Gut microbe–derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice
Fang R. Zhao, Maksim Kleverov, Emma S. Winkler, Russell B. Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T. Baldridge, Thaddeus S. Stappenbeck, Larissa B. Thackray, Chyi-Song Hsieh, Scott A. Handley, Chun-Jun Guo, Michael A. Fischbach, Maxim N. Artyomov, Michael S. Diamond
Fang R. Zhao, Maksim Kleverov, Emma S. Winkler, Russell B. Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T. Baldridge, Thaddeus S. Stappenbeck, Larissa B. Thackray, Chyi-Song Hsieh, Scott A. Handley, Chun-Jun Guo, Michael A. Fischbach, Maxim N. Artyomov, Michael S. Diamond
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Research Article Immunology Infectious disease Microbiology

Gut microbe–derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice

Abstract

Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.

Authors

Fang R. Zhao, Maksim Kleverov, Emma S. Winkler, Russell B. Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T. Baldridge, Thaddeus S. Stappenbeck, Larissa B. Thackray, Chyi-Song Hsieh, Scott A. Handley, Chun-Jun Guo, Michael A. Fischbach, Maxim N. Artyomov, Michael S. Diamond

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Figure 4

Microbial dysbiosis results in reduced SCFA production, increased intestinal permeability, and enhanced joint swelling.

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Microbial dysbiosis results in reduced SCFA production, increased intest...
(A) Foot swelling after CHIKV infection in water-treated, AV-treated, or AV-treated mice after FMT (AV + FMT) (3 experiments, n = 13–14 per group). (B and C) Foot swelling (B) and immune cell infiltrates in the feet (C) after CHIKV infection of water-treated, AV-treated, or AV-treated mice colonized with either aerobic or anaerobic fecal cultures (2 experiments, n = 8–9 per group). (D and E) Foot swelling after CHIKV infection of water-treated, AV-treated, or AV-treated mice colonized with either C. scindens (D) or B. thetaiotaomicron (E) (2 experiments, n = 9 per group). (F) Plasma concentrations of 10, 70, and 250 kDa dextrans at 1.5 h after oral gavage (2 experiments, n = 8). (G and H) GF mice received PBS or colonization with B. thetaiotaomicron via oral gavage prior to MAYV infection. Foot swelling after MAYV infection (G) and MAYV burden (H) in tissue homogenates from the feet of GF mice or GF mice colonized with B. thetaiotaomicron. (I) Plasma concentrations of 10, 70, and 250 kDa dextrans at 1.5 h after oral gavage. (J) Fecal SCFA levels in water- or AV-treated mice. Statistical analysis: A, B, D, and E, 2-way ANOVA with Dunnett’s post test; AUC analyses were performed with 1-way ANOVA with Šidák’s post test; mean values ± SEM. C and F, 1-way ANOVA with Šidák’s post test. H, Mann-Whitney test. I and J, unpaired t test. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.