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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice
Fang R Zhao1, Maksim Kleverov2, Emma S Winkler1
1Department of Medicine and.
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.
Insights
Oral antibiotics worsen alphavirus arthritis by disrupting gut bacteria and reducing beneficial short-chain fatty acids (SCFAs). Restoring SCFAs can mitigate this joint inflammation, highlighting the gut-immune axis in musculoskeletal health.
Area of Science:
- Immunology
- Microbiology
- Rheumatology
Background:
- Oral antibiotics can trigger joint inflammation, a process not fully understood.
- Gut microbiota and its metabolites play a role in host immunity and inflammation.
Purpose of the Study:
- To investigate how gut dysbiosis induced by oral antibiotics affects alphavirus-induced arthritis.
- To identify the immune mechanisms and microbial factors involved in antibiotic-associated joint inflammation.
Main Methods:
- Utilized mouse models of chikungunya (CHIKV) and Mayaro virus-induced arthritis.
- Administered oral antibiotics and analyzed effects on arthritis severity, gut permeability, and immune cell activation.
- Investigated the role of short-chain fatty acids (SCFAs) and TLR4 signaling.
- Performed single-cell RNA sequencing (scRNA-seq) on joint tissues.
Main Results:
- Antibiotic treatment exacerbated CHIKV and Mayaro virus arthritis, correlating with SCFA loss and increased intestinal permeability.
- This worsened arthritis required TLR4, MyD88, monocytes, CD4+ T cells, and proinflammatory cytokines.
- Exogenous SCFAs or SCFA-producing bacteria reduced CHIKV-induced joint inflammation.
- SCFAs modulated the inflammatory profiles of synovial CD4+ T cells, monocytes, and osteoclast-like cells.
Conclusions:
- Antibiotic-induced gut dysbiosis exacerbates alphavirus arthritis.
- Gut-derived SCFAs ameliorate joint inflammation by influencing immune cell phenotypes in the joint.
- The gut-immune axis is a critical factor in alphavirus-induced musculoskeletal inflammation.
