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 6

Rescue of CHIKV-induced foot swelling by bacterial colonization depends on microbe-derived SCFA.

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Rescue of CHIKV-induced foot swelling by bacterial colonization depends ...
(A) In vitro production of propionate by isogenic WT and mutant (ΔP) B. thetaiotaomicron. (B) In vitro growth properties of isogenic WT and mutant B. thetaiotaomicron. (C and D) AV-treated mice were gavaged with sterile PBS or with WT or mutant B. thetaiotaomicron. (C) Fecal colony-forming unit counts on Bacteroides bile esculin agar. (D) Cecal SCFA levels determined by gas chromatography–mass spectrometry. (E–I) Water-treated, AV-treated, or AV-treated mice colonized with either WT or mutant B. thetaiotaomicron were inoculated with CHIKV. (E) CHIKV infection at 4 dpi in homogenates of the ipsilateral feet (2 experiments, n = 6 per group). (F) Plasma concentrations of 10 and 70 kDa dextran were measured at 1.5 h after gavage (3 experiments, n = 10–13 per group). (G) Foot swelling after CHIKV infection (2 experiments, n = 10 per group). Numbers of joint-associated immune cells (H) and percentages of cytokine-producing CD4+ T cells at 4 dpi (I) (2 experiments, n = 8–10 per group). Statistical analysis: C and E, Mann-Whitney test; D, unpaired t test; F, H, and I, 1-way ANOVA with Šidák’s post test. G, 2-way ANOVA with Tukey’s post test; AUC was analyzed using 1-way ANOVA with Dunnett’s post test; mean values ± SEM. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.