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Debusschere K, Souza D, Nabozny GH, Dumas E, Verheugen E, Coudenys J, Manuello T, Stappers F, Decruy T, Maelegheer M, Schryvers N, Gilis E, Elewaut D. Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis. Rheumatology (Oxford) 2025; 64:3116-3124. [PMID: 39292604 DOI: 10.1093/rheumatology/keae507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 08/08/2024] [Accepted: 08/29/2024] [Indexed: 09/20/2024] Open
Abstract
OBJECTIVES Gut and joint disease commonly co-occur in SpA. Up to 50% of patients with SpA show signs of subclinical gut inflammation, of which 10% develops IBD. However, the mechanisms underlying this gut-joint axis are still unclear. Here we investigated the hypothesis that restricted expression of a pro-inflammatory cytokine in the intestine may trigger the onset of combined gut and joint inflammation. METHODS Intestinal expression of human TNF (hTNF) was achieved by driving hTNF gene expression using the rat FAPB2 promoter, creating a new animal model, TNFgut mice, that expresses hTNF in the proximal intestinal tract. Intestinal-specific TNFgut mice were examined for pathological changes in the intestine and extra-intestinal tissues by means of histology, reverse transcription PCR (RT-PCR) and flow cytometry, along with 16S sequencing on stools. RESULTS Local expression of hTNF in the epithelium of the small intestine induces a pro-inflammatory state of the proximal intestinal tract, with epithelial alterations and induction of members of the S100 family, as well as local upregulation of Th17 and Treg, but no obvious signs of dysbiosis. Curiously, TNFgut mice develop sacroiliitis (P <0.05) in addition to small bowel inflammation (P <0.05). However, no signs of peripheral arthritis or enthesitis could be documented. CONCLUSION Intestinal expression of hTNF is sufficient to initiate a pro-inflammatory cascade culminating in small bowel inflammation and sacroiliitis. Thus, gut-derived cytokines are sufficient to induce SpA.
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Affiliation(s)
- Karlijn Debusschere
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Donald Souza
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
| | - Gerald H Nabozny
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
| | - Emilie Dumas
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Eveline Verheugen
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Julie Coudenys
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Teddy Manuello
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Flore Stappers
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Tine Decruy
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Margaux Maelegheer
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Nadia Schryvers
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Elisabeth Gilis
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
| | - Dirk Elewaut
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, Unit for Molecular Immunology and Inflammation, Ghent, Belgium
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Qaiyum Z, Inman RD. Response to Correspondence on 'Why the term nr-axSpA should not be used for diagnosis'. Ann Rheum Dis 2025; 84:e21-e22. [PMID: 39919970 DOI: 10.1016/j.ard.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 12/09/2024] [Indexed: 02/09/2025]
Affiliation(s)
- Zoya Qaiyum
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
| | - Robert D Inman
- Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.
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Ladehesa-Pineda ML, Ruiz-Vilchez D, Barranco AM, Puche-Larrubia MÁ, Font-Ugalde P, Granados REM, Gratacós-Mastmijà J, Juanola X, Escudero-Contreras A, Collantes-Estévez E, López-Medina C. Association Between Diagnostic Delay and Short-Term Outcomes in Patients with Radiographic Axial Spondyloarthritis: Results from the Regisponser-AS Registry. J Clin Med 2025; 14:1977. [PMID: 40142783 PMCID: PMC11943167 DOI: 10.3390/jcm14061977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/03/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
Objectives: To evaluate whether the diagnostic delay in patients with radiographic axial spondyloarthritis (r-axSpA) is associated with poorer short-term outcomes after two years of follow-up. Methods: This was an observational, longitudinal, and prospective study including patients with r-axSpA from the national multicentre Spanish REGISPONSER-AS registry. Patients were divided into two groups according to the mean diagnostic delay (<5 years, ≥5 years). Binary logistic regression models adjusted for disease duration were constructed and used to evaluate the association between diagnostic delay and disease outcomes at two years. The retention rate for first-line treatment with anti-TNF across the groups was evaluated using a log-rank test. Results: A total of 565 patents were included. The mean diagnostic delay was 5.6 ± 6.2 years, with 325 patients experiencing a delay of <5 years and 240 patients experiencing a delay of ≥5 years. A diagnostic delay of ≥5 years was associated, after 2 years, with a higher prevalence of inflammatory bowel disease (IBD) (OR 2.01 (95%CI 1.06-3.83)), a lower prevalence of synovitis (OR 0.68 (95%CI 0.47-0.98)) and dactylitis (OR 0.24 (95%CI 0.11-0.55)), and worse disease activity after adjusting by disease duration. However, no impact was observed on quality of life, structural damage, or work disability, probably due to the short follow-up period. Finally, no differences between the groups were found with regard to the retention rate for first-line anti-TNF treatment. Conclusions: Diagnostic delay is associated with poorer short-term outcomes in terms of structural damage, dactylitis, and disability in patients with r-axSpA.
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Affiliation(s)
- María Lourdes Ladehesa-Pineda
- Rheumatology Department, Reina Sofia University Hospital, 14004 Cordoba, Spain; (M.Á.P.-L.); (R.E.M.G.); (A.E.-C.); (C.L.-M.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Desirée Ruiz-Vilchez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Antonio Manuel Barranco
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - María Ángeles Puche-Larrubia
- Rheumatology Department, Reina Sofia University Hospital, 14004 Cordoba, Spain; (M.Á.P.-L.); (R.E.M.G.); (A.E.-C.); (C.L.-M.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Pilar Font-Ugalde
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Raquel Ena María Granados
- Rheumatology Department, Reina Sofia University Hospital, 14004 Cordoba, Spain; (M.Á.P.-L.); (R.E.M.G.); (A.E.-C.); (C.L.-M.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Jordi Gratacós-Mastmijà
- Rheumatology Department, University Hospital Parc Tauli, 08208 Sabadell, Spain;
- Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
| | - Xavier Juanola
- Rheumatology Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;
| | - Alejandro Escudero-Contreras
- Rheumatology Department, Reina Sofia University Hospital, 14004 Cordoba, Spain; (M.Á.P.-L.); (R.E.M.G.); (A.E.-C.); (C.L.-M.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Eduardo Collantes-Estévez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
| | - Clementina López-Medina
- Rheumatology Department, Reina Sofia University Hospital, 14004 Cordoba, Spain; (M.Á.P.-L.); (R.E.M.G.); (A.E.-C.); (C.L.-M.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (D.R.-V.); (A.M.B.); (P.F.-U.); (E.C.-E.)
- Medical and Surgical Department, University of Cordoba, 14004 Cordoba, Spain
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Thiran A, Vereecke L. New thoughts on the gut-immune axis of arthritis. Trends Immunol 2025; 46:206-218. [PMID: 40069048 DOI: 10.1016/j.it.2025.01.006] [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: 11/20/2024] [Revised: 12/23/2024] [Accepted: 01/27/2025] [Indexed: 03/21/2025]
Abstract
Arthritis is associated with varying degrees of intestinal inflammation and microbiota dysbiosis, leading to the 'gut-joint axis hypothesis' in which intestinal and joint inflammation are suggested to be interconnected through immune-microbiota interactions. While clinical observations support this, causality remains uncertain. Rodent models have provided insights into potential mechanisms by uncovering microbial influences and immune pathways that either connect or uncouple gut and joint inflammation. Based on recent findings, we propose the 'immune hypersensitivity hypothesis' whereby central immune hyper-reactivity can independently drive joint inflammation via local sterile triggers, and gut inflammation via microbial triggers. We argue that this suggests a more nuanced role of the microbiota in arthritis pathogenesis that varies according to the predominant immune mechanisms in disease subtypes. We explore gut-immune interactions in arthritis, highlight ongoing challenges, and propose future research directions.
