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 3

Oral antibiotics increase joint inflammation during CHIKV infection.

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Oral antibiotics increase joint inflammation during CHIKV infection. (A)...
(A) Heatmap of cytokine and chemokine levels in foot-associated musculoskeletal tissue homogenates from water- or AV-treated mice at 0 and 4 dpi (2 experiments, n = 5–8 per group, log10 fold differences in protein levels are relative to water-treated animals at 0 dpi; see also Supplemental Figure 1J and Supplemental Tables 1 and 2). (B and C) Numbers of immune cells in joint-associated tissues in the ipsilateral feet of water- or AV-treated mice at 4 (B) or 7 (C) dpi (2 experiments, n = 6–9 per group). (D) Percentages of IFN-γ–, TNF-, IL-17–, and IL-22–producing CD4+ T cells in the ipsilateral feet of water- and AV-treated mice at 4 dpi (2–3 experiments, n = 6–11 per group). (E) Percentages of IFN-γ– and TNF-producing, perforin-expressing, or CD107a-cycling CD8+ T cells in the ipsilateral feet of control and AV-treated mice at 4 dpi (3 experiments, n = 8–17 per group). (F–I) Percentages and numbers CD4+CD25+FoxP3+ Tregs in the draining popliteal lymph nodes (F and G) and spleens (H and I) of water- and AV-treated mice at 4 dpi. (J) IL-17A/F levels in joint-associated tissue homogenates from ipsilateral feet (2 experiments, n = 5–8 per group). (K–M) Foot swelling of water- and AV-treated mice that were administered isotype control or neutralizing mAb against TNF (K), IL-17A (L), or IFN-γ (M) (2 experiments, n = 8–9 per group). Statistical analysis: B–J, unpaired t test; K–M, 2-way ANOVA with Šidák’s post test or 1-way ANOVA with Dunnett’s post test for AUC; mean values ± SEM are shown. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.