja Hospital, Mumbai, 400 016, India
| | - Chetan B Bhatt
- Sir HN Reliance Foundation Hospital, Mumbai, 400 004, India
| | - Karmabir Chakravartty
- Department of Gastroenterology, Woodland Multispeciality Hospital, Kolkata, 700 027, India
| | - Sujit Chaudhuri
- Department of Gastroenterology, AMRI Hospitals, Salt Lake, Kolkata, 700 098, India
| | - Omesh Goyal
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, 141 001, India
| | - Govind K Makharia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Manas Kumar Panigrahi
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, 751 019, India
| | - Prasanta Kumar Parida
- Department of Gastroenterology, SCB Medical College and Hospital, Cuttack, 753 001, India
| | | | - Rajesh Sainani
- Department of Gastroenterology, Jaslok Hospital, Mumbai, 400 026, India
| | - Shine Sadasivan
- Department of Gastroenterology, Amrita Institute of Medical Sciences, Kochi, 682 041, India
| | - M Srinivas
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, 600 100, India
| | - Rajesh Upadhyay
- Department of Gastroenterology, Max Superspeciality Hospital, New Delhi, 110 017, India
| | - Jayanthi Venkataraman
- Department of Gastroenterology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600 116, India
| |
Collapse
|
|
16
|
Wang X, Shao L, Hua H, Chen Y. Metabotropic glutamate receptor-8 relieves neonatal maternal separation-induced visceral hypersensitivity in rats by regulating expression of TNF-α. ANNALS OF TRANSLATIONAL MEDICINE 2023; 11:118. [PMID: 36819583 PMCID: PMC9929757 DOI: 10.21037/atm-22-6452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/07/2023] [Indexed: 02/03/2023]
Abstract
BACKGROUND Visceral hypersensitivity (VH) is one of the most common causes of irritable bowel syndrome (IBS). The anti-hyperalgesic effects of metabotropic glutamate receptor 8 (mGluR8) has been identified in the central nervous system (CNS). However, whether this receptor has a similar function in the gastrointestinal tract has not been well studied. The present study aimed to explore the role of this receptor in a visceral hypersensitivity-related IBS rat model. METHODS Neonatal rats were separated from their mothers for 3 hours daily from postnatal day 2 to day 14 to establish neonatal maternal separation (NMS) models. The mGluR8 agonist (S)-3,4-DCPG (10 mg/kg) and the mGluR8 antagonist (RS)-α- methylserine-O-phosphate (MSOP) (10 mg/kg) were used to examine the role of mGLuR8 in the NMS rats. The expression of mGluR8, related inflammatory factors, and inflammatory signal pathways were assessed in colon tissues. RESULTS Our data showed that mGluR8 expression was increased in the colonic mucosa of NMS rats compared to controls. In addition, selective activation of mGluR8 ameliorated visceral hypersensitivity, whereas antagonization of mGluR8 aggravated visceral hypersensitivity. Treatment with (S)-3,4-DCPG (10 mg/kg) reduced the expression of myeloperoxidase (MPO) in intestinal mucosa of NMS rats. Furthermore, activating mGluR8 reduced the expression of tumor necrosis factor-α (TNF-α), whereas antagonizing mGluR8 promoted that. The expressions of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) did not significantly change upon activation or antagonization of mGluR8 receptor. CONCLUSIONS The activation of mGluR8 receptor ameliorates visceral hypersensitivity in NMS rats, and the underlying mechanisms may be associated with the inhibition of TNF-α and the suppression of colonic inflammatory response.
Collapse
Affiliation(s)
- Xiaobo Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Limei Shao
- Department of Gastroenterology, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjun Hua
- Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, China
| | - Yanping Chen
- Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, China
| |
Collapse
|
|
17
|
Jahani-Sherafat S, Taghavi H, Asri N, Rezaei Tavirani M, Razzaghi Z, Rostami-Nejad M. The effectiveness of photobiomodulation therapy in modulation the gut microbiome dysbiosis related diseases. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2023; 16:386-393. [PMID: 38313351 PMCID: PMC10835098 DOI: 10.22037/ghfbb.v16i4.2687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/08/2023] [Indexed: 02/06/2024]
Abstract
Maintaining a healthy balance between commensal, and pathogenic bacteria within the gut microbiota is crucial for ensuring the overall health, and well-being of the host. In fact, by affecting innate, and adaptive immune responses, the gut microbiome plays a key role in maintaining intestinal homeostasis and barrier integrity. Dysbiosis is the loss of beneficial microorganisms and the growth of potentially hazardous microorganisms in a microbial community, which has been linked to numerous diseases. As the primary inducer of circadian rhythm, light can influence the human intestinal microbiome. Photobiomodulation therapy (PBMT), which is the use of red (630-700 nm), and near-infrared light (700 and 1200 nm), can stimulate healing, relieve pain, and reduce inflammation, and affect the circadian rhythm and gut microbiome beneficially. Our focus in this paper is on the effects of PBMT on gut microbiota, to provide an overview of how it can help control gut microbiota dysbiosis-related disorders.
Collapse
Affiliation(s)
- Somayeh Jahani-Sherafat
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hooman Taghavi
- Student Research Committee, School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Zahra Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
18
|
Zhou Y, Zhang F, Mao L, Feng T, Wang K, Xu M, Lv B, Wang X. Bifico relieves irritable bowel syndrome by regulating gut microbiota dysbiosis and inflammatory cytokines. Eur J Nutr 2023; 62:139-155. [PMID: 35918555 PMCID: PMC9899748 DOI: 10.1007/s00394-022-02958-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 07/08/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE Gut microbiota dysbiosis, a core pathophysiology of irritable bowel syndrome (IBS), is closely related to immunological and metabolic functions. Gut microbiota-based therapeutics have been recently explored in several studies. Bifico is a probiotic cocktail widely used in gastrointestinal disorders which relate to the imbalance of gut microbiota. However, the efficacy and potential mechanisms of Bifico treatment in IBS remains incompletely understood. METHODS Adopting a wrap restraint stress (WRS) -induced IBS mice model. Protective effect of Bifico in IBS mice was examined through abdominal withdrawal reflex (AWR) scores. 16S rDNA, 1H nuclear magnetic resonance (1H-NMR) and western blot assays were performed to analyze alterations of gut microbiota, microbiome metabolites and inflammatory cytokines, respectively. RESULTS Bifico could decrease intestinal visceral hypersensitivity. Although gut microbiota diversity did not increase, composition of gut microbiota was changed after treatment of Bifico, which were characterized by an increase of Proteobacteria phylum and Actinobacteria phylum, Muribaculum genus, Bifidobacterium genus and a decrease of Parabacteroides genus, Sutterella genus and Lactobacillus genus. Moreover, Bifico elevated the concentration of short-chain fatty acids (SCFAs) and reduced protein levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From further Spearman's correlation analysis, Bifidobacterium genus were positively correlated with SCFAs including propionate, butyrate, valerate and negatively correlated with IL-6 and TNF-α. CONCLUSION Bifico could alleviate symptoms of IBS mice through regulation of the gut microbiota, elevating production of SCFAs and reducing the colonic inflammatory response.