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Affiliation(s)
- Alexandra Thiran
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Vlaams Instituut voor Biotechnologie (VIB)-University of Ghent (UGent) Center for Inflammation Research, Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent, Belgium
| | - Lars Vereecke
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Vlaams Instituut voor Biotechnologie (VIB)-University of Ghent (UGent) Center for Inflammation Research, Ghent, Belgium; Ghent Gut Inflammation Group (GGIG), Ghent, Belgium.
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Cheng M, Xiao S, Kayi S, Guan Y, Liu Y, Chen J, Chen H, Wang L, He X. Colon mucosal proteomics of ankylosing spondylitis versus gut inflammation. PLoS One 2024; 19:e0315324. [PMID: 39671362 PMCID: PMC11642932 DOI: 10.1371/journal.pone.0315324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 11/23/2024] [Indexed: 12/15/2024] Open
Abstract
OBJECTIVE Ankylosing spondylitis (AS) patients often present with microscopic signs of gut inflammation. We used proteomic techniques to identify the differentially expressed proteins (DEPs) in the colon tissues of patients with AS and patients with gut inflammation, and then used investigated the influence of NMRAL1 protein on inflammatory cytokines to explore its potential role in the pathogenesis of AS and gut inflammation. METHODS Colonic mucosal tissues were collected from four different groups: healthy individuals (group A), patients with gut inflammation only (group B), patients with AS only (group C), and patients with AS combined with gut inflammation (group D). A total of 20 samples were processed for proteomic analysis, wherein proteins were extracted using SDT lysis, followed by separation via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The proteins were digested using the filter-aided sample preparation (FASP) method and then analyzed using a timsTOF Pro mass spectrometer. The resulting peptide data were used to identify differentially expressed proteins (DEPs) across the different groups. To further explore the inflammation-related function of NMRAL1 protein, the murine monocyte/macrophage cell line RAW264.7 was used. NMRAL1 mRNA expression levels were assessed via RT-qPCR, and inflammatory cytokine levels (TNF-α, IL-1β, IL-17 and IL-23) were measured using ELISA following NMRAL1 siRNA transfection in LPS-treated macrophages. RESULTS We collected colonic mucosa specimens from 20 patients, including groups A,B, C and D with 5 patients in each group. We established a database of DEPs and identified 107 (63 upregulated and 44 downregulated) between group B and group A, 78 (16 upregulated and 62 downregulated) between group D and group C, 45 (8 upregulated and 37 downregulated) between group D and group B, and 57 (33 upregulated and 24 downregulated) between group C and group A. Further analysis revealed that the NmrA-like family domain containing 1 (NMRAL1) protein was identified as a DEP specifically associated with group D. The results of in vitro results showed a significant decrease in NMRAL1 mRNA expression in LPS-treated cells (P<0.001), which was further reduced in NMRAL1 siRNA-transfected cells (P<0.0001), confirming successful transfection. ELISA results revealed that the levels of key inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-23) were significantly elevated in the LPS-treated model group (P<0.0001, P<0.001), but these levels were significantly decreased after NMRAL1 siRNA transfection (P<0.0001, P<0.01, P<0.05). CONCLUSION NMRAL1 is identified as a key differentially expressed protein in AS patients with gut inflammation. Knockdown of NMRAL1 significantly reduced the levels of inflammatory cytokines, suggesting its potential role in the pathogenesis of AS and gut inflammation, and as a possible therapeutic target.
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Affiliation(s)
- Miao Cheng
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Siqi Xiao
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Shaer Kayi
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Yujie Guan
- Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, China
| | - Yingxin Liu
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Jianmei Chen
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Hua Chen
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Wang
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Xiaojin He
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, China
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Yau E, Lim M, Qaiyum Z, Boroojeni SF, Tang M, Pacheco A, Tavasolian F, Inman RD. Effect of Integrin Blockade on Experimental Spondyloarthritis. Biomolecules 2024; 14:1386. [PMID: 39595563 PMCID: PMC11591768 DOI: 10.3390/biom14111386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Spondyloarthritis (SpA) describes a group of diseases characterized by chronic inflammation in the spine and peripheral joints. While pathogenesis is still unclear, proinflammatory gut-derived immune cells have been identified in the joints of SpA patients. We previously identified an enriched population of integrin-expressing cells in the joints of SpA patients. Entry of gut-derived cells into joints may be mediated by these integrins. In the current study, we used the SKG murine model of SpA to study the impact of integrin blockade. Mice were injected with antibodies against the integrin α4β7 or the β7 monomer twice a week. Treatment with antibodies against α4β7 reduced disease severity in curdlan-injected SKG mice, with disease scores being comparable between treatment initiation times. Targeting the β7 monomer led to reduced arthritis severity compared to targeting the α4β7 dimer. Treatment with antibodies against α4β7 or β7 decreased expression of these integrins in CD4+ T cells, with the frequency of αE+β7+ T cells in the spleen and lymph nodes correlating with disease severity. In summary, we showed that integrin blockade showed potential for ameliorating disease in a murine model of SpA, lending support for further studies testing integrin blockade in SpA.
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Affiliation(s)
- Enoch Yau
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Melissa Lim
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Zoya Qaiyum
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Shaghayegh Foroozan Boroojeni
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Michael Tang
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Addison Pacheco
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Fataneh Tavasolian
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
| | - Robert D. Inman
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; (E.Y.)
- Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
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Qaiyum Z, Seidman MA, Ross HJ, Inman RD. Cardiac valve immune profiling in non-radiographic axial spondyloarthritis. Ann Rheum Dis 2024; 83:1394-1399. [PMID: 38925886 DOI: 10.1136/ard-2024-225942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Affiliation(s)
- Zoya Qaiyum
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
| | - Michael Aaron Seidman
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Heather Joan Ross
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
- Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Robert D Inman
- Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Luo K, Zeng W, Li Q, Zhang Y, Liu S, Liu X, Liu S. Causal effects of specific gut microbiota on spinal stenosis diseases: a two-sample mendelian randomization study. Front Genet 2024; 15:1400847. [PMID: 39399222 PMCID: PMC11467959 DOI: 10.3389/fgene.2024.1400847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/16/2024] [Indexed: 10/15/2024] Open
Abstract
Background Although recent observational studies and clinical trials have indicated a strong association between the gut microbiota and spinal stenosis diseases, the causal relationship between them remains unclear. Methods Based on large-scale genome-wide association studies, we employed two-sample Mendelian randomization (MR) to analyse the causal relationships between the gut microbiota (GM) and 3 spinal stenosis diseases: adolescent idiopathic scoliosis (AIS), lumbar spondylolisthesis (LS), and spinal stenosis (SS). MR analysis was performed using the inverse variance weighting (IVW) method as the primary approach, supplemented by MR‒Egger regression, weighted median, and weighted mode analyses. MR-PRESSO and MR‒Egger regression were employed to assess horizontal pleiotropy. Cochran's Q test was used to evaluate heterogeneity. Further leave-one-out sensitivity analysis was conducted to ascertain the reliability of the causal relationships. Results The IVW method identified 9 gut microbiota taxa (9 genera) that were causally related to AIS, 14 taxa (4 phyla, 2 classes, 2 orders, 1 family, and 5 genera) to LS, and 4 taxa (2 classes, 1 order, and 1 genus) to SS. The Cochrane Q test results did not indicate heterogeneity. Moreover, both the MR‒Egger intercept test and the MR-PRESSO global test demonstrated that our findings were robust against potential horizontal pleiotropy. Furthermore, leave-one-out analysis provided additional evidence supporting the reliability of our identified causal relationships. Conclusion Our findings have substantiated the potential causal impact of specific GM taxa on AIS, LS, and SS, thereby offering novel insights into the mechanisms mediated by the gut microbiota in these three diseases and laying the foundation for targeted preventive measures in further research.
