|
1
|
Unzueta-Medina JA, González-Chávez SA, Salas-Leiva JS, Silva-Sánchez SE, Pacheco-Tena C. Differential Composition and Structure of the Microbiota from Active and Inactive Stages of HLA-B27-associated Uveitis by Paired Fecal Metagenomes. Ocul Immunol Inflamm 2025; 33:56-64. [PMID: 38709227 DOI: 10.1080/09273948.2024.2346818] [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: 08/26/2023] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE To compare the diversities and abundances of bacterial taxa in the microbiome of patients with HLA B27-positive acute anterior uveitis (AAU) in the active and inactive phases. METHODS An observational descriptive prospective and comparative study was conducted in ten HLA-B27-positive AAU patients (44.6 ± 13.4 years). The microbiome of the stool samples obtained in the active and inactive stages was analyzed by sequencing the V3 region of the 16S rRNA gene. RESULTS The differences in the bacteria profile between active and inactive stages in each individual were confirmed (p < 0.0001). Ten OTUs were found exclusively in the active phase of 90% of the individuals, suggesting a proinflammatory association. Blautia OUT_4 and Faecalibacterium OUT_2 abundances showed a direct relationship between abundance and severity of ocular inflammation. Two OTUs were exclusive of the inactive stage, suggesting an anti-inflammatory role. CONCLUSION The metagenomic profile of the fecal microbiota differs in the acute phase of the AAU compared to when the inflammation subsides, despite being the same individual and a short time-lapse. AAU is a fertile field for studying the connection between subtle rapid changes in microbiota and their systemic consequences.
Collapse
Affiliation(s)
- José Antonio Unzueta-Medina
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - Susana Aideé González-Chávez
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - Joan Sebastian Salas-Leiva
- Departamento de medio ambiente y energía, CONAHCyT, Centro de Investigación en Materiales Avanzados, Chihuahua, México
| | - Sandra Estela Silva-Sánchez
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| | - César Pacheco-Tena
- Laboratorio PABIOM, Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, México
| |
Collapse
|
|
2
|
Moulin D, Millard M, Taïeb M, Michaudel C, Aucouturier A, Lefèvre A, Bermúdez-Humarán LG, Langella P, Sereme Y, Wanherdrick K, Gautam P, Mariette X, Dieudé P, Gottenberg JE, Jouzeau JY, Skurnik D, Emond P, Mulleman D, Sellam J, Sokol H. Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis. Ann Rheum Dis 2024; 83:312-323. [PMID: 38049981 PMCID: PMC10894831 DOI: 10.1136/ard-2023-224014] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 10/26/2023] [Indexed: 12/06/2023]
Abstract
OBJECTIVES Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question. METHODS Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model. RESULTS Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model. CONCLUSIONS Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.
Collapse
Affiliation(s)
- David Moulin
- UMR 7365 IMoPA, Université de Lorraine, Nancy, Grand Est, France
| | - Marie Millard
- UMR 7365 IMoPA, Université de Lorraine, Nancy, Grand Est, France
| | - Mahdia Taïeb
- UMR 7365 IMoPA, Université de Lorraine, Nancy, Grand Est, France
| | - Chloé Michaudel
- ProbiHote, MICALIS, Jouy-en-Josas, Île-de-France, France
- Paris Center for Microbiome Medicine, Paris, France
| | - Anne Aucouturier
- ProbiHote, MICALIS, Jouy-en-Josas, Île-de-France, France
- Paris Center for Microbiome Medicine, Paris, France
| | | | - Luis G Bermúdez-Humarán
- ProbiHote, MICALIS, Jouy-en-Josas, Île-de-France, France
- Paris Center for Microbiome Medicine, Paris, France
| | | | - Youssouf Sereme
- CNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, France
| | - Kristell Wanherdrick
- Centre de Recherche Saint-Antoine, Inserm UMRS_938, Sorbonne Université, Paris, France
| | - Preeti Gautam
- UMR 7365 IMoPA, Université de Lorraine, Nancy, Grand Est, France
| | - Xavier Mariette
- Rheumatology department, Université Paris-Saclay, INSERM UMR 1184, AP-HP, Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Philippe Dieudé