Collapse
Affiliation(s)
- Yanlin Zhou
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,grid.268505.c0000 0000 8744 8924The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Fan Zhang
- grid.268505.c0000 0000 8744 8924The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China ,grid.417400.60000 0004 1799 0055Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China
| | - Liqi Mao
- grid.411440.40000 0001 0238 8414Department of Gastroenterology, The First People’s Hospital of Huzhou, The First Affiliated Hospital of Huzhou Teachers College, Huzhou, 313000 Zhejiang China
| | - Tongfei Feng
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Kaijie Wang
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Maosheng Xu
- grid.417400.60000 0004 1799 0055Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China
| | - Bin Lv
- grid.417400.60000 0004 1799 0055Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310003 Zhejiang China ,Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| | - Xi Wang
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006 China
| |
Collapse
|
|
19
|
Chi ZC. Progress in research of low-grade inflammation in irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2022; 30:1051-1065. [DOI: 10.11569/wcjd.v30.i24.1051] [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] [Indexed: 12/27/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common intestinal disease with a prevalence of 10%-15%. However, its pathophysiology is still not completely clear, and it has long been considered as a functional disease. In recent years, it has been found that low-grade inflammation plays a pathogenic role in IBS. Studies have confirmed that there is persistent mucosal inflammation at the microscopic and molecular levels. This review discusses the evidence, role, and clinical relevance of mucosal inflammation in IBS. In addition to mucosal inflammation, neuroinflammation may lead to changes in neuroendocrine pathways and glucocorticoid receptor genes through the "gut-brain" axis, and thus cause IBS through proinflammatory phenotype and hypothalamic pituitary adrenal axis and 5-hydroxytryptamine dysfunction. The observation that IBS patients can benefit from anti-inflammatory therapy also confirms that IBS is associated with inflammation.
Collapse
Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| |
Collapse
|
|
20
|
Ruiz-Malagón AJ, Rodríguez-Sanchez MJ, Rodríguez-Sojo MJ, Vezza T, Pischel I, Algieri F, Rodríguez-Cabezas ME, Rodríguez-Nogales A, Gálvez J. Intestinal anti-inflammatory and visceral analgesic effects of a Serpylli herba extract in an experimental model of irritable bowel syndrome in rats. Front Pharmacol 2022; 13:967644. [PMID: 36120292 PMCID: PMC9479127 DOI: 10.3389/fphar.2022.967644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Ethnopharmacological relevance:Serpylli herba extract (SHE), composed of the aerial parts of wild thyme (Thymus serpyllum L.) (Lamiaceae family), is traditionally used in Europe and North Africa to treat diarrhea, gastric ulcers, intestinal parasites and upper respiratory tract infections. Recently, SHE has generated a great interest for irritable bowel syndrome (IBS) management, probably due to its intestinal anti-inflammatory properties shown in experimental colitis and the fact that its active components could preserve the intestinal barrier integrity, which is altered in patients with IBS.Aim of study: We aimed to test the effects of a SHE in a rat experimental model resembling human IBS.Materials and methods: IBS was provoked by deoxycholic acid (DCA). Rats were then treated with SHE (100 mg/kg) or gabapentin (70 mg/kg) and different inflammatory and gut barrier integrity markers were evaluated. Moreover, several gut hypersensitivity and hyperalgesia determinations were performed.Results: SHE improved referred pain and visceral hypersensitivity. Additionally, SHE enhanced immune status by downregulating of the expression of the pro-inflammatory mediators Il-1β, Il-6, Ifn-γ, Tlr-4, and the inducible enzyme Cox-2, thus inducing visceral analgesia, and promoting the restore of the gut barrier function by upregulating the mucins Muc-2 and Muc-3. These anti-inflammatory effects could be related to its action on mast cells since it significantly inhibited the β-Hexosaminidase production in RBL-2H3 cells. Lastly, SHE also seems to modulate the serotonin pathway by restoring the altered expression of the 5-HT receptors Htr-3 and Htr-4.Conclusion: SHE could be considered a potential new treatment for IBS, since it ameliorates hypersensitivity, visceral hyperalgesia, and inflammation. These beneficial effects may be due to the inhibition of mast cells degranulation and serotonin pathway.
Collapse
Affiliation(s)
- Antonio Jesús Ruiz-Malagón
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - María José Rodríguez-Sanchez
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- Servicio de Digestivo, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - María Jesús Rodríguez-Sojo
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Teresa Vezza
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Ivo Pischel
- Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, University of London, London, United Kingdom
| | - Francesca Algieri
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- *Correspondence: Francesca Algieri, ; María Elena Rodríguez-Cabezas,
| | - María Elena Rodríguez-Cabezas
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- *Correspondence: Francesca Algieri, ; María Elena Rodríguez-Cabezas,
| | - Alba Rodríguez-Nogales
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- Servicio de Digestivo, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Julio Gálvez
- Center for Biomedical Research (CIBM), Department of Pharmacology, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| |
Collapse
|
|
21
|
Mallaret G, Lashermes A, Meleine M, Boudieu L, Barbier J, Aissouni Y, Gelot A, Chassaing B, Gewirtz AT, Ardid D, Carvalho FA. Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation. World J Gastroenterol 2022; 28:3903-3916. [PMID: 36157543 PMCID: PMC9367235 DOI: 10.3748/wjg.v28.i29.3903] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/09/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity (CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors (TLRs), which play a central role in innate immunity.
AIM To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.
METHODS Maternal separation model (NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension (CRD) coupled with intracolonic pressure variation (IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes. Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin (FliC) on CHS in adult naive wildtype mice was analyzed.
RESULTS Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5 mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.
CONCLUSION Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.
Collapse
Affiliation(s)
- Geoffroy Mallaret
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Amandine Lashermes
- Department of Microbiology, Université Paris-Saclay, National Research Institute for Agriculture, Food and the Environment, AgroParisTech, Micalis Institute, Jouy-en-Josas 78350, France
| | - Mathieu Meleine
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Ludivine Boudieu
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Julie Barbier
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Youssef Aissouni
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Agathe Gelot
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Benoit Chassaing
- Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris 75014, France
| | - Andrew T Gewirtz
- Center for Inflammation, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA30033, United States
| | - Denis Ardid
- Department of Pharmacology, UMR 1107 NeuroDol, University of Clermont Auvergne, Clermont-Ferrand 63000, France
| | - Frederic Antonio Carvalho
- Department of Pharmacology, INSERM 1107 NeuroDOL/University of Clermont Auvergne, Clermont-Ferrand 63000, France
| |
Collapse
|
|
22
|
Jiang FR, Hang L, Zhou Y, Feng Y, Yuan JY. Estrogen-gut microbiota interactions and irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2022; 30:511-520. [DOI: 10.11569/wcjd.v30.i12.511] [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] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with a complex pathogenesis that has a serious impact on the quality of life of patients. Abnormal visceral sensation, disordered gut motility, dysregulated immunity, and damaged intestinal barrier are thought to be involved in the pathogenesis of IBS. Female predisposition to IBS strongly suggests that sex hormones such as estrogen are involved in the development of IBS. In addition, dysbiosis of the intestinal flora is closely related to IBS. The interaction between estrogen and gut microbiota in IBS has not been fully elucidated. This review summarizes and evaluates the progress of related studies. Based on the new findings and shortcomings of current studies, we discuss the directions and issues that need to be resolved in future research.
