Background/Purpose: The intestinal microbiota regulates musculoskeletal inflammation and antibiotic use increases risk for the development or relapse of inflammatory arthritis. However, the basis for this is not well understood. Even less is known about the effects of the commensal intestinal microbiota on tissue inflammation in the context of viral arthritis such as that resulting from chikungunya virus (CHIKV). We aimed to define the cellular and immunological mechanisms by which the commensal gut microbiome regulates inflammation in a mouse model of CHIKV arthritis.

Methods: Subcutaneous footpad injection of CHIKV in mice recapitulates many features of human disease, including joint swelling, tenosynovitis, and myositis. To perturb the gut microbiome, mice were treated with a 3-day course of the minimally absorbed oral antibiotics, vancomycin and ampicillin, which depletes many gut bacteria, primarily from the Bacteroidetes phylum, leading to relative overrepresentation of Proteobacteria and Firmicutes. Using a combination of germ-free mice, genetic mouse models, and genetically modified bacteria, we examined mechanisms by which gut microbes regulate viral arthritis.

Results: We show that perturbation of the intestinal microbiome with oral antibiotics results in increased infiltration of inflammatory cells and exacerbation of musculoskeletal inflammation in our mouse model of CHIKV arthritis. Antibiotic-induced gut dysbiosis leads to increased paracellular intestinal permeability. Joint swelling depends partially on MyD88 expression in the intestinal epithelium, with contributions from Toll-like receptor 4, monocytes, and inflammatory effector CD4⁺ T cells. Germ-free mice do not exhibit enhanced alphavirus-induced inflammatory arthritis seen after microbiota depletion. The effects of gut dysbiosis occur independently of viral burden, and are mediated by depletion of gut microbe-derived short chain fatty acids (SCFA). Indeed, treatment with exogenous SCFA (butyrate and propionate, but not acetate), or gut microbial transplant with bacterial species that generate SCFA, leads to reversal of intestinal permeability and ameliorates arthritis and myositis during CHIKV infection.

Conclusion: While microbial dysbiosis in the gastrointestinal tract has previously been linked to arthritis, the underlying mechanisms had been less well understood. Our work provides key mechanistic insight into how intestinal microbes and their metabolites regulate the pathogenesis of viral arthritis through an interplay between intestinal epithelial cells, pattern recognition receptors, and immune cells. Relevant pathways elucidated by our work may serve as potential therapeutic targets for modulating musculoskeletal inflammation in the context of autoimmunity and arthritogenic virus infection.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gut-microbe-derived-short-chain-fatty-acids-regulate-arthritis-and-myositis-during-chikungunya-virus-infection/