- Université de Paris Cité, INSERM UMR 1152, F-75018, Paris, France
| | - Jacques-Eric Gottenberg
- Hôpitaux Universitaires de Strasbourg et Université de Strasbourg, and Centre de Référence pour les Maladies Auto-Immunes Systémiques Rares, CNRS, IBMC, UPR3572, Strasbourg, France
| | | | - David Skurnik
- CNRS, INSERM, Institut Necker Enfants Malades-INEM, F-75015 Paris, France; Faculté de Médecine, University of Paris City, Paris, France
- Department of Clinical Microbiology, Fédération Hospitalo-Universitaire Prématurité (FHU PREMA), Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris City, Paris, France
| | - Patrick Emond
- R 1253, iBrain, University of Tours, Inserm, Tours, France
- CHRU Tours Medical Biology Center, Tours, France
| | - Denis Mulleman
- Service de Rhumatologie, CHRU de Tours, Tours, France
- EA 6295, Nano Medicine & Nano Probes, University of Tours, Tours, France
| | - Jérémie Sellam
- Paris Center for Microbiome Medicine, Paris, France
- Centre de Recherche Saint-Antoine, Inserm UMRS_938, Sorbonne Université, Paris, France
- Department of Rheumatology, Saint-Antoine Hospital, APHP, Paris, France
| | - Harry Sokol
- ProbiHote, MICALIS, Jouy-en-Josas, Île-de-France, France
- Paris Center for Microbiome Medicine, Paris, France
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Paris, France
| |
Collapse
|
|
3
|
Gill T, Rosenbaum JT. Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy. Front Immunol 2021; 11:586494. [PMID: 33537028 PMCID: PMC7848169 DOI: 10.3389/fimmu.2020.586494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
Collapse
Affiliation(s)
- Tejpal Gill
- Division of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - James T Rosenbaum
- Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University, Portland, OR, United States.,Legacy Devers Eye Institute, Portland, OR, United States
| |
Collapse
|
|
4
|
Schmidt CJ, Wenndorf K, Ebbers M, Volzke J, Müller M, Strübing J, Kriebel K, Kneitz S, Kreikemeyer B, Müller-Hilke B. Infection With Clostridioides difficile Attenuated Collagen-Induced Arthritis in Mice and Involved Mesenteric T reg and T h2 Polarization. Front Immunol 2020; 11:571049. [PMID: 33193352 PMCID: PMC7662472 DOI: 10.3389/fimmu.2020.571049] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022] Open
Abstract
Objectives Rheumatoid arthritis is an autoimmune disease with multifactorial etiopathogenesis. Among the environmental factors, mucosal infections and the inducing pathobionts are gaining increasing attention. We here set out to explore the gut-joint-axis and the impact of Clostridioides difficile infection on subsequent arthritis. Methods We combined C. difficile infection in DBA/1J × B10.Q F1 mice with collagen induced arthritis (CIA). Mice were infected via oral gavage and infection was monitored by weight loss, colonic histology, and antibodies against bacteria. Scoring of arthritis was performed macroscopically. Intestinal microbiomes were analyzed and immune responses were monitored via quantification of transcription factor-specific mRNA isolated from the inguinal and mesenteric lymph nodes. Results Infection with C. difficile VPI 10463 resulted in significant weight loss and severe colitis yet accelerated the reversal towards the original microbiome after antibiotic treatment. Spontaneous clearance of VPI 10463 infection reduced the incidence of subsequent CIA and led to mesenteric Treg and Th2 polarization. However, this attenuating effect was abrogated if VPI 10463 was eradicated via vancomycin followed by fecal microbiota transplantation. Moreover, VPI 10463 infection following the onset of CIA lacked therapeutic potential. Conclusion Our results demonstrate that infection with C. difficile VPI10463 induced an inflammation of the gut that protected from subsequent arthritis development in mice. Both, microbial changes to the gut and immune cell mobilization and/or polarization may have contributed to arthritis protection. The prospect of potential therapeutic benefits resulting from C. difficile infections or some byproduct thereof call for further experiments that help elucidate exact mechanisms.