Collapse
Affiliation(s)
- Feng-Ru Jiang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lu Hang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ya Feng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jian-Ye Yuan
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| |
Collapse
|
|
23
|
Bellés A, Aguirre-Ramírez D, Abad I, Parras-Moltó M, Sánchez L, Grasa L. Lactoferrin modulates gut microbiota and Toll-like receptors (TLRs) in mice with dysbiosis induced by antibiotics. Food Funct 2022; 13:5854-5869. [PMID: 35545893 DOI: 10.1039/d2fo00287f] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background: Antibiotic administration can result in gut microbiota and immune system alterations that impact health. Bovine lactoferrin is a milk protein with anticancer, anti-inflammatory, antimicrobial and immune modulatory activities. The aim was to study the ability of native and iron-saturated lactoferrin to reverse the effects of clindamycin on gut microbiota and intestinal Toll-like receptor (TLR) expression in a murine model. Methods: Male C57BL/6 mice were treated with vehicle, clindamycin (Clin), native bovine lactoferrin (nLf), nLf + clindamycin (nLf_Clin), iron-saturated bovine lactoferrin (sLf) and sLf + clindamycin (sLf_Clin). Fecal samples of each group were collected, and bacterial DNA was extracted. Sequencing of 16s rRNA V4 hypervariable gene regions was conducted to assess the microbial composition. mRNA expression levels of TLRs (1-9) were determined in mouse colon by qPCR. Pearson's correlation test was carried out between bacteria showing differences in abundance among samples and TLR2, TLR8 and TLR9. Results: Beta-diversity analysis showed that the microbial community of the vehicle was different from the communities of Clin, nLf_Clin and sLf_Clin. At the family level, Bacteroidaceae, Prevotellaceae and Rikenellaceae decreased in the Clin group, and treatment with nLf or sLf reverted these effects. Clin reduced the expression of TLR2, TLR8 and TLR9 and sLf reverted the decrease in the expression of these receptors. Finally, TLR8 was positively correlated with Rikenellaceae abundance. Conclusion: In a situation of intestinal dysbiosis induced by clindamycin, lactoferrin restores the normal levels of some anti-inflammatory bacteria and TLRs and, therefore, could be a good ingredient to be added to functional foods.
Collapse
Affiliation(s)
- Andrea Bellés
- Universidad de Zaragoza, Facultad de Veterinaria, Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Zaragoza, Spain. .,Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
| | - Diego Aguirre-Ramírez
- Universidad de Zaragoza, Facultad de Veterinaria, Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Zaragoza, Spain.
| | - Inés Abad
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain.,Universidad de Zaragoza, Facultad de Veterinaria, Departamento de Producción Animal y Tecnología de los Alimentos, Zaragoza, Spain
| | - Marcos Parras-Moltó
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden.,Centre for Antibiotic Resistance Research, University of Gothenburg, Gothenburg, Sweden.,Igenomix Foundation/INCLIVA Biomedical Research Institute, Spain.,Department of Science, Universidad Internacional de Valencia-VIU, Valencia, Spain
| | - Lourdes Sánchez
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain.,Universidad de Zaragoza, Facultad de Veterinaria, Departamento de Producción Animal y Tecnología de los Alimentos, Zaragoza, Spain
| | - Laura Grasa
- Universidad de Zaragoza, Facultad de Veterinaria, Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Zaragoza, Spain. .,Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| |
Collapse
|
|
24
|
Yoshimoto T, Oshima T, Huang X, Tomita T, Fukui H, Miwa H. Microinflammation in the intestinal mucosa and symptoms of irritable bowel syndrome. J Gastroenterol 2022; 57:62-69. [PMID: 34854984 DOI: 10.1007/s00535-021-01838-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Potential etiological mechanisms of irritable bowel syndrome (IBS) have been reported, and emerging data suggest that immune activation is present in a major subset of IBS, especially in those with diarrhea. Intestinal mucosal mast cell and intraepithelial lymphocyte (IEL) infiltration and related factors were examined in patients with IBS. In addition, the correlations of symptoms and micro-inflammation were assessed. METHODS Intestinal biopsy specimens were obtained from patients with IBS and controls. Mast cells and IELs were stained with specific antibodies. The mRNA levels of cytokines and chemokines were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS Infiltration of mast cells in the duodenum was significantly higher in IBS patients than in control subjects. The infiltration of IELs was higher in the duodenum and terminal ileum of IBS patients compared to the control subjects. The numbers of duodenal and ileal IELs were significantly correlated. The number of IELs but not mast cells in the duodenum and terminal ileum was significantly correlated with diarrhea frequency in control subjects and IBS patients. The expression level of the chemotactic chemokine CXCL11 was significantly higher in the duodenum of IBS patients. CONCLUSION Duodenal mast cells and IELs were increased in IBS patients. In addition, a positive correlation was found between the number of duodenal and ileal IELs and the frequency of diarrhea. Given that the present study was strictly observational, further studies are needed to clarify the pathophysiological functions associated with micro-inflammation in IBS.
Collapse
Affiliation(s)
- Takanori Yoshimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Xinyi Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| |
Collapse
|
|
25
|
Hillestad EMR, van der Meeren A, Nagaraja BH, Bjørsvik BR, Haleem N, Benitez-Paez A, Sanz Y, Hausken T, Lied GA, Lundervold A, Berentsen B. Gut bless you: The microbiota-gut-brain axis in irritable bowel syndrome. World J Gastroenterol 2022; 28:412-431. [PMID: 35125827 PMCID: PMC8790555 DOI: 10.3748/wjg.v28.i4.412] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/24/2021] [Accepted: 01/13/2022] [Indexed: 12/16/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal symptoms, recently described as a disturbance of the microbiota-gut-brain axis. Despite decades of research, the pathophysiology of this highly heterogeneous disorder remains elusive. However, a dramatic change in the understanding of the underlying pathophysiological mechanisms surfaced when the importance of gut microbiota protruded the scientific picture. Are we getting any closer to understanding IBS' etiology, or are we drowning in unspecific, conflicting data because we possess limited tools to unravel the cluster of secrets our gut microbiota is concealing? In this comprehensive review we are discussing some of the major important features of IBS and their interaction with gut microbiota, clinical microbiota-altering treatment such as the low FODMAP diet and fecal microbiota transplantation, neuroimaging and methods in microbiota analyses, and current and future challenges with big data analysis in IBS.
