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 1

Depletion of the intestinal microbiota by oral antibiotics exacerbates musculoskeletal tissue inflammation after CHIKV infection.

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Depletion of the intestinal microbiota by oral antibiotics exacerbates m...
(A) Schematic of experimental setup. (B–D) Colonic contents were collected from water- or AV-treated C57BL/6J mice at 0 or 7 dpi. Relative abundance of bacterial phyla (B), number of bacterial taxa (richness) (C), and beta diversity (weighted UniFrac distance) (D) in colonic contents (2 experiments, n = 8–9 per group). (E–G) Foot swelling after CHIKV infection in mice treated with ampicillin (E, n = 10), vancomycin (F, n = 10), AV (G, n = 15), or water (E–G, n = 15). (H–J) H&E staining of foot tissues from water- or AV-treated mice at 0 (H), 3 (I), and 6 (J) dpi (n = 7–10 per group). Original magnification, ×2.5; scale bars: 1 mm. D, dermis; B, bone; BM, bone marrow; M, muscle. Double-headed arrows indicate edema. Arrowheads indicate periosteal inflammation. (K) H&E staining showing synovitis (arrows) in the mid-foot of water- or AV-treated mice at 6 dpi. Original magnification, ×5; scale bars: 100 μm. (L) Scoring of joint inflammation and tissue damage. (M) Toluidine blue staining of foot tissues from water- or AV-treated mice at 0 and 6 dpi (representative of n = 2 uninfected and n = 8 infected mice per group). Original magnification, ×40; scale bars: 100 μm. SC, superficial noncalcified cartilage; DC, deeper calcified cartilage. Arrowheads indicate destaining (proteoglycan loss) of superficial hyaline cartilage. Statistical analysis: C, Wilcoxon’s test; D, permutational multivariate ANOVA (Adonis); E–G, mean ± SEM, 2-way ANOVA with Šidák’s post test or 1-way ANOVA with Dunnett’s post test for AUC; L, unpaired 2-tailed t test. ****P < 0.0001; ***P < 0.001; *P < 0.05.