Collapse
Affiliation(s)
- Christian Johann Schmidt
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Katharina Wenndorf
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Meinolf Ebbers
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany.,Department of Tropical Medicine and Infectious Diseases, University Medical Center Rostock, Rostock, Germany
| | - Johann Volzke
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Michael Müller
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany
| | - Julia Strübing
- Microbiology, Institute for Life Sciences, University of Rostock, Rostock, Germany
| | - Katja Kriebel
- Microbiology, Institute for Life Sciences, University of Rostock, Rostock, Germany
| | - Susanne Kneitz
- Physiological Chemistry, Theodor Boveri Institute (Biocenter), University of Wuerzburg, Wuerzburg, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Rostock, Rostock, Germany
| | - Brigitte Müller-Hilke
- Laboratory for Clinical Immunology, Core Facility for Cell Sorting & Cell Analysis, University Medical Center Rostock, Rostock, Germany
| |
Collapse
|
|
5
|
Interactions between Gut Microbiota and Immunomodulatory Cells in Rheumatoid Arthritis. Mediators Inflamm 2020; 2020:1430605. [PMID: 32963490 PMCID: PMC7499318 DOI: 10.1155/2020/1430605] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.
Collapse
|
|
6
|
The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases. J Immunol Res 2019; 2019:7546047. [PMID: 31772949 PMCID: PMC6854958 DOI: 10.1155/2019/7546047] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 09/14/2019] [Indexed: 12/11/2022] Open
Abstract
The human gut-resident commensal microbiota is a unique ecosystem associated with various bodily functions, especially immunity. Gut microbiota dysbiosis plays a crucial role in autoimmune disease pathogenesis as well as in bowel-related diseases. However, the role of the gut microbiota, which causes or influences systemic immunity in autoimmune diseases, remains elusive. Aryl hydrocarbon receptor, a ligand-activated transcription factor, is a master moderator of host-microbiota interactions because it shapes the immune system and impacts host metabolism. In addition, treatment optimization while minimizing potential adverse effects in autoimmune diseases remains essential, and modulation of the gut microbiota constitutes a potential clinical therapy. Here, we present evidence linking gut microbiota dysbiosis with autoimmune mechanisms involved in disease development to identify future effective approaches based on the gut microbiota for preventing autoimmune diseases.
Collapse
|
|
7
|
Abstract
The human gut-resident commensal microbiota is a unique ecosystem associated with various bodily functions, especially immunity. Gut microbiota dysbiosis plays a crucial role in autoimmune disease pathogenesis as well as in bowel-related diseases. However, the role of the gut microbiota, which causes or influences systemic immunity in autoimmune diseases, remains elusive. Aryl hydrocarbon receptor, a ligand-activated transcription factor, is a master moderator of host-microbiota interactions because it shapes the immune system and impacts host metabolism. In addition, treatment optimization while minimizing potential adverse effects in autoimmune diseases remains essential, and modulation of the gut microbiota constitutes a potential clinical therapy. Here, we present evidence linking gut microbiota dysbiosis with autoimmune mechanisms involved in disease development to identify future effective approaches based on the gut microbiota for preventing autoimmune diseases.