Collapse
Affiliation(s)
- Eline Margrete Randulff Hillestad
- Department of Clinical Medicine, University of Bergen, Bergen 5021, Norway
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| | - Aina van der Meeren
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| | - Bharat Halandur Nagaraja
- Mohn Medical Imaging and Visualization Center, Department of Radiology, Haukeland University Hospital, Bergen 5021, Norway
| | - Ben René Bjørsvik
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
- Mohn Medical Imaging and Visualization Center, Department of Radiology, Haukeland University Hospital, Bergen 5021, Norway
| | - Noman Haleem
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
- Mohn Medical Imaging and Visualization Center, Department of Radiology, Haukeland University Hospital, Bergen 5021, Norway
| | - Alfonso Benitez-Paez
- Host-Microbe Interactions in Metabolic Health Laboratory, Principe Felipe Research Center, Valencia 46012, Spain
| | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council, Paterna-Valencia 46980, Spain
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, Bergen 5021, Norway
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| | - Gülen Arslan Lied
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
- Center for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen 5021, Norway
| | - Arvid Lundervold
- Mohn Medical Imaging and Visualization Center, Department of Radiology, Haukeland University Hospital, Bergen 5021, Norway
- Department of Biomedicine, University of Bergen, Bergen 5021, Norway
| | - Birgitte Berentsen
- Department of Clinical Medicine, University of Bergen, Bergen 5021, Norway
- National Center for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen 5021, Norway
| |
Collapse
|
|
26
|
Lazebnik LB, Golovanova EV, Volel BA, Korochanskaya NV, Lyalyukova EA, Mokshina MV, Mekhtiev SN, Mekhtieva OA, Metsaeva ZV, Petelin DS, Simanenkov VI, Sitkin SI, Cheremushkin SV, Chernogorova MV, Khavkin АI. Functional gastrointestinal disorders. Overlap syndrome Clinical guidelines of the Russian Scientific Medical Society of Internal Medicine and Gastroenterological Scientific Society of Russia. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:5-117. [DOI: 10.31146/1682-8658-ecg-192-8-5-117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- L. B. Lazebnik
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - E. V. Golovanova
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - B. A. Volel
- I. M. Sechenov First Moscow Medical State University
| | - N. V. Korochanskaya
- Federal State Budgetary Educational Institution of Higher Education “Kuban State Medical University” Health Ministry of Russian Federation; State Budgetary Institution of Health Care “Region Clinic Hospital Nr 2” Health Ministry of Krasnodar Region
| | - E. A. Lyalyukova
- FSBEI VO “Omsk State Medical University” of the Ministry of Health
| | - M. V. Mokshina
- Institute of therapy a. instrumental diagnostics of FSBEI VO “Pacifi c State Medical Unuversity”
| | | | | | - Z. V. Metsaeva
- Republican clinical hospital of Health Care Ministry of Northen Ossetia- Alania Republic
| | - D. S. Petelin
- I. M. Sechenov First Moscow Medical State University
| | - V. I. Simanenkov
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. I. Sitkin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. V. Cheremushkin
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - M. V. Chernogorova
- Moscow regional research and clinical Institute of M. F. Vladimirsky; GBUZ MO “Podolsk City Clinical Hospital No. 3”
| | - А. I. Khavkin
- FSBAI HPE “N. I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation
| |
Collapse
|
|
27
|
Wei L, Singh R, Ro S, Ghoshal UC. Gut microbiota dysbiosis in functional gastrointestinal disorders: Underpinning the symptoms and pathophysiology. JGH Open 2021; 5:976-987. [PMID: 34584964 PMCID: PMC8454481 DOI: 10.1002/jgh3.12528] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023]
Abstract
Functional gastrointestinal disorders (FGIDs), currently known as disorders of gut-brain interaction, are emerging microbiota-gut-brain abnormalities that are prevalent worldwide. The pathogenesis of FGIDs is heterogeneous and is intertwined with gut microbiota and its derived molecule-modulated mechanisms, including gut dysmotility, visceral hypersensitivity, gut immune abnormalities, abnormal secretion, and impaired barrier function. There has been phenomenal progress in understanding the role of gut microbiota in FGIDs by underpinning the species alternations between healthy and pathological conditions such as FGIDs. However, the precise gut microbiota-directed cellular and molecular pathogeneses of FGIDs are yet enigmatic. Determining the mechanistic link between the gut microbiota and gastrointestinal (GI) diseases has been difficult due to (i) the lack of robust animal models imitating the various aspects of human FGID pathophysiology; (ii) the absence of longitudinal human and/or animal studies to unveil the interaction of the gut microbiota with FGID-relevant pathogenesis; (iii) uncertainty about connections between human and animal studies; and (iv) insufficient data supporting a holistic view of disease-specific pathophysiological changes in FGID patients. These unidentified gaps open possibilities to explore pathological mechanisms directed through gut microbiota dysbiosis in FGIDs. The current treatment options for dysbiotic gut microbiota are limited; dietary interventions, antibiotics, probiotics, and fecal microbiota transplantation are the front-line clinical options. Here, we review the contribution of gut microbiota and its derived molecules in gut homeostasis and explore the possible pathophysiological mechanisms involved in FGIDs leading to potential therapeutics options.
Collapse
Affiliation(s)
- Lai Wei
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Rajan Singh
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Seungil Ro
- Department of Physiology and Cell BiologyUniversity of Nevada, Reno, School of MedicineRenoNevadaUSA
| | - Uday C Ghoshal
- Department of GastroenterologySanjay Gandhi Postgraduate Institute of Medical SciencesLucknowIndia
| |
Collapse
|
|
28
|
Pérez de Arce E, Quera R, Quigley EMM. The Dilemma of Persistent Irritable Bowel Syndrome Symptoms in Patients with Quiescent Inflammatory Bowel Disease. Gastroenterol Clin North Am 2021; 50:689-711. [PMID: 34304795 DOI: 10.1016/j.gtc.2021.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome and inflammatory bowel disease differ in their natural evolution, etiopathogenesis, diagnostic criteria, and therapeutic approach. However, recent evidence has suggested some similarities in mechanisms underlying symptom development and progression. There is a relevant role for alterations in the microbiome-brain-gut axis in both diseases. The presence of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is common in clinical practice. To determine the cause of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is a clinical challenge. This review aims to illustrate possible causes and solutions for these patients.
Collapse
Affiliation(s)
- Edith Pérez de Arce
- Department of Medicine, Division of Gastroenterology, Hospital Clínico Universidad de Chile, Dr. Carlos Lorca Tobar 999, Independencia, Región Metropolitana, Santiago, Chile
| | - Rodrigo Quera
- Division of Gastroenterology, Inflammatory Bowel Disease Program, Clínica Universidad de los Andes, Estoril 450, Las Condes, Región Metropolitana, Santiago, Chile
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA.
| |
Collapse
|
|
29
|
Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice. J Transl Med 2021; 19:317. [PMID: 34301274 PMCID: PMC8306367 DOI: 10.1186/s12967-021-02995-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 07/17/2021] [Indexed: 02/07/2023] Open
Abstract
Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02995-z.
Collapse
|
|
30
|
Lajoie F, Rousseau G, Blanquet-Diot S, Etienne-Mesmin L. [Irritable bowel syndrome: Role of gut microbiota]. Med Sci (Paris) 2021; 37:593-600. [PMID: 34180818 DOI: 10.1051/medsci/2021095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Irritable Bowel Syndrome (IBS) is a functional disorder of the gastrointestinal tract with high prevalence. IBS, in particular the diarrheic subtype, is associated with alterations in gut microbiota composition and functionality, called dysbiosis. However, the treatment of this disease mainly relies on the patient's symptoms without considering the gut microbiota perturbations. In this review, we present epidemiological data about IBS-D. Then, we describe the main pathophysiological mechanisms associated with this disease, by focusing on gut microbiota alterations. We end up discussing the current therapies now available.
