Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation of unknown cause in the synovial joints, requiring both genetic and environmental factors to manifest. It has been previously reported that individuals with RA have specific alterations in their gut and oral microbiomes.
Two recent studies, led by Dr. Veena Taneja from the Department of Immunology and Division of Rheumatology at Mayo Clinic in Rochester (USA), allow a better understanding of the role of gut microbiota in people with rheumatoid arthritis and how manipulation of the gut microbiota may provide an additional approach to therapy.
The first paper, published in Genome Medicine, has found that the gut microbiota of RA patients (n=40) exhibited decreased diversity with increased disease duration and autoantibody levels, compared with controls (15 first-degree relatives of the patients and 17 non-related healthy controls). The dysbiotic gut microbiota in patients with RA stemmed from an expansion of rare microbial lineages like Eggerthella and Collinsella and from a decrease in the abundant beneficial genera like Faecalibacterium. A gut microbial profile for RA patients was identified based on the abundance of the three genera: Collinsella, Eggerthella, and Faecalibacterium.
Analysis of microbial metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The metabolome profile was associated with the intestinal microbiota in patients with RA, as the abundance of the Collinsella genus correlated strongly with high levels of three metabolites (beta-alanine, alpha-aminoadipic acid, and asparagine). The role of the RA-associated bacteria Collinsella was confirmed using a human epithelial cell line and a humanized mouse model of arthritis consisting of transgenic mice in which arthritis was induced by immunization with type II collagen (as previously described by Taneja et al., 2007). Collinsella increased gut permeability by reducing the expression of tight junction protein in the human intestinal epithelial cell line CACO-2, and it induced production of the proinflammatory cytokine interleukin (IL)-17A. In addition, Collinsella enhanced disease severity in a humanized mouse model. All together, these data suggest that RA patients showed a dysbiotic gut microbiota characterized by a decrease in Faecalibacterium and an increase in Collinsella and Eggerthella. Collinsella seems to have an essential role in altering gut permeability and disease severity as confirmed in experimental arthritis.
“After further research in mice and, eventually, humans, intestinal microbiota and metabolic signatures could help scientists build a predictive profile for who is likely to develop rheumatoid arthritis and the course the disease will take”, said Dr. Taneja.
The second paper, published in Arthritis & Rheumatology, explored the role of a human gut-derived commensal in treating arthritis in a humanized mouse model. The researchers treated one group of arthritis-susceptible mice with the human gut-derived commensal bacterium Prevotella histicola in therapeutic control (n=21; 1 x 109 live bacteria/day 8 weeks post collagen-induced arthritis induction) or as a prophylactic measure (n=12; 1 x 109 live bacteria/day 10 days prior to induction of collagen-induced arthritis and continued for 6 weeks post-induction) and compared that to a group without treatment. Oral feeding of P. histicola in the mouse model of RA led to decreased symptom frequency and severity, and fewer signs of inflammation associated with RA as compared to controls. Suppression of arthritis was also demonstrated in a second mouse model of arthritis treated with P. histicola. An observed increase in IL-10 levels and T regulatory cells in the lamina propria and spleen of mice with collagen-induced arthritis supports the role of P. histicola in decreasing immune inflammatory responses. Lowered gut permeability and increased expression of tight junction proteins (zonulin and occludin) in treated compared to control mice suggest that P. histicola protects by preserving gut epithelium integrity in the context of inflammation. Treatment with P. histicola produced fewer of the side effects (such as weight gain, villous atrophy, and increased gut permeability) that are linked with nonsteroidal anti-inflammatory drugs and other traditional medications used for treating RA. These results suggest that P. histicola could be explored as a novel therapy for RA with low/no side effects.
In children, the most common form of chronic arthritis is called juvenile idiopathic arthritis and recent evidence suggests that the microbiota may influence this disease. However, in order to target gut microbiota in arthritis during childhood, further research is needed, as mechanisms by which the gut microbiota might contribute to inflammation and immune function need to be elucidated.
Although there is a correlation between alterations in the gut microbiota and clinical disease in RA patients, a recent review, led by Dr. Simon Milling from the Centre of Immunobiology at University of Glasgow (United Kingdom) explains that to date, administration of probiotics and modifying the gut microbiota through diet has had limited success in improving patient well-being and has had little effect on systemic inflammation.
In conclusion, gut dysbiosis in RA patients may result from the increased abundance of certain rare bacterial lineages. Ameliorating arthritis by manipulating the gut microbiota is a new area of research that may provide additional therapeutic options for people living with RA.
Arvonen M, Berntson L, Pokka T, Karttunen TJ, Vähäsalo P, Stoll ML. Gut microbiota-host interactions and juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2016; 14(1):44. doi:10.1186/s12969-016-0104-6.
Bravo-Blas A, Wessel H, Milling S. Microbiota and arthritis: correlations or cause? Curr Opin Rheumatol. 2016; 28(2):161-7. doi:10.1097/BOR.0000000000000261.
Chen J, Wright K, Davis JM, et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016; 8(1):43. doi:10.1186/s13073-016-0299-7.
Marietta EV, Murray JA, Luckey DH, et al. Human gut-derived Prevotella histicola suppresses inflammatory arthritis in humanized mice. Arthritis Rheumatol. 2016, doi: 10.1002/art.39785.
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