Gut microbe-derived short-chain fatty acids regulate joint inflammation and activation of infiltrating and resident myeloid cells after alphavirus infection
Although oral antibiotics can predispose to joint inflammation, 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 (SCFA), greater intestinal permeability, and activation of gut-associated immune cells, and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4 <sup>+</sup> T cells, and pro-inflammatory cytokines. Administration of exogenous SCFA or colonization of mice with bacterial species that generate SCFA mitigated CHIKV-induced joint inflammation. Single-cell RNA sequencing revealed that gut-derived SCFA ameliorate the inflammatory phenotype of synovial CD4 <sup>+</sup> 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
- Hana Jáňová (ORCID: https://orcid.org/0000-0003-2578-0982)
- Ana Jung (ORCID: https://orcid.org/0000-0003-0832-095X)
- Leah Heath
- Scott A. Handley (ORCID: https://orcid.org/0000-0002-2143-6570)
- Fang Zhao (ORCID: https://orcid.org/0000-0002-5059-0833)
- Larissa B. Thackray (ORCID: https://orcid.org/0000-0002-9380-6569)
- Russell B. Williams (ORCID: https://orcid.org/0000-0003-4534-3173)
- Chyi‐Song Hsieh (ORCID: https://orcid.org/0000-0001-5976-9250)
- Michael Andrew Fischbach (ORCID: https://orcid.org/0000-0003-3079-8247)
- Thaddeus S. Stappenbeck (ORCID: https://orcid.org/0000-0002-6023-3901)
- Lindsay Droit (ORCID: https://orcid.org/0000-0002-5771-1490)
- Michael Diamond (ORCID: https://orcid.org/0000-0002-8791-3165)
- Megan T. Baldridge (ORCID: https://orcid.org/0000-0002-7030-6131)
- Maksim Kleverov (ORCID: https://orcid.org/0009-0008-0353-8945)
- Matthias Mack (ORCID: https://orcid.org/0000-0002-3157-7262)
- Maxim N. Artyomov (ORCID: https://orcid.org/0000-0002-1133-4212)
- Chun‐Jun Guo (ORCID: https://orcid.org/0000-0002-7227-4591)
- Tingting Li (ORCID: https://orcid.org/0000-0002-2303-6394)
- Leran Wang (ORCID: https://orcid.org/0009-0003-6928-9893)
- Emma S. Winkler (ORCID: https://orcid.org/0000-0001-8510-1385)
Institutions
- Cleveland Clinic (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- Donald Danforth Plant Science Center (US)
- University Hospital Regensburg (DE)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-03
- DOI
- https://doi.org/10.64898/2025.12.03.691668
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00