Collapse
Affiliation(s)
- Frédérique Lajoie
- Département de pharmacologie et physiologie, Faculté de médecine, université de Montréal, CP 6128 - Succursale Centre-ville, H3C 3J7 Montréal (Québec), Canada
| | - Guy Rousseau
- Département de pharmacologie et physiologie, Faculté de médecine, université de Montréal, CP 6128 - Succursale Centre-ville, H3C 3J7 Montréal (Québec), Canada
| | - Stéphanie Blanquet-Diot
- Université Clermont Auvergne, INRAe, UMR454 MEDIS (microbiologie, environnement digestif et santé), 28 place Henri-Dunant, 63000, Clermont-Ferrand, France
| | - Lucie Etienne-Mesmin
- Université Clermont Auvergne, INRAe, UMR454 MEDIS (microbiologie, environnement digestif et santé), 28 place Henri-Dunant, 63000, Clermont-Ferrand, France
| |
Collapse
|
|
31
|
Ma G, Hu Q, Han Y, Du H, Yang W, Pan C, Cao X, Muinde Kimatu B, Pei F, Xiao H. Inhibitory effects of β-type glycosidic polysaccharide from Pleurotus eryngii on dextran sodium sulfate-induced colitis in mice. Food Funct 2021; 12:3831-3841. [PMID: 33977958 DOI: 10.1039/d0fo02905j] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The aim of the present study was to determine the inhibitory effects and the potential underlying mechanisms of a novel Pleurotus eryngii β-type glycosidic polysaccharide (WPEP) on colitis. To achieve this, sixty CD-1 (ICR) mice were divided into six groups including healthy and colitic mice treated with or without WPEP at two different doses (n = 10). The results showed that WPEP displayed a significant inhibitory effect on colitis as indicated by the lowered disease activity index in the treated colitic mice compared to the untreated colitic mice (2.78 ± 0.50 to 1.80 ± 0.17). A decrease in pro-inflammatory cytokine concentrations and pro-inflammatory protein expressions and an increase in the colon length (9.31 ± 0.59 cm to 10.89 ± 1.20 cm) along with histological improvements were also observed in the treated colitic mice compared to the untreated colitic mice in the present study. Flow cytometry and western blotting analysis revealed that these anti-colitis effects were associated with decreased accumulation of CD45+ immune cells, CD45 + F4/80+ macrophages and CD45 + Gr1+ neutrophils. Moreover, the 16s rRNA sequencing analysis of the gut microbiota revealed that WPEP partially reversed gut microbiota dysbiosis in the colitic mice including the decreased abundance of Akkermansia muciniphila (35.80 ± 9.10% to 18.24 ± 6.23%) and Clostridium cocleatum (2.34 ± 1.78% to 0.011 ± 0.003%) and the increased abundance of Bifidobacterium pseudolongum (3.48 ± 2.72% to 9.65 ± 3.74%), Lactobacillus reuteri (0.007 ± 0.002% to 0.21 ± 0.12%), Lactobacillus salivarius (1.23 ± 0.87% to 2.22 ± 1.53%) and Ruminococcus bromii (0.009 ± 0.001% to 3.83 ± 1.98%). In summary, our results demonstrated that WPEP could be utilized as a functional food component in colitis management as well as a potential prebiotic agent to improve inflammation-related disorders.
Collapse
Affiliation(s)
- Gaoxing Ma
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing 210023, People's Republic of China and Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| | - Qiuhui Hu
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing 210023, People's Republic of China
| | - Yanhui Han
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| | - Hengjun Du
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| | - Wenjian Yang
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing 210023, People's Republic of China
| | - Che Pan
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| | - Xiaoqiong Cao
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| | - Benard Muinde Kimatu
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China and Department of Dairy and Food Science and Technology, Egerton University, P.O. Box 536-20115, Egerton, Kenya
| | - Fei Pei
- College of Food Science and Engineering, Nanjing University of Finance and Economics, Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing 210023, People's Republic of China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA 01002, USA.
| |
Collapse
|
|
32
|
The Potential Protective Role of RUNX1 in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms22105239. [PMID: 34063472 PMCID: PMC8156882 DOI: 10.3390/ijms22105239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role.
Collapse
|
|
33
|
Jalanka J, Lam C, Bennett A, Hartikainen A, Crispie F, Finnegan LA, Cotter PD, Spiller R. Colonic Gene Expression and Fecal Microbiota in Diarrhea-predominant Irritable Bowel Syndrome: Increased Toll-like Receptor 4 but Minimal Inflammation and no Response to Mesalazine. J Neurogastroenterol Motil 2021; 27:279-291. [PMID: 33795545 PMCID: PMC8026366 DOI: 10.5056/jnm20205] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/23/2020] [Accepted: 11/09/2020] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Diarrhea-predominant irritable bowel syndrome (IBS-D) has been previously associated with evidence of immune activation and altered microbiota. Our aim is to assess the effect of the anti-inflammatory agent, mesalazine, on inflammatory gene expression and microbiota composition in IBS-D. Methods We studied a subset of patients (n = 43) from a previously published 12-week radomized placebo-controlled trial of mesalazine. Mucosal biopsies were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction for a range of markers of inflammation, altered permeability, and sensory receptors including Toll-like receptors (TLRs) at randomization after treatment. All biopsy data were compared to 21 healthy controls. Patient’s stool microbiota composition was analysed through 16S ribosomal RNA sequencing. Results We found no evidence of increased immune activation compared to healthy controls. However, we did find increased expression of receptors in both sensory pathways and innate immune response including TLR4. Higher TLR4 expression was associated with greater urgency. TLR4 expression correlated strongly with the expression of the receptors bradykinin receptor B2, chemerin chemokine-like receptor 1, and transient receptor potential cation channel, subfamily A, member 1 as well as TLR4’s downstream adaptor myeloid differentiation factor 88. Mesalazine had minimal effect on either gene expression or microbiota composition. Conclusions Biopsies from a well-characterized IBS-D cohort showed no substantial inflammation. Mesalazine has little effect on gene expression and its previous reported effect on fecal microbiota associated with much greater inflammation found in inflammatory bowel diseases is likely secondary to reduced inflammation. Increased expression of TLR4 and correlated receptors in IBS may mediate a general increase in sensitivity to external stimuli, particularly those that signal via the TLR system.
Collapse
Affiliation(s)
- Jonna Jalanka
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
| | - Ching Lam
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
| | - Andrew Bennett
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK.,FRAME Alternatives Laboratory, School of Life Sciences, University of Nottingham, Medical School, QMC, Nottingham, Notts, UK
| | - Anna Hartikainen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Fiona Crispie
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Laura A Finnegan
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Paul D Cotter
- Teagasc Food Research Center, Moorepark, Fermoy, Co. Cork, Ireland.,APC Microbiome Ireland, Cork, Ireland
| | - Robin Spiller
- Nottingham Digestive Diseases Center and NIHR Nottingham Biomedical Research Center at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
| |
Collapse
|
|
34
|
Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model. Nutrients 2020; 12:nu12092764. [PMID: 32927823 PMCID: PMC7551189 DOI: 10.3390/nu12092764] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/30/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1β in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1β, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.
Collapse
|
|
35
|
Carco C, Young W, Gearry RB, Talley NJ, McNabb WC, Roy NC. Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis. Front Cell Infect Microbiol 2020; 10:468. [PMID: 33014892 PMCID: PMC7509092 DOI: 10.3389/fcimb.2020.00468] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal tract harbors most of the microbial cells inhabiting the body, collectively known as the microbiota. These microbes have several implications for the maintenance of structural integrity of the gastrointestinal mucosal barrier, immunomodulation, metabolism of nutrients, and protection against pathogens. Dysfunctions in these mechanisms are linked to a range of conditions in the gastrointestinal tract, including functional gastrointestinal disorders, ranging from irritable bowel syndrome, to functional constipation and functional diarrhea. Irritable bowel syndrome is characterized by chronic abdominal pain with changes in bowel habit in the absence of morphological changes. Despite the high prevalence of irritable bowel syndrome in the global population, the mechanisms responsible for this condition are poorly understood. Although alterations in the gastrointestinal microbiota, low-grade inflammation and immune activation have been implicated in the pathophysiology of functional gastrointestinal disorders, there is inconsistency between studies and a lack of consensus on what the exact role of the microbiota is, and how changes to it relate to these conditions. The complex interplay between host factors, such as microbial dysbiosis, immune activation, impaired epithelial barrier function and motility, and environmental factors, including diet, will be considered in this narrative review of the pathophysiology of functional gastrointestinal disorders.