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Affiliation(s)
- Kaihang Luo
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weizheng Zeng
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiushuang Li
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuliang Zhang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
| | - Shengkai Liu
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xizhe Liu
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shaoyu Liu
- Department of Spinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Navid F, Gill T, Fones L, Allbritton-King JD, Zhou K, Shen I, Van Doorn J, LiCausi F, Cougnoux A, Randazzo D, Brooks SR, Colbert RA. CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis. Sci Rep 2024; 14:12293. [PMID: 38811719 PMCID: PMC11137091 DOI: 10.1038/s41598-024-62940-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/22/2024] [Indexed: 05/31/2024] Open
Abstract
HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human β2m (hβ2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.
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Affiliation(s)
- Fatemeh Navid
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA.
| | - Tejpal Gill
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Lilah Fones
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | | | - Kelly Zhou
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Isabel Shen
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Jinny Van Doorn
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Francesca LiCausi
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Antony Cougnoux
- Section on Molecular Dysmorphology, NICHD, NIH, Bethesda, MD, 20892, USA
| | | | - Stephen R Brooks
- Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD, 20892, USA
| | - Robert A Colbert
- Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA
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10
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Wang M, He X. Mendelian randomization analysis reveals causal associations of inflammatory bowel disease with Spondylarthritis. Gene 2024; 902:148170. [PMID: 38237812 DOI: 10.1016/j.gene.2024.148170] [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: 11/14/2023] [Revised: 12/28/2023] [Accepted: 01/15/2024] [Indexed: 01/28/2024]
Abstract
OBJECTIVE Inflammatory bowel disease (IBD) is strongly associated with Spondylarthritis (SpA), but the causal relationship remains unclear. This study explores the causal associations between IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and several common subtypes of SpA (Ankylosing Spondylitis [AS], Psoriatic Arthritis [PsA], and Reactive Arthritis [ReA]), using bidirectional two-sample Mendelian randomization (TSMR). METHODS The causal effects of genetically predicted IBD on AS, PsA, and ReA were firstly investigated in this forward study. The causal effects from AS, PsA, and ReA on IBD were analyzed in the reverse MR. Inverse variance weighted, weighted median, and MR-Egger were applied in the MR analyses. The pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis were also evaluated. RESULTS The forward MR analysis demonstrated that IBD increased risk for AS (OR:1.278; P = 1.273 × 10-5), PsA (OR:1.192; P = 1.690 × 10-5), and ReA (OR:1.106; P = 1.524 × 10-3). Among them, CD increased risk of AS (OR:1.196; P = 3.424 × 10-4), PsA (OR:1.101; P = 1.537 × 10-3), ReA (OR:1.079; P = 6.321 × 10-3) whereas UC increased risk of AS (OR:1.166; P = 2.727 × 10-2), PsA (OR:1.110; P = 1.944 × 10-2), and ReA (OR:1.091; P = 1.768 × 10-2). The reverse-direction MR disclosed no notable association; neither was any evidence of pleiotropy detected. CONCLUSION Our study verifies a causal effect of IBD to AS, PsA as well as ReA, but not vice versa. This might bring new insights for the management of IBD and SpA in clinical practice.
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Affiliation(s)
- Min Wang
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Department of Rheumatology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Xiaojin He
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Department of Rheumatology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China.
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11
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Bragazzi MC, Pianigiani F, Venere R, Ridola L. Dysbiosis in Inflammatory Bowel Disease and Spondyloarthritis: Still a Long Way to Go? J Clin Med 2024; 13:2237. [PMID: 38673510 PMCID: PMC11050776 DOI: 10.3390/jcm13082237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/02/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
The association between Inflammatory Bowel Disease (IBD) and Spondyloarthritis (SpA) has been known for years, as has the concept that IBD is associated with an altered intestinal bacterial composition, a condition known as "dysbiosis". Recently, a state of intestinal dysbiosis has also been found in SpA. Dysbiosis in the field of IBD has been well characterized so far, as well as in SpA. The aim of this review is to summarize what is known to date and to emphasize the similarities between the microbiota conditions in these two diseases: particularly, an altered distribution in the gut of Enterobacteriaceae, Streptococcus, Haemophilus, Clostridium, Akkermansia, Ruminococcus, Faecalibacterium Prausnitzii, Bacteroides Vulgatus, Dialister Invisus, and Bifidubacterium Adolescentis is common to both IBD and SpA. At the same time, little is known about intestinal dysbiosis in IBD-related SpA. Only a single recent study has found an increase in Escherichia and Shigella abundances and a decrease in Firmicutes, Ruminococcaceae, and Faecalibacterium abundances in an IBD-related SpA group. Based on what has been discovered so far about the altered distribution of bacteria that unite both pathologies, it is appropriate to carry out further studies aiming to improve the understanding of IBD-related SpA for the purpose of developing new therapeutic strategies.
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Affiliation(s)
| | | | | | - Lorenzo Ridola
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome, Polo Pontino, 04100 Rome, Italy; (M.C.B.); (F.P.); (R.V.)
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12
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Longo UG, Lalli A, Bandini B, de Sire R, Angeletti S, Lustig S, Ammendolia A, Budhiparama NC, de Sire A. Role of the Gut Microbiota in Osteoarthritis, Rheumatoid Arthritis, and Spondylarthritis: An Update on the Gut-Joint Axis. Int J Mol Sci 2024; 25:3242. [PMID: 38542216 PMCID: PMC10970477 DOI: 10.3390/ijms25063242] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/16/2024] [Accepted: 03/11/2024] [Indexed: 01/06/2025] Open
Abstract
Dysregulation of the gut microbiota and their metabolites is involved in the pathogenic process of intestinal diseases, and several pieces of evidence within the current literature have also highlighted a possible connection between the gut microbiota and the unfolding of inflammatory pathologies of the joints. This dysregulation is defined as the "gut-joint axis" and is based on the joint-gut interaction. It is widely recognized that the microbiota of the gut produce a variety of compounds, including enzymes, short-chain fatty acids, and metabolites. As a consequence, these proinflammatory compounds that bacteria produce, such as that of lipopolysaccharide, move from the "leaky gut" to the bloodstream, thereby leading to systemic inflammation which then reaches the joints, with consequences such as osteoarthritis, rheumatoid arthritis, and spondylarthritis. In this state-of-the-art research, the authors describe the connections between gut dysbiosis and osteoarthritis, rheumatoid arthritis, and spondylarthritis. Moreover, the diagnostic tools, outcome measures, and treatment options are elucidated. There is accumulating proof suggesting that the microbiota of the gut play an important part not only in immune-mediated, metabolic, and neurological illnesses but also in inflammatory joints. According to the authors, future studies should concentrate on developing innovative microbiota-targeted treatments and their effects on joint pathology as well as on organizing screening protocols to predict the onset of inflammatory joint disease based on gut dysbiosis.