Collapse
|
|
8
|
Salem F, Kindt N, Marchesi JR, Netter P, Lopez A, Kokten T, Danese S, Jouzeau JY, Peyrin-Biroulet L, Moulin D. Gut microbiome in chronic rheumatic and inflammatory bowel diseases: Similarities and differences. United European Gastroenterol J 2019; 7:1008-1032. [PMID: 31662859 DOI: 10.1177/2050640619867555] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 07/13/2019] [Indexed: 02/06/2023] Open
Abstract
Introduction Inflammatory bowel diseases (IBDs) and chronic rheumatic diseases (CRDs) are systemic chronic disorders sharing common genetic, immune and environmental factors. About half of patients with IBD develop rheumatic ailments and microscopic intestinal inflammation is present in up to half of CRD patients. IBD and CRD patients also share a common therapeutic armamentarium. Disequilibrium in the complex realm of microbes (known as dysbiosis) that closely interact with the gut mucosal immune system has been associated with both IBD and CRD (spondyloarthritis and rheumatoid arthritis). Whether dysbiosis represents an epiphenomenon or a prodromal feature remains to be determined. Methods In an attempt to further investigate whether specific gut dysbiosis may be the missing link between IBD and CRD in patients developing both diseases, we performed here a systematic literature review focusing on studies looking at bacterial microbiota in CRD and/or IBD patients. Results We included 80 studies, with a total of 3799 IBD patients without arthritis, 1084 CRD patients without IBD, 132 IBD patients with arthropathy manifestations and 12 spondyloarthritis patients with IBD history. Overall, this systematic review indicates that an increase in Bifidobacterium, Staphylococcus, Enterococcus, Lactobacillus, Pseudomonas, Klebsiella and Proteus genera, as well as a decrease in Faecalibacterium, Roseburia genera and species belonging to Verrucomicrobia and Fusobacteria phyla are common features in IBD and CRD patients, whereas dozens of bacterial species are specific features of CRD and IBD. Conclusion Further work is needed to understand the functions of bacteria and of their metabolites but also to characterize fungi and viruses that are commonly found in these patients.
Collapse
Affiliation(s)
- Fatouma Salem
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre Les Nancy, France
| | - Nadège Kindt
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre Les Nancy, France
| | - Julian R Marchesi
- Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, UK.,School of Biosciences, Museum Avenue, Cardiff University, UK
| | - Patrick Netter
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre Les Nancy, France
| | - Anthony Lopez
- NGERE, UMR_ U1256 INSERM-Université de Lorraine, Vandœuvre Les Nancy, France.,Service d'hépato-gastroentérologie, CHRU de Nancy, Vandœuvre Les Nancy, France
| | - Tunay Kokten
- NGERE, UMR_ U1256 INSERM-Université de Lorraine, Vandœuvre Les Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Jean-Yves Jouzeau
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre Les Nancy, France
| | - Laurent Peyrin-Biroulet
- NGERE, UMR_ U1256 INSERM-Université de Lorraine, Vandœuvre Les Nancy, France.,Service d'hépato-gastroentérologie, CHRU de Nancy, Vandœuvre Les Nancy, France
| | - David Moulin
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre Les Nancy, France.,CHRU de Nancy, Contrat d'interface, Vandœuvre Les Nancy, France
| |
Collapse
|
|
9
|
Associations between Adipokines in Arthritic Disease and Implications for Obesity. Int J Mol Sci 2019; 20:ijms20061505. [PMID: 30917508 PMCID: PMC6471239 DOI: 10.3390/ijms20061505] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/18/2019] [Accepted: 03/21/2019] [Indexed: 12/16/2022] Open
Abstract
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines including leptin, adiponectin, visfatin, resistin, chemerin and apelin, in cartilage and bone homeostasis in the pathogenesis of rheumatoid arthritis and osteoarthritis, which has important implications for obesity.
Collapse
|
|
10
|
Yang L, Liu B, Zheng J, Huang J, Zhao Q, Liu J, Su Z, Wang M, Cui Z, Wang T, Zhang W, Li Q, Lu H. Rifaximin Alters Intestinal Microbiota and Prevents Progression of Ankylosing Spondylitis in Mice. Front Cell Infect Microbiol 2019; 9:44. [PMID: 30886835 PMCID: PMC6409347 DOI: 10.3389/fcimb.2019.00044] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 02/12/2019] [Indexed: 12/11/2022] Open
Abstract
Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased Bacteroidetes/Firmicutes phylum ratio, as well as selectively promoting some probiotic populations, including Lactobacillales. Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.
