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 8

Monocytes and CD4+ T cells drive increased joint inflammation associated with gut dysbiosis.

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Monocytes and CD4+ T cells drive increased joint inflammation associated...
(A–C) Foot swelling after CHIKV infection of water- or AV-treated mice receiving isotype mAb or mAbs against Gr-1 (Ly6C/Ly6G) (3 experiments, n = 14–15 per group) (A), Ly6G (3 experiments, n = 13 per group) (B), or CCR2 (3 experiments, n = 13–14 per group) (C). (D–F) Mice receiving isotype, anti-CD4, or anti-CD8 mAbs were treated with water or AV and assessed for foot swelling after infection (D), immune cells in the joint (E), and viral burden in the ipsilateral foot at 4 dpi (F) (2–3 experiments, n = 7–12 per group). (G) Foot swelling after CHIKV infection of water- or AV-treated OT-II Rag1–/– mice (2 experiments, n = 6–7 per group). (H) Percentage of CD4+ T cells in the colonic lamina propria producing the indicated cytokines. (I and J) CD4+ T cells enriched from MLNs and Peyer’s patches of water- or AV-treated mice were transferred into Tcrbd–/– mice 1 day prior to CHIKV infection (I) and evaluated for foot swelling (J). (K and L) Mice receiving isotype or anti–MAdCAM-1 mAbs prior to treatment with water or AV were evaluated for immune cells in the colonic lamina propria (K) and foot swelling after CHIKV infection (L) (2 experiments, n = 8 per group). Statistical analysis: A–D, G, J, and L, 2-way ANOVA with Dunnett’s (A–D and L) or Šidák’s (G and J) post test; AUC analyses were performed with 1-way ANOVA with Dunnett’s post test (A–D and L) or unpaired t test (G and J); mean values ± SEM. E, F, and K, 1-way ANOVA with Šidák’s post test. H, unpaired t test. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05.