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Affiliation(s)
- Umile Giuseppe Longo
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (U.G.L.); (A.L.); (B.B.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Alberto Lalli
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (U.G.L.); (A.L.); (B.B.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Benedetta Bandini
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (U.G.L.); (A.L.); (B.B.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Roberto de Sire
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy;
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80126 Naples, Italy
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, 00128 Rome, Italy;
| | - Sebastien Lustig
- Orthopaedic Department, Lyon North University Hospital, Hôpital de La Croix Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69004 Lyon, France;
| | - Antonio Ammendolia
- Department of Medical and Surgical Sciences, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy;
- Research Center on Musculoskeletal Health, MusculoSkeletalHealth@UMG, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy
| | | | - Alessandro de Sire
- Department of Medical and Surgical Sciences, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy;
- Research Center on Musculoskeletal Health, MusculoSkeletalHealth@UMG, University of Catanzaro “Magna Graecia”, 88100 Catanzaro, Italy
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13
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Tang J, Mo S, Fan L, Fu S, Liu X. Causal association of gut microbiota on spondyloarthritis and its subtypes: a Mendelian randomization analysis. Front Immunol 2024; 15:1284466. [PMID: 38390322 PMCID: PMC10883304 DOI: 10.3389/fimmu.2024.1284466] [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: 08/28/2023] [Accepted: 01/18/2024] [Indexed: 02/24/2024] Open
Abstract
Background Despite establishing an association between gut microbiota and spondyloarthritis (SpA) subtypes, the causal relationship between them remains unclear. Methods Gut microbiota data were obtained from the MiBioGen collaboration, and SpA genome-wide association study (GWAS) summary data were obtained from the FinnGen collaboration. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance-weighted method supplemented with four additional MR methods (MR-Egger, weighted median, simple mode, and weighted mode). Pleiotropy and heterogeneity were also assessed. Reverse MR analysis was used to detect reverse causal relationships. Results We identified 23 causal links between specific gut microbiota taxa and SpA levels. Of these, 22 displayed nominal causal associations, and only one demonstrated a robust causal connection. Actinobacteria id.419 increased the risk of ankylosing spondylitis (AS) (odds ratio (OR) = 1.86 (95% confidence interval (CI): 1.29-2.69); p = 8.63E-04). The family Rikenellaceae id.967 was associated with a reduced risk of both AS (OR = 0.66 (95% CI: 0.47-0.93); p = 1.81E-02) and psoriatic arthritis (OR = 0.70 (95% CI: 0.50-0.97); p = 3.00E-02). Bacillales id.1674 increased the risk of AS (OR = 1.23 (95% CI: 1.00-1.51); p = 4.94E-02) and decreased the risk of enteropathic arthritis (OR = 0.56 (95% CI: 0.35-0.88); p = 1.14E-02). Directional pleiotropy, or heterogeneity, was not observed. No reverse causal associations were observed between the diseases and the gut microbiota. Conclusion Our MR analysis suggested a genetic-level causal relationship between specific gut microbiota and SpA, providing insights into the underlying mechanisms behind SpA development mediated by gut microbiota.
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Affiliation(s)
- Jun Tang
- Experimental Teaching Management Center, Chongqing Medical University, Chongqing, China
| | - Shiyan Mo
- Department of Rheumatology and Immunology, Hainan Hospital of Chinese People's Liberation Army of China (PLA) General Hospital, Sanya, Hainan, China
| | - Lina Fan
- Department of Rheumatology and Immunology, Hainan Hospital of Chinese People's Liberation Army of China (PLA) General Hospital, Sanya, Hainan, China
| | - Shihui Fu
- Department of Cardiovascular, Hainan Hospital of Chinese People’s Liberation Army of China (PLA) General Hospital, Sanya, Hainan, China
| | - Xiaofei Liu
- Department of Rheumatology and Immunology, Hainan Hospital of Chinese People's Liberation Army of China (PLA) General Hospital, Sanya, Hainan, China
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14
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Zhangni L, Mofan X, Yuling C, Yingchao L. Clinical features and fecal microbiota characteristics of patients with both ulcerative colitis and axial spondyloarthritis. BMC Gastroenterol 2024; 24:56. [PMID: 38297219 PMCID: PMC10832282 DOI: 10.1186/s12876-024-03150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/26/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND The role of the intestinal microbiota in the pathogenesis of inflammatory bowel disease combined with axial spondyloarthritis (axSpA) is gaining widespread interest. AIMS This study was conducted to investigate the clinical and fecal microbiota characteristics of patients with both ulcerative colitis (UC) and axSpA. METHODS Clinical data were collected from patients with UC. Patients were divided into the axSpA and non-axSpA groups according to human leukocyte antigen-B27 serology and sacroiliac joint imaging results. We obtained fecal specimens from 14 axSpA and 26 non-axSpA patients. All samples underwent 16S ribosomal DNA sequencing. RESULTS Seventy-three patients with UC were included in this study, and the axSpA incidence was 19.2%. This incidence was significantly higher in patients with C-reactive protein > 10 mg/L. Firmicutes and Faecalibacterium abundances were decreased, and Proteobacteria and Escherichia_Shigella abundances were increased in the axSpA group compared with those of the non-axSpA group. Indicator analysis showed that Escherichia_Shigella was more likely to be an indicator species of axSpA. Additionally, many biosynthetic and metabolic pathways, including glutathione metabolism, fatty acid degradation, geraniol degradation, and biosynthesis of siderophore group nonribosomal peptides, were upregulated in the axSpA group. CONCLUSION Patients with UC have a high axSpA incidence, which may be related to the relative abundances of Escherichia_Shigella in these patients. The abundances of various biosynthetic and metabolic pathways of the fecal flora were upregulated in patients with axSpA.
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Affiliation(s)
- Lei Zhangni
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, China
| | - Xiao Mofan
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, China
| | - Chen Yuling
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, China
| | - Li Yingchao
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710061, China.
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15
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Morimoto T, Kobayashi T, Kakiuchi T, Esaki M, Tsukamoto M, Yoshihara T, Hirata H, Yabuki S, Mawatari M. Gut-spine axis: a possible correlation between gut microbiota and spinal degenerative diseases. Front Microbiol 2023; 14:1290858. [PMID: 37965563 PMCID: PMC10641865 DOI: 10.3389/fmicb.2023.1290858] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/10/2023] [Indexed: 11/16/2023] Open
Abstract
As society ages, the number of patients with spinal degenerative diseases (SDD) is increasing, posing a major socioeconomic problem for patients and their families. SDD refers to a generic term for degenerative diseases of spinal structures, including osteoporosis (bone), facet osteoarthritis (joint), intervertebral disk degeneration (disk), lumbar spinal canal stenosis (yellow ligament), and spinal sarcopenia (muscle). We propose the term "gut-spine axis" for the first time, given the influence of gut microbiota (GM) on the metabolic, immune, and endocrine environment in hosts through various potential mechanisms. A close cross-talk is noted between the aforementioned spinal components and degenerative diseases. This review outlines the nature and role of GM, highlighting GM abnormalities associated with the degeneration of spinal components. It also summarizes the evidence linking GM to various SDD. The gut-spine axis perspective can provide novel insights into the pathogenesis and treatment of SDD.