Collapse
Affiliation(s)
- Caterina Carco
- School of Food and Advanced Technology, Massey University, Palmerston North, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,Food Nutrition and Health Team, AgResearch Grasslands, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Wayne Young
- Riddet Institute, Massey University, Palmerston North, New Zealand.,Food Nutrition and Health Team, AgResearch Grasslands, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Richard B Gearry
- The High-Value Nutrition National Science Challenge, Auckland, New Zealand.,Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Nicholas J Talley
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Warren C McNabb
- Riddet Institute, Massey University, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Nicole C Roy
- Riddet Institute, Massey University, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand.,Liggins Institute, University of Auckland, Auckland, New Zealand.,Department of Human Nutrition, University of Otago, Dunedin, New Zealand
| |
Collapse
|
|
36
|
Akhmedov VA, Sargsyan AK, Gaus OV. Prospects for the use of biomarkers in the diagnosis of irritable bowel syndrome. ACTA ACUST UNITED AC 2020. [DOI: 10.31146/1682-8658-ecg-175-3-94-101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome is a chronic functional disorder of the intestine, manifested by altered intestinal habits and recurrent abdominal pain in combination with two or more criteria: association with defecation, association with a change in the frequency of defecation, association with a change in the appearance of the stool. To date, IBS remains a diagnosis of exclusion that needs to be differentiated from a wide range of organic diseases. In recent years, a large number of publications have appeared on the research of etiopathogenesis, diagnosis and treatment of IBS. This literary review highlights the problems of searching for biomarkers of IBS as a way to solve the problem of diagnosis of this pathology and understanding the causes of its occurrence.
Collapse
Affiliation(s)
- V. A. Akhmedov
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - A. K. Sargsyan
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - O. V. Gaus
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| |
Collapse
|
|
37
|
Ghoshal UC. Marshall and Warren Lecture 2019: A paradigm shift in pathophysiological basis of irritable bowel syndrome and its implication on treatment. J Gastroenterol Hepatol 2020; 35:712-721. [PMID: 32162356 DOI: 10.1111/jgh.15032] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder (FGID), has often been considered rather inappropriately as psychogenic in the past. Though psychological issues are important comorbidities in a proportion of IBS patients, the evidences are far from enough to label this condition as psychogenic only. In the recent past, evidences are emerging that underscores the concept supporting pure psychogenic theory of IBS and suggest this disorder to be rather microorganic. Accordingly, a move of Rome IV Committee attempting to delete the term "functional" and designating these to be disorders of "gut-brain interaction" rather than that of "brain-gut interaction," it emphasizes the importance of the gut over the brain in the pathogenesis. The introduction of the concept of multidimensional clinical profile in Rome IV requires attention to diagnostic category of FGID, overlap, severity, psychological issues, and physiological dysfunction or biomarkers; this attempts to recognize clinical variability and multidimensionality of pathophysiology and management of these disorders. The recognition of the biological factors in the pathogenesis of IBS is a significant paradigm shift in the recent time. This is somewhat similar to the progress in the pathogenesis of peptic ulcer disease from psychological factor to acid to Helicobacter pylori infection. It is expected that in the near future, therapeutic modalities targeting the different pathogenic mechanisms of different subtypes of IBS may bring revolution in management of the disorder.
Collapse
Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| |
Collapse
|
|
38
|
Ni WW, Zhang QM, Zhang X, Li Y, Yu SS, Wu HY, Chen Z, Li AL, Du P, Li C. Modulation effect of Lactobacillus acidophilus KLDS 1.0738 on gut microbiota and TLR4 expression in β-lactoglobulin-induced allergic mice model. Allergol Immunopathol (Madr) 2020; 48:149-157. [PMID: 31477403 DOI: 10.1016/j.aller.2019.06.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/24/2019] [Accepted: 06/03/2019] [Indexed: 12/26/2022]
Abstract
OBJECTIVES β-lactoglobulin (β-Lg)-sensitized mice model was employed to investigate the correlation between Lactobacillus acidophilus KLDS 1.0738 (Lap KLDS 1.0738) modulating gut microbiota and inducting Toll-like receptors (TLRs) expression. METHODS The alterations of mice fecal microbiota were analyzed by 16S rRNA gene sequencing. The serum cytokines production and TLR4/NF-κB mRNA expression in the colon tissues were measured by ELISA kit and quantitative RT-PCR, respectively. RESULTS The results showed that Lap KLDS 1.0738 pretreatment attenuated β-Lg-induced hypersensitivity, accompanied with a diminished expression of TLR4/NF-κB signaling. Moreover, oral administration of Lap KLDS 1.0738 improved the richness and diversity of fecal microbiota, which was characterized by fewer Proteobacteria phylum and Helicobacteraceae family, and higher Firmicutes phylum and Lachnospiraceae family than allergic group. Notably, TLR4/NF-κB expression was positively correlated with the family of Helicobacteraceae in allergic group, but negatively correlated with the family of Lachnospiraceae, Ruminococcaceae and anti-inflammatory cytokines level. A significant positive correlation was observed between TLR4/NF-κB expression and the production of histamine, total IgE and pro-inflammatory cytokines. CONCLUSIONS Intake of Lap KLDS 1.0738 can influence the gut bacterial composition, which might result in recognizing TLRs signaling so as to inhibit allergic response.
Collapse
Affiliation(s)
- W-W Ni
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - Q-M Zhang
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - X Zhang
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - Y Li
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - S-S Yu
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - H-Y Wu
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - Z Chen
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| | - A-L Li
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China.
| | - P Du
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China.
| | - C Li
- Key Laboratory of Dairy Science, Food Science College, Northeast Agriculture University, Northeast Agriculture University, Harbin, China
| |
Collapse
|
|
39
|
Ghoshal UC, Goel A, Quigley EMM. Gut microbiota abnormalities, small intestinal bacterial overgrowth, and non-alcoholic fatty liver disease: An emerging paradigm. Indian J Gastroenterol 2020; 39:9-21. [PMID: 32291578 DOI: 10.1007/s12664-020-01027-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Evidence accumulates to implicate a role for the gut microbiota in non-alcoholic fatty liver disease (NAFLD)-a disorder that has reached almost epidemic proportions around the globe. For some time a disturbance in the gut microbiome, small intestinal bacterial overgrowth (SIBO), has been described among patients with liver disease, in general, and in the development and progression of NAFLD to nonalcoholic steatohepatitis (NASH), decompensated liver disease and hepatocellular cancer (HCC), in particular. More recently and permitted by the advent of high-throughput sequencing and allied molecular techniques, a much more detailed analysis of gut microbiota in NAFLD and NASH has become possible. In animal models, several mechanisms have been delineated which reveal how gut bacteria and their products could promote steatosis, hepatic inflammation, fibrosis, cirrhosis, and carcinogenesis. For understandable reasons evidence from human studies is less complete, but here again a plausible case is beginning to emerge to incriminate microbiota in NAFLD and NASH pathogenesis. Therapeutic interventions based on the modulation of the microbiome have been explored to some extent, but their application to everyday medical practice is still in the future.
Collapse
Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Eamonn M M Quigley
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India. .,Gastroenterology and Hepatology, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, 6550 Fannin St, SM 1201, Houston, TX, 77030, USA.
| |
Collapse
|
|
40
|
Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. Therap Adv Gastroenterol 2020; 13:1756284819897531. [PMID: 32047534 PMCID: PMC6984424 DOI: 10.1177/1756284819897531] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/02/2019] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with a multifactorial pathophysiology. The gut microbiota differs between patients with IBS and healthy individuals. After a bout of acute gastroenteritis, postinfection IBS may result in up to approximately 10% of those affected. Small intestinal bacterial overgrowth (SIBO) is more common in patients with IBS than in healthy individuals, and eradication of SIBO with systemic antibiotics has decreased symptoms of IBS in some patients with IBS and SIBO. The nonsystemic (i.e. low oral bioavailability) antibiotic rifaximin is indicated in the United States and Canada for the treatment of adults with IBS with diarrhea (IBS-D). The efficacy and safety of 2-week single and repeat courses of rifaximin have been demonstrated in randomized, placebo-controlled studies of adults with IBS. Rifaximin is widely thought to exert its beneficial clinical effects in IBS-D through manipulation of the gut microbiota. However, current studies indicate that rifaximin induces only modest effects on the gut microbiota of patients with IBS-D, suggesting that the efficacy of rifaximin may involve other mechanisms. Indeed, preclinical data reveal a potential role for rifaximin in the modulation of inflammatory cytokines and intestinal permeability, but these two findings have not yet been examined in the context of clinical studies. The mechanism of action of rifaximin in IBS is likely multifactorial, and further study is needed.