Collapse
Affiliation(s)
- Lianjun Yang
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Bin Liu
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Junchi Zheng
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Jincheng Huang
- Department of Orthopedics, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Qinghao Zhao
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Jinshi Liu
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Zhihai Su
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Min Wang
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Zhifei Cui
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Tingxuan Wang
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Weicong Zhang
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qingchu Li
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Hai Lu
- Department of Orthopedic Surgery, Orthopaedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
11
|
Forbes JD, Chen CY, Knox NC, Marrie RA, El-Gabalawy H, de Kievit T, Alfa M, Bernstein CN, Van Domselaar G. A comparative study of the gut microbiota in immune-mediated inflammatory diseases-does a common dysbiosis exist? MICROBIOME 2018; 6:221. [PMID: 30545401 PMCID: PMC6292067 DOI: 10.1186/s40168-018-0603-4] [Citation(s) in RCA: 285] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 11/25/2018] [Indexed: 05/12/2023]
Abstract
BACKGROUND Immune-mediated inflammatory disease (IMID) represents a substantial health concern. It is widely recognized that IMID patients are at a higher risk for developing secondary inflammation-related conditions. While an ambiguous etiology is common to all IMIDs, in recent years, considerable knowledge has emerged regarding the plausible role of the gut microbiome in IMIDs. This study used 16S rRNA gene amplicon sequencing to compare the gut microbiota of patients with Crohn's disease (CD; N = 20), ulcerative colitis (UC; N = 19), multiple sclerosis (MS; N = 19), and rheumatoid arthritis (RA; N = 21) versus healthy controls (HC; N = 23). Biological replicates were collected from participants within a 2-month interval. This study aimed to identify common (or unique) taxonomic biomarkers of IMIDs using both differential abundance testing and a machine learning approach. RESULTS Significant microbial community differences between cohorts were observed (pseudo F = 4.56; p = 0.01). Richness and diversity were significantly different between cohorts (pFDR < 0.001) and were lowest in CD while highest in HC. Abundances of Actinomyces, Eggerthella, Clostridium III, Faecalicoccus, and Streptococcus (pFDR < 0.001) were significantly higher in all disease cohorts relative to HC, whereas significantly lower abundances were observed for Gemmiger, Lachnospira, and Sporobacter (pFDR < 0.001). Several taxa were found to be differentially abundant in IMIDs versus HC including significantly higher abundances of Intestinibacter in CD, Bifidobacterium in UC, and unclassified Erysipelotrichaceae in MS and significantly lower abundances of Coprococcus in CD, Dialister in MS, and Roseburia in RA. A machine learning approach to classify disease versus HC was highest for CD (AUC = 0.93 and AUC = 0.95 for OTU and genus features, respectively) followed by MS, RA, and UC. Gemmiger and Faecalicoccus were identified as important features for classification of subjects to CD and HC. In general, features identified by differential abundance testing were consistent with machine learning feature importance. CONCLUSIONS This study identified several gut microbial taxa with differential abundance patterns common to IMIDs. We also found differentially abundant taxa between IMIDs. These taxa may serve as biomarkers for the detection and diagnosis of IMIDs and suggest there may be a common component to IMID etiology.
Collapse
Affiliation(s)
- Jessica D. Forbes
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB Canada
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, MB Canada
- National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2 Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Chih-yu Chen
- National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2 Canada
| | - Natalie C. Knox
- National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2 Canada
| | - Ruth-Ann Marrie
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB Canada
- Department of Community Health Sciences, University of Manitoba, Winnipeg, MB Canada
| | - Hani El-Gabalawy
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB Canada
- Arthritis Centre, University of Manitoba, Winnipeg, MB Canada
| | - Teresa de Kievit
- Department of Microbiology, University of Manitoba, Winnipeg, MB Canada
| | - Michelle Alfa
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB Canada
| | - Charles N. Bernstein
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB Canada
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, MB Canada
| | - Gary Van Domselaar
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, MB Canada
- National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2 Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB Canada
| |
Collapse
|