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Affiliation(s)
- Tadatsugu Morimoto
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Takaomi Kobayashi
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Toshihiko Kakiuchi
- Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan
| | - Motohiro Esaki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Masatsugu Tsukamoto
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Tomohito Yoshihara
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Hirohito Hirata
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Shoji Yabuki
- Fukushima Medical University School of Health Sciences, Fukushima, Japan
| | - Masaaki Mawatari
- Department of Orthopedic Surgery, Faculty of Medicine, Saga University, Saga, Japan
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16
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Thiran A, Petta I, Blancke G, Thorp M, Planckaert G, Jans M, Andries V, Barbry K, Gilis E, Coudenys J, Hochepied T, Vanhove C, Gracey E, Dumas E, Manuelo T, Josipovic I, van Loo G, Elewaut D, Vereecke L. Sterile triggers drive joint inflammation in TNF- and IL-1β-dependent mouse arthritis models. EMBO Mol Med 2023; 15:e17691. [PMID: 37694693 PMCID: PMC10565626 DOI: 10.15252/emmm.202317691] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/12/2023] Open
Abstract
Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed "the gut-joint-axis." The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data, however, support a correlative relationship between gut and joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF- or IL-1β dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full-blown articular inflammation under germ-free conditions. In contrast, TNF-driven gut inflammation is fully rescued in germ-free conditions, indicating that the microbiota is driving TNF-induced gut inflammation. Together, our study demonstrates that although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.
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17
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Lin A, Tan Y, Chen J, Liu X, Wu J. Development of ankylosing spondylitis in patients with ulcerative colitis: A systematic meta-analysis. PLoS One 2023; 18:e0289021. [PMID: 37527250 PMCID: PMC10393153 DOI: 10.1371/journal.pone.0289021] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/09/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a manifestation of inflammatory bowel disease (IBD), which can cause inflammation of the intestinal tract. Ankylosing spondylitis (AS) is an inflammatory disease of the sacroiliac joints. Many studies have found that some UC patients progress to AS. In this study, we conducted a literature search and meta-analysis to investigate the prevalence of AS among UC patients during follow-up. METHODS The studies related to the AS among patients with UC were obtained from PubMed, Web of Science, Embase, and Cochrane Library databases since its inception-December 2022. The literature was screened strictly according to inclusion and exclusion criteria. Forest plots were used to detect the overall incidence of AS in UC and to compare the risk ratios for the development of AS in the UC. The heterogeneity of studies was assessed using I2 statistical methods. RESULTS 1) 17 studies with 98704 UC patients were included. 2)700 UC patients developed AS during follow-up (1.66%, 95% CI: 0.89-2.62%). Human leukocyte antigen B27 (HLA-B27) was reported in 3 studies. HLA-B27 positivity was significantly higher than the incidence of HLA-B27 negativity in AS patients (68.29% vs 31.71%, P < 0.0001). There was significantly increased risk of AS development in HLA-B27 positive IBD patients (RR: 22.17, 95% CI: 11.79-41.66, P < 0.0001). 3)The definite follow-up time was reported in 12 studies (range: 0.3-40 years). After follow-up for ≥5 years, the incidence of AS among patients with UC was 1.75% (95% CI: 0.62-3.37%). Meanwhile, after follow-up for <5 years, the incidence of AS among patients with UC was 1.41% (95% CI: 0.65-2.37%) which was significant. CONCLUSION Patients with UC are more likely to develop AS in the future. Furthermore, the IBD patients are at a higher risk of AS who have positive HLA-B27. The incidence of AS increased with longer follow-up time.
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Affiliation(s)
- Aitao Lin
- Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Yongyi Tan
- Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Jinxia Chen
- Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Xiaoyu Liu
- Department of Rheumatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jinyu Wu
- Department of Rheumatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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18
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Efremova I, Maslennikov R, Poluektova E, Vasilieva E, Zharikov Y, Suslov A, Letyagina Y, Kozlov E, Levshina A, Ivashkin V. Epidemiology of small intestinal bacterial overgrowth. World J Gastroenterol 2023; 29:3400-3421. [PMID: 37389240 PMCID: PMC10303511 DOI: 10.3748/wjg.v29.i22.3400] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 03/31/2023] [Accepted: 05/11/2023] [Indexed: 06/06/2023] Open
Abstract
Small intestinal bacterial overgrowth (SIBO) is defined as an increase in the bacterial content of the small intestine above normal values. The presence of SIBO is detected in 33.8% of patients with gastroenterological complaints who underwent a breath test, and is significantly associated with smoking, bloating, abdominal pain, and anemia. Proton pump inhibitor therapy is a significant risk factor for SIBO. The risk of SIBO increases with age and does not depend on gender or race. SIBO complicates the course of a number of diseases and may be of pathogenetic significance in the development of their symptoms. SIBO is significantly associated with functional dyspepsia, irritable bowel syndrome, functional abdominal bloating, functional constipation, functional diarrhea, short bowel syndrome, chronic intestinal pseudo-obstruction, lactase deficiency, diverticular and celiac diseases, ulcerative colitis, Crohn's disease, cirrhosis, metabolic-associated fatty liver disease (MAFLD), primary biliary cholangitis, gastroparesis, pancreatitis, cystic fibrosis, gallstone disease, diabetes, hypothyroidism, hyperlipidemia, acromegaly, multiple sclerosis, autism, Parkinson's disease, systemic sclerosis, spondylarthropathy, fibromyalgia, asthma, heart failure, and other diseases. The development of SIBO is often associated with a slowdown in orocecal transit time that decreases the normal clearance of bacteria from the small intestine. The slowdown of this transit may be due to motor dysfunction of the intestine in diseases of the gut, autonomic diabetic polyneuropathy, and portal hypertension, or a decrease in the motor-stimulating influence of thyroid hormones. In a number of diseases, including cirrhosis, MAFLD, diabetes, and pancreatitis, an association was found between disease severity and the presence of SIBO. Further work on the effect of SIBO eradication on the condition and prognosis of patients with various diseases is required.
