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 2

Oral antibiotics increase subchondral osteoclasts without altering viral infection during CHIKV infection.

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Oral antibiotics increase subchondral osteoclasts without altering viral...
(A and B) TRAP staining of foot tissues from water- or AV-treated mice at 0 and 6 dpi (representative of n = 8 per group); red staining shows TRAP+ cells. Original magnification, ×10; scale bars: 200 μm. B, bone; BM, bone marrow; S, synovium; C, cartilage. In the higher magnification views, double-headed arrows indicate the width of the vascular channels. Dashed ovals in B encircle subchondral TRAP+ osteoclasts (red, nucleated). (C) Quantitation of subchondral TRAP+ osteoclasts in water- and AV-treated mice at 0 and 6 dpi. (D) CHIKV infection in ipsilateral feet of water- and AV-treated mice at 1, 3, and 6 dpi was determined by focus-forming assay (2 experiments, n = 5–8 per group). FFU, focus-forming units. (E) CHIKV RNA in situ hybridization of foot tissue sections from Zika virus–infected mice (negative control, top panel) and CHIKV-infected, water- or AV-treated mice at 3 dpi (middle panels) or 6 dpi (bottom panels) (representative of n = 3 per group). Original magnification, ×2.5; scale bars: 1 mm. Statistical analysis: C and D, Mann-Whitney test. *P < 0.05.