Collapse
Affiliation(s)
- William D. Chey
- Department of Nutrition Sciences, Division of Gastroenterology, Michigan Medicine, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109-5362, USA
| | - Eric D. Shah
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Herbert L. DuPont
- Division of Epidemiology, Human Genetics and Environmental Sciences and Center for Infectious Diseases, University of Texas School of Public Health, Houston, TX, USA
- Mary W. Kelsey Chair in Medical Sciences, Division of Internal Medicine, University of Texas McGovern Medical School Houston, TX, USA
- Kelsey Research Foundation, Houston, TX, USA
| |
Collapse
|
|
41
|
Andrews CN, Sidani S, Marshall JK. Clinical Management of the Microbiome in Irritable Bowel Syndrome. J Can Assoc Gastroenterol 2020; 4:36-43. [PMID: 33644675 PMCID: PMC7898379 DOI: 10.1093/jcag/gwz037] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022] Open
Abstract
Background A growing body of evidence suggests that dysbiosis contributes to the onset and symptomatology of irritable bowel syndrome (IBS) and other functional bowel disorders. Changes to the gastrointestinal microbiome may contribute to the underlying pathophysiology of IBS. Methods The present review summarizes the potential effects of microbiome changes on GI transit, intestinal barrier function, immune dysregulation and inflammation, gut–brain interactions and neuropsychiatric function. Results A multimodal approach to IBS management is recommended in accordance with current Canadian guidelines. Pharmacologic treatments are advised to target the presumed underlying pathophysiological mechanism, such as dysregulation of GI transit, peristalsis, intestinal barrier function and pain signalling. The management plan for IBS may also include treatments directed at dysbiosis, including dietary modification and use of probiotics, which may promote the growth of beneficial bacteria, affect intestinal gas production and modulate the immune response; and the administration of periodic short courses of a nonsystemic antibiotic such as rifaximin, which may re-establish microbiota diversity and improve IBS symptoms. Conclusion Dysregulated host–microbiome interactions are complex and the use of microbiome-directed therapies will necessarily be empiric in individual patients. A management algorithm comprising microbiome- and nonmicrobiome-directed therapies is proposed.
Collapse
Affiliation(s)
- Christopher N Andrews
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sacha Sidani
- Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - John K Marshall
- Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| |
Collapse
|
|
42
|
Aragonès G, Colom-Pellicer M, Aguilar C, Guiu-Jurado E, Martínez S, Sabench F, Antonio Porras J, Riesco D, Del Castillo D, Richart C, Auguet T. Circulating microbiota-derived metabolites: a "liquid biopsy? Int J Obes (Lond) 2019; 44:875-885. [PMID: 31388096 DOI: 10.1038/s41366-019-0430-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/08/2019] [Accepted: 06/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND/OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, from simple steatosis (SS) to cirrhosis. SS and non-alcoholic steatohepatitis (NASH) cannot be distinguished by clinical or laboratory features. Dysregulation of the gut microbiota is involved in NASH pathogenesis. The aim of this study was to assess the relationship between microbiota-derived metabolites and the degrees of NAFLD; also, to investigate whether these metabolites could be included in a panel of NASH biomarkers. SUBJECTS/METHODS We used liquid chromatography coupled to triple-quadrupole-mass spectrometry (LC-QqQ) analysis to quantify choline and its derivatives, betaine, endogenous ethanol, bile acids, short-chain fatty acids and soluble TLR4 in serum from women with normal weight (n = 29) and women with morbid obesity (MO) (n = 82) with or without NAFLD. We used real-time polymerase chain reaction (RT-PCR) analysis to evaluate the hepatic and intestinal expression level of all genes studied (TLR2, TLR4, TLR9, LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, ABCG1 and FXR in the liver; TLR2, TLR4, TLR5, TLR9, GLP-1R, DPP-4, FXR and PPARɣ in the jejunum) in 82 women with MO with normal liver histology (NL, n = 29), SS (n = 32), and NASH (n = 21). RESULTS Hepatic FAS, TLR2, and TLR4 expression were overexpressed in NAFLD patients. TLR2 was overexpressed in NASH patients. In women with MO with NAFLD, we found upregulation of intestinal TLR9 expression and downregulation of intestinal FXR expression in women with NASH. Circulating TMAO, glycocholic acid and deoxycholic acid levels were significantly increased in NAFLD patients. Endogenous circulating ethanol levels were increased in NASH patients in comparison to those in SS patients. CONCLUSIONS These findings suggest that the intestine participates in the progression of NAFLD. Moreover, levels of certain circulating microbiota-related metabolites are associated with NAFLD severity and could be used as a "liquid biopsy" in the noninvasive diagnosis of NASH.
Collapse
Affiliation(s)
- Gemma Aragonès
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Marina Colom-Pellicer
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain
| | - Esther Guiu-Jurado
- IFB-Adiposity Diseases, Leipzig University, Liebigstraße 19-21, 04103, Leipzig, Germany
| | - Salomé Martínez
- Servei Anatomia Patològica, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Fàtima Sabench
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, Avinguda Doctor Josep Laporte, 2, 43204, Reus, Spain
| | - José Antonio Porras
- Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - David Riesco
- Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Daniel Del Castillo
- Servei de Cirurgia, Hospital Sant Joan de Reus, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, Avinguda Doctor Josep Laporte, 2, 43204, Reus, Spain
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain.,Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain
| | - Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR) - Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), 43007, Tarragona, Spain. .,Servei Medicina Interna, Hospital Universitari Joan XXIII Tarragona, Mallafré Guasch, 4, 43007, Tarragona, Spain.
| |
Collapse
|
|
43
|
Gwee KA, Gonlachanvit S, Ghoshal UC, Chua ASB, Miwa H, Wu J, Bak YT, Lee OY, Lu CL, Park H, Chen M, Syam AF, Abraham P, Sollano J, Chang CS, Suzuki H, Fang X, Fukudo S, Choi MG, Hou X, Hongo M. Second Asian Consensus on Irritable Bowel Syndrome. J Neurogastroenterol Motil 2019; 25:343-362. [PMID: 31327218 PMCID: PMC6657923 DOI: 10.5056/jnm19041] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/13/2019] [Accepted: 06/24/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND/AIMS There has been major progress in our understanding of the irritable bowel syndrome (IBS), and novel treatment classes have emerged. The Rome IV guidelines were published in 2016 and together with the growing body of Asian data on IBS, we felt it is timely to update the Asian IBS Consensus. METHODS Key opinion leaders from Asian countries were organized into 4 teams to review 4 themes: symptoms and epidemiology, pathophysiology, diagnosis and investigations, and lifestyle modifications and treatments. The consensus development process was carried out by using a modified Delphi method. RESULTS Thirty-seven statements were developed. Asian data substantiate the current global viewpoint that IBS is a disorder of gut-brain interaction. Socio-cultural and environmental factors in Asia appear to influence the greater overlap between IBS and upper gastrointestinal symptoms. New classes of treatments comprising low fermentable oligo-, di-, monosacharides, and polyols diet, probiotics, non-absorbable antibiotics, and secretagogues have good evidence base for their efficacy. CONCLUSIONS Our consensus is that all patients with functional gastrointestinal disorders should be evaluated comprehensively with a view to holistic management. Physicians should be encouraged to take a positive attitude to the treatment outcomes for IBS patients.