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Affiliation(s)
- Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Ekaterina Vasilieva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Yury Zharikov
- Department of Human Anatomy and Histology, Sechenov University, Moscow 125009, Russia
| | - Andrey Suslov
- Department of Human Anatomy and Histology, Sechenov University, Moscow 125009, Russia
| | - Yana Letyagina
- N.V. Sklifosovsky Institute of Clinical Medicine, Sechenov University, Moscow 119991, Russia
| | - Evgenii Kozlov
- Department of Clinical Immunology and Allergy, Sechenov University, Moscow 119991, Russia
| | - Anna Levshina
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Department of Clinical Immunology and Allergy, Sechenov University, Moscow 119991, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
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19
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Brahem M, Jomaa O, Arfa S, Sarraj R, Tekaya R, Berriche O, Hachfi H, Younes M. Acute arthritis following SARS-CoV-2 infection: About two cases. Clin Case Rep 2023; 11:e7334. [PMID: 37205154 PMCID: PMC10185734 DOI: 10.1002/ccr3.7334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 02/22/2023] [Accepted: 04/25/2023] [Indexed: 05/21/2023] Open
Abstract
Joint involvement in COVID-19 may occur at different stages of the disease and maybe represented by non-specific arthralgia or by acute arthritis. We report two cases of COVID-19 infection that were complicated by postviral reactive arthritis. Case 1: A 47-year-old male was presented 20 days after a COVID-19 infection with acute right knee arthritis. On biologic data, erythrocyte sedimentation rate and C-reactive protein were normal, and immunologic data were negative. A joint puncture was performed showing a turbid fluid. Testing for microcrystals was negative, as well as the synovial fluid culture. An infectious investigation was conducted, which was negative. The patient's complaints improved significantly, with analgesics and non-steroidal anti-inflammatory drugs (NSAID). Case 2: A 33-year-old female presented with acute left knee arthritis evolving for 48 h, free of fever, after a COVID-19 infection treated 15 days ago. On examination, besides knee arthritis, the osteoarticular examination was normal. A biological inflammatory syndrome was noted in laboratory tests. A yellow fluid with multiple PNN was detected in the joint fluid aspiration, with a negative culture. The patient was treated by analgesics and NSAID. The follow-up was highlighted by the arthritis resolution. Conclusion: Both of our cases are consistent with what has already been reported in the literature confirming the development of PostCOVID arthritis and strengthen the impending necessity of wider studies to identify rheumatologic manifestations in the short- and long-terms after surviving COVID-19.
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Affiliation(s)
- Mouna Brahem
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Olfa Jomaa
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Sondess Arfa
- Endocrinology and Internal Medicine DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Rihab Sarraj
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Rami Tekaya
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Olfa Berriche
- Endocrinology and Internal Medicine DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Haifa Hachfi
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
| | - Mohamed Younes
- Rheumatology DepartmentTaher Sfar University HospitalMahdiaTunisia
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Tavasolian F, Inman RD. Biology and therapeutic potential of mesenchymal stem cell extracellular vesicles in axial spondyloarthritis. Commun Biol 2023; 6:413. [PMID: 37059822 PMCID: PMC10104809 DOI: 10.1038/s42003-023-04743-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/21/2023] [Indexed: 04/16/2023] Open
Abstract
Axial spondyloarthritis (AxSpA) is a chronic, inflammatory, autoimmune disease that predominantly affects the joints of the spine, causes chronic pain, and, in advanced stages, may result in spinal fusion. Recent developments in understanding the immunomodulatory and tissue-differentiating properties of mesenchymal stem cell (MSC) therapy have raised the possibility of applying such treatment to AxSpA. The therapeutic effectiveness of MSCs has been shown in numerous studies spanning a range of diseases. Several studies have been conducted examining acellular therapy based on MSC secretome. Extracellular vesicles (EVs) generated by MSCs have been proven to reproduce the impact of MSCs on target cells. These EVs are associated with immunological regulation, tissue remodeling, and cellular homeostasis. EVs' biological effects rely on their cargo, with microRNAs (miRNAs) integrated into EVs playing a particularly important role in gene expression regulation. In this article, we will discuss the impact of MSCs and EVs generated by MSCs on target cells and how these may be used as unique treatment strategies for AxSpA.
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Affiliation(s)
- Fataneh Tavasolian
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada
| | - Robert D Inman
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
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21
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Coletto LA, Rizzo C, Guggino G, Caporali R, Alivernini S, D’Agostino MA. The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations. Int J Mol Sci 2023; 24:4108. [PMID: 36835520 PMCID: PMC9959122 DOI: 10.3390/ijms24044108] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Spondyloarthritis (SpA) contemplates the inflammatory involvement of the musculoskeletal system, gut, skin, and eyes, delineating heterogeneous diseases with a common pathogenetic background. In the framework of innate and adaptive immune disruption in SpA, neutrophils are arising, across different clinical domains, as pivotal cells crucial in orchestrating the pro-inflammatory response, both at systemic and tissue levels. It has been suggested they act as key players along multiple stages of disease trajectory fueling type 3 immunity, with a significant impact in the initiation and amplification of inflammation as well as in structural damage occurrence, typical of long-standing disease. The aim of our review is to focus on neutrophils' role within the spectrum of SpA, dissecting their functions and abnormalities in each of the relevant disease domains to understand their rising appeal as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Lavinia Agra Coletto
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
| | - Chiara Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, 90127 Palermo, Italy
| | - Giuliana Guggino
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, 90127 Palermo, Italy
| | - Roberto Caporali
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Stefano Alivernini
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
| | - Maria Antonietta D’Agostino
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
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Prada P, Brunel B, Moulin D, Rouillon L, Netter P, Loeuille D, Slimano F, Bouche O, Peyrin-Biroulet L, Jouzeau JY, Piot O. Identification of circulating biomarkers of Crohn's disease and spondyloarthritis using Fourier transform infrared spectroscopy. JOURNAL OF BIOPHOTONICS 2023; 16:e202200200. [PMID: 36112612 DOI: 10.1002/jbio.202200200] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 06/15/2023]
Abstract
Crohn's disease (CD) and spondyloarthritis (SpA) are two inflammatory diseases sharing many common features (genetic polymorphism, armamentarium). Both diseases lack diagnostic markers of certainty. While the diagnosis of CD is made by a combination of clinical, and biological criteria, the diagnosis of SpA may take several years to be confirmed. Based on the hypothesis that CD and SpA alter the biochemical profile of plasma, the objective of this study was to evaluate the analytical capability of Fourier transform infrared spectroscopy (FTIR) in identifying spectral biomarkers. Plasma from 104 patients was analyzed. After data processing of the spectra by Extended Multiplicative Signal Correction and linear discriminant analysis, we demonstrated that it was possible to distinguish CD and SpA from controls with an accuracy of 97% and 85% respectively. Spectral differences were mainly associated with proteins and lipids. This study showed that FTIR analysis is efficient to identify plasma biosignatures specific to CD or SpA.