Collapse
Affiliation(s)
- Kok Ann Gwee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, and Gleneagles Hospital,
Singapore
| | - Sutep Gonlachanvit
- Center of Excellence on Neurogastroenterology and Motility, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok,
Thailand
- Correspondence: Sutep Gonlachanvit, MD, Center of Excellence on Neurogastroenterology and Motility, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand, Tel: +66-2-256-4265, Fax: +66-2-252-7839, E-mail:
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,
India
| | | | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo,
Japan
| | - Justin Wu
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, New Territories,
Hong Kong
| | - Young-Tae Bak
- Department of Internal Medicine, Korea University College of Medicine, Seoul,
Korea
| | - Oh Young Lee
- Department of Gastroenterology, College of Medicine, Hanyang University, Seoul,
Korea
| | - Ching-Liang Lu
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei,
Taiwan
| | - Hyojin Park
- Division of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou,
China
| | - Ari F Syam
- Division of Gastroenterology, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta,
Indonesia
| | - Philip Abraham
- Division of Gastroenterology, P D Hinduja Hospital, Mumbai,
India
| | - Jose Sollano
- Department of Internal Medicine, Division of Gastroenterology, University of Santo Tomas, Manila,
Philippine
| | - Chi-Sen Chang
- Taichung Veterans General Hospital, Taiwan Boulevard, Taichung City,
Taiwan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa,
Japan
| | - Xiucai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,
China
| | - Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Aoba Sendai,
Japan
| | - Myung-Gyu Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Xiaohua Hou
- Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
China
| | - Michio Hongo
- Department of Medicine, Kurokawa General Hospital, Kurokawa, Miyagi,
Japan
| |
Collapse
|
|
44
|
Tian X, Zhang Z, Li W. Expression of TLR2 and TLR5 in distal ileum of mice with obstructive jaundice and their role in intestinal mucosal injury. Arch Med Sci 2019; 18:237-250. [PMID: 35154543 PMCID: PMC8826794 DOI: 10.5114/aoms.2019.85648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 04/18/2019] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION The aim was to investigate the expression of TLR2 and TLR5 in the distal ileum of mice with obstructive jaundice (OJ) and their role in intestinal mucosal injury. MATERIAL AND METHODS A total of 100 male C57BL/6J mice were randomly assigned to two groups: (I) sham operation (SH); (II) bile duct ligation (BDL). The mice were respectively sacrificed before operation and on the 1st, 3rd, 5th and 7th days after operation to collect specimens. Various indicators were detected by PCR, immunohistochemistry and other methods. RESULTS TLR2 was increased gradually with the extension of OJ time in the BDL group (p < 0.05). However, the changes in the expression of TLR5 were not obvious at different time points. The amount of Bifidobacteria and Lactobacillus showed downward trends in intestinal tract of the BDL group. Furthermore, the amount of Escherichia coli was increased in intestinal tract of the BDL group. The pathological score of intestinal mucosa and the expression of NF-κB increased gradually in the BDL group with the extension of OJ time. There were positive correlations between the pathological score of intestinal mucosa and expressions of TLR2(r = 0.767, p < 0.05) and NF-κB (r = 0.817, p < 0.05) in BDL group. NF-κB expression was positively correlated with TLR2 expression(r = 0.706, p < 0.05). CONCLUSIONS Disturbance of intestinal flora caused by OJ could increase the expression of NF-κB via up-regulating the expression of TLR2 to activate the downstream signaling pathway, thus aggravated the injury of intestinal mucosa.
Collapse
Affiliation(s)
- Xiaopeng Tian
- Medical School of Chinese PLA, Beijing, China
- Department of Gastroenterology, Xingtai People’s Hospital, Xingtai, Hebei, China
| | | | - Wen Li
- Medical School of Chinese PLA, Beijing, China
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
45
|
Mendes V, Galvão I, Vieira AT. Mechanisms by Which the Gut Microbiota Influences Cytokine Production and Modulates Host Inflammatory Responses. J Interferon Cytokine Res 2019; 39:393-409. [PMID: 31013453 DOI: 10.1089/jir.2019.0011] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract encounters a wide variety of microorganisms, including beneficial symbionts, pathobionts, and pathogens. Recent evidence has shown that the gut microbiota, directly or indirectly through its components, such as metabolites, actively participates in the host inflammatory response by cytokine-microbiota or microbiota-cytokine modulation interactions, both in the gut and systemically. Therefore, further elucidation of host cytokine molecular pathways and microbiota components will provide a novel and promising therapeutic approach to control or prevent inflammatory disease and to maintain host homeostasis. The purpose of this review is to summarize well-established scientific findings and provide an updated overview regarding the direct and indirect mechanisms by which the gut microbiota can influence the inflammatory response by modulating the host's cytokine pathways that are mostly involved, but not exclusively so, with gut homeostasis. In addition, we will highlight recent results from our group, which suggest that the microbiota promotes cytokine release from inflammatory cells though activation of microbial metabolite sensor receptors that are more highly expressed on inflammatory and intestinal epithelial cells.
Collapse
Affiliation(s)
- Viviani Mendes
- 1 Laboratory of Microbiota and Immunomodulation, Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,2 Department of General Biology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Izabela Galvão
- 3 Department of Cellular Biology ICB, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Angelica Thomaz Vieira
- 1 Laboratory of Microbiota and Immunomodulation, Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,2 Department of General Biology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| |
Collapse
|
|
46
|
Gajula P, Quigley EM. Overlapping irritable bowel syndrome and inflammatory bowel disease. MINERVA GASTROENTERO 2019; 65:107-115. [PMID: 30746927 DOI: 10.23736/s1121-421x.19.02559-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pathogenesis of irritable bowel-type symptoms occurring in patients with inflammatory bowel disease who are in apparent remission continues to generate scientific controversy and the interpretation and management of these symptoms, so distressing to the sufferer, represent major challenges for the clinician. On the one hand, these symptoms often satisfy Rome IV criteria for IBS and their occurrence correlates highly with anxiety, a known trigger for IBS. On the other hand, recent studies have shown that many of these patients exhibit subtle inflammatory changes. These observations beg the question: are these symptoms "true" IBS superimposed on IBD, or an active but subclinical form of IBD? While it is certain that earlier studies failed to detect subclinical inflammation, it is also evident that even with the use of sensitive biomarkers for inflammation, such as calprotectin and lactoferrin backed up by pan-endoscopy and biopsy to exclude ongoing inflammatory activity in its most subtle form, the prevalence of IBS-type symptoms remains higher than expected in the IBD patient. Pending further definition of its etiology and pathology, we coined the term irritable inflammatory bowel syndrome (IIBS) to refer to this phenomenon. Here we explore the risk factors for this entity, sift through clues to its pathogenesis and attempt to provide, albeit bereft of a robust evidence base, an approach to its management.
Collapse
Affiliation(s)
- Prianka Gajula
- Department of Medicine, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Eamonn M Quigley
- Division of Gastroenterology and Hepatology, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA -
| |
Collapse
|
|
47
|
Kim HJ. Do Toll-like Receptors Play a New Role as a Biomarker of Irritable Bowel Syndrome? J Neurogastroenterol Motil 2018; 24:510-511. [PMID: 30347933 PMCID: PMC6175550 DOI: 10.5056/jnm18153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/22/2022] Open
Affiliation(s)
- Hyun Jin Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Gyeongsangnam-do, Korea
| |
Collapse
|