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Affiliation(s)
- Pierre Prada
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
| | - Benjamin Brunel
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
- FEMTO-ST Institute, CNRS UMR-6174, Université de Bourgogne Franche-Comté, Besançon, France
| | - David Moulin
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, Université de Lorraine et Hôpital Universitaire de Nancy, Nancy, France
| | - Lise Rouillon
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
| | - Patrick Netter
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, Université de Lorraine et Hôpital Universitaire de Nancy, Nancy, France
| | - Damien Loeuille
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, Université de Lorraine et Hôpital Universitaire de Nancy, Nancy, France
| | - Florian Slimano
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
| | - Olivier Bouche
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
| | - Laurent Peyrin-Biroulet
- Département de Gastroentérologie, Hôpital Universitaire de Nancy-Brabois, Vandœuvre-lès-Nancy, France
| | - Jean-Yves Jouzeau
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, Université de Lorraine et Hôpital Universitaire de Nancy, Nancy, France
| | - Olivier Piot
- EA7506-BioSpectroscopie Translationnelle (BioSpecT), Université de Reims Champagne-Ardenne, Reims, France
- Plateforme d'Imagerie Cellulaire ou Tissulaire (PICT), Université de Reims Champagne-Ardenne, Reims, France
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Zhang M, Zhou J, Wang H, He L, Wang J, Yang X, Zhong X. Exploration of the shared pathways and common biomarker PAN3 in ankylosing spondylitis and ulcerative colitis using integrated bioinformatics analysis. Front Immunol 2023; 14:1089622. [PMID: 36742304 PMCID: PMC9891726 DOI: 10.3389/fimmu.2023.1089622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/04/2023] [Indexed: 01/19/2023] Open
Abstract
Background Ulcerative colitis (UC) is a chronic autoimmune-related disease that causes inflammation of the intestine. Ankylosing spondylitis (AS) is a common extraintestinal complication of UC involving the sacroiliac joint. However, the pathogenesis of AS secondary to UC has not been studied. This study aimed to investigate the shared pathways and potential common biomarkers of UC and AS. Methods Microarray data downloaded from the Gene Expression Omnibus (GEO) database were used to screen differentially expressed genes (DEGs) in the UC and AS datasets. Weighted gene co-expression network analysis (WGCNA) was performed to identify co-expression modules related to UC and AS. Shared genes were then further analyzed for functional pathway enrichment. Next, the optimal common biomarker was selected using SVM-RFF and further validated using two independent GEO datasets. Finally, immune infiltration analysis was used to investigate the correlation of immune cell infiltration with common biomarkers in UC and AS. Results A total of 4428 and 2438 DEGs in UC and AS, respectively, were screened. Four modules were identified as significant for UC and AS using WGCNA. A total of 25 genes overlapped with the strongest positive and negative modules of UC and AS. KEGG analysis showed these genes may be involved in the mitogen-activated protein kinase (MAPK) signaling pathway. GO analysis indicated that these genes were significantly enriched for RNA localization. PAN3 was selected as the optimal common biomarker for UC and AS. Immune infiltration analysis showed that the expression of PAN3 was correlated with changes in immune cells. Conclusion This study first explored the common pathways and genetic diagnostic markers involved in UC and AS using bioinformatic analysis. Results suggest that the MAPK signaling pathway may be associated with both pathogeneses and that PAN3 may be a potential diagnostic marker for patients with UC complicated by AS.
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Affiliation(s)
- Minna Zhang
- Department of Gastroenterology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Junyi Zhou
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Honggang Wang
- Department of Gastroenterology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.,Digestive Disease Center, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Le He
- Department of Gastroenterology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Jingyi Wang
- Department of Gastroenterology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiaozhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiaomin Zhong
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China
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Pott NM, Atschekzei F, Pott CC, Ernst D, Witte T, Sogkas G. Primary antibody deficiency-associated arthritis shares features with spondyloarthritis and enteropathic arthritis. RMD Open 2022; 8:rmdopen-2022-002664. [PMID: 36583733 PMCID: PMC9730402 DOI: 10.1136/rmdopen-2022-002664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE The clinical spectrum of primary antibody deficiencies (PADs) and especially common variable immunodeficiency (CVID) includes various autoimmune disorders. We studied the prevalence and the features of articular rheumatic disease in a cohort of patient with PADs. METHODS In this retrospective cohort study, complete clinical data of 268 patients with PADs, mainly consisting of patients with CVID, visiting the immunology outpatient clinic of a German tertiary hospital between 2018 and 2021 were collected. Those included case history, physical examination, laboratory as well as radiological findings. RESULTS Inflammatory arthritis was diagnosed in 16.4% of studied patients and was significantly more common among patients with PAD-associated enteropathy (OR 13.39, p=0.0001), splenomegaly (OR 6.09, p=0.0001) or atopic diseases (OR 3.31, p=0.021). Given HLA-B27 status, the involvement of the axial skeleton and the presence of features, such as anterior uveitis, inflammatory bowel disease, psoriasis and/or dactylitis, 75% of studied patients fulfilled the Assessment of Spondyloarthritis International Society classification criteria. CONCLUSION PAD-associated arthritis frequently shares features with spondyloarthritis (SpA) and enteropathic arthritis. The latter may suggest the interconnected pathomechanisms of inflammatory arthritis in SpA and PADs.
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Affiliation(s)
- Nina Mee Pott
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
| | - Faranaz Atschekzei
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Carl Christoph Pott
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
| | - Diana Ernst
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
| | - Torsten Witte
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Georgios Sogkas
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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Zeng L, Deng Y, He Q, Yang K, Li J, Xiang W, Liu H, Zhu X, Chen H. Safety and efficacy of probiotic supplementation in 8 types of inflammatory arthritis: A systematic review and meta-analysis of 34 randomized controlled trials. Front Immunol 2022; 13:961325. [PMID: 36217542 PMCID: PMC9547048 DOI: 10.3389/fimmu.2022.961325] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To evaluate Safety and efficacy of probiotic supplementation in inflammatory arthritis. Methods The literature on the treatment of inflammatory arthritis with probiotics has been collected in databases such as CNKI, Pubmed, Cochrane library, Embase, etc. The search time is for them to build the database until May 2022. The included literatures are randomized controlled trials (RCTs) of probiotics in the treatment of hyperuricemia and gout. The Cochrane risk assessment tool was used for quality evaluation, and the Rev Man5.3 software was used for meta-analysis. Results A total of 37 records were finally included, involving 34 RCTs and 8 types of autoimmune disease (Hyperuricemia and gout, Inflammatory bowel disease arthritis, juvenile idiopathic arthritis [JIA], Osteoarthritis [OA], Osteoporosis and Osteopenia, Psoriasis, rheumatoid arthritis (RA), Spondyloarthritis). RA involved 10 RCTs (632 participants) whose results showed that probiotic intervention reduced CRP. Psoriasis involved 4 RCTs (214 participants) whose results showed that probiotic intervention could reduce PASI scores. Spondyloarthritis involved 2 RCTs (197 participants) whose results showed that probiotic intervention improved symptoms in patients. Osteoporosis and Ostepenia involving 10 RCTs (1156 participants) showed that probiotic intervention improved bone mineral density in patients. Hyperuricemia and gout involving 4 RCTs (294 participants) showed that probiotic intervention improved serum uric acid in patients. OA involving 1 RCTs (433 participants) showed that probiotic intervention improved symptoms in patients. JIA involving 2 RCTs (72 participants) showed that probiotic intervention improved symptoms in patients. Inflammatory bowel disease arthritis involving 1 RCTs (120 participants) showed that probiotic intervention improved symptoms in patients. All of the above RCTs showed that probiotics did not increase the incidence of adverse events. Conclusion Probiotic supplements may improve Hyperuricemia and gout, Inflammatory bowel disease arthritis, JIA, OA, Osteoporosis and Osteopenia, Psoriasis, RA, Spondyloarthritis. However, more randomized controlled trials are needed in the future to determine the efficacy and optimal dosing design of probiotics. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021286425, identifier CRD42021286425.
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Affiliation(s)
- Liuting Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Ying Deng
- People’s Hospital of Ningxiang City, Ningxiang, China
| | - Qi He
- People’s Hospital of Ningxiang City, Ningxiang, China
| | - Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Jun Li
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Wang Xiang
- The First People's Hospital of Changde City, Changde, China
| | - Huiping Liu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | | | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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Lyu X, Chen J, Gao X, Yang J. Emerging story of gut dysbiosis in spondyloarthropathy: From gastrointestinal inflammation to spondyloarthritis. Front Cell Infect Microbiol 2022; 12:973563. [PMID: 36072223 PMCID: PMC9441705 DOI: 10.3389/fcimb.2022.973563] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
As a set of inflammatory disorders, spondyloarthritis (SpA) exhibits distinct pathophysiological, clinical, radiological, and genetic characteristics. Due to the extra-articular features of this disorder, early recognition is crucial to limiting disability and improving outcomes. Gut dysbiosis has been linked to SpA development as evidence grows. A pathogenic SpA process is likely to occur when a mucosal immune system interacts with abnormal local microbiota, with subsequent joint involvement. It is largely unknown, however, how microbiota alterations predate the onset of SpA within the “gut-joint axis”. New microbiome therapies, such as probiotics, are used as an adjuvant therapy in the treatment of SpA, suggesting that the modulation of intestinal microbiota and/or intestinal barrier function may contribute to the prevention of SpA. In this review, we highlight the mechanisms of SpA by which the gut microbiota impacts gut inflammation and triggers the activation of immune responses. Additionally, we analyze the regulatory role of therapeutic SpA medication in the gut microbiota and the potential application of probiotics as adjunctive therapy for SpA.
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Affiliation(s)
- Xing Lyu
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jieli Chen
- Discipline Construction Office, Tianjin Medical University, Tianjin, China
| | - Xingjie Gao
- Department of Biochemistry and Molecular Biology, Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
| | - Jie Yang
- Department of Biochemistry and Molecular Biology, Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China
- *Correspondence: Jie Yang,
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Gut Microbiota and Inflammatory Cytokine Changes in Patients with Ankylosing Spondylitis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1005111. [PMID: 36033581 PMCID: PMC9417757 DOI: 10.1155/2022/1005111] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/16/2022] [Indexed: 11/25/2022]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by sacroiliac joint lesions and spinal ascending involvement. The aim of this work was at investigating the gut microbiota profile and proinflammatory cytokines in AS patients. Gut microbiota of AS patients was clearly different from that of healthy human controls. 16S rRNA sequencing analysis demonstrated a changed microbial diversity in the AS patients, and there was a significant increase in the abundance of Cyanobacteria, Deinococcota, Patescibacteria, Actinobacteriota, and Synergistota at a phyla level increased in AS, while the relative abundance of Acidobacteriota, Bdellovibrionota, Campylobacterota, Chloroflexi, Gemmatimonadota, Myxococcota, Nitrospirota, Proteobacteria, and Verrucomicrobiota declined in AS patients. ELISA results for the markers of inflammation in the AS patients revealed increased concentrations of proinflammatory cytokines such as IL-23, IL-17, and IFN-γ. Our findings support the fact that the intestinal microbiota are altered in AS with an inflammatory status, which indicates that gut microbiota should be a potential target for ankylosing spondylitis therapy.
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Ramires LC, Santos GS, Ramires RP, da Fonseca LF, Jeyaraman M, Muthu S, Lana AV, Azzini G, Smith CS, Lana JF. The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut? Int J Mol Sci 2022; 23:1494. [PMID: 35163417 PMCID: PMC8835947 DOI: 10.3390/ijms23031494] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/11/2022] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.
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Affiliation(s)
- Luciano C. Ramires
- Department of Orthopaedics and Sports Medicine, Mãe de Deus Hospital, Porto Alegre 90110-270, RS, Brazil;
| | - Gabriel Silva Santos
- Department of Orthopaedics, The Bone and Cartilage Institute, Indaiatuba 13334-170, SP, Brazil; (G.A.); (J.F.L.)
| | - Rafaela Pereira Ramires
- Department of Biology, Cellular, Molecular and Biomedical Science, Boise State University, 1910 W University Drive, Boise, ID 83725, USA;
| | - Lucas Furtado da Fonseca
- Department of Orthopaedics, The Federal University of São Paulo, São Paulo 04024-002, SP, Brazil
| | - Madhan Jeyaraman
- Department of Orthopaedics, Faculty of Medicine, Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India;
| | - Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624304, Tamil Nadu, India;
| | - Anna Vitória Lana
- Department of Medicine, Max Planck University Center, Indaiatuba 13343-060, SP, Brazil;
| | - Gabriel Azzini
- Department of Orthopaedics, The Bone and Cartilage Institute, Indaiatuba 13334-170, SP, Brazil; (G.A.); (J.F.L.)
| | - Curtis Scott Smith
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 83703, USA;
| | - José Fábio Lana
- Department of Orthopaedics, The Bone and Cartilage Institute, Indaiatuba 13334-170, SP, Brazil; (G.A.); (J.F.L.)
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Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Gut-liver axis in cirrhosis: Are hemodynamic changes a missing link? World J Clin Cases 2021; 9:9320-9332. [PMID: 34877269 PMCID: PMC8610853 DOI: 10.12998/wjcc.v9.i31.9320] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/03/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease, especially cirrhosis. This introduces the concept of the gut-liver axis, which can be imagined as a chain connected by several links. Gut dysbiosis, small intestinal bacterial overgrowth, and intestinal barrier alteration lead to bacterial translocation, resulting in systemic inflammation. Systemic inflammation further causes vasodilation, arterial hypotension, and hyperdynamic circulation, leading to the aggravation of portal hypertension, which contributes to the development of complications of cirrhosis, resulting in a poorer prognosis. The majority of the data underlying this model were obtained initially from animal experiments, and most of these correlations were further reproduced in studies including patients with cirrhosis. However, despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development, the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied. They remain a missing link in the gut-liver axis and a challenge for future research.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
- Department of Internal Medicine, Consultative and Diagnostic Center of the Moscow City Health Department, Moscow 107564, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
| | - Elena Shirokova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
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Post-COVID-19 Arthritis and Sacroiliitis: Natural History with Longitudinal Magnetic Resonance Imaging Study in Two Cases and Review of the Literature. Viruses 2021; 13:v13081558. [PMID: 34452422 PMCID: PMC8402767 DOI: 10.3390/v13081558] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/01/2021] [Accepted: 08/04/2021] [Indexed: 12/24/2022] Open
Abstract
Severe acute respiratory coronavirus-2 syndrome (SARS-CoV-2) is a well-known pandemic infectious disease caused by an RNA virus belonging to the coronaviridae family. The most important involvement during the acute phase of infection concerns the respiratory tract and may be fatal. However, COVID-19 may become a systemic disease with a wide spectrum of manifestations. Herein, we report the natural history of sacroiliac inflammatory involvement in two females who developed COVID-19 infection with mild flu-like symptoms. After the infection they reported inflammatory back pain, with magnetic resonance imaging (MRI) studies showing typical aspects of sacroiliitis. Symptoms improved with NSAIDs therapy over the following months while MRI remained positive. A literature review was performed on this emerging topic. To our knowledge, this is the first MRI longitudinal study of post-COVID-19 sacroiliitis with almost one year of follow-up. Predisposing factors for the development of articular involvement are unclear but a long-lasting persistence of the virus, demonstrated by nasopharyngeal swab, may enhance the probability of altering the immune system in a favourable background.
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Haroon N, Inman RD. Recent advances in spondyloarthritis: positive developments in the seronegative domain. Semin Immunopathol 2021; 43:159-161. [PMID: 33763750 DOI: 10.1007/s00281-021-00839-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Nigil Haroon
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, M5T2S8, Canada.
| | - Robert D Inman
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, M5T2S8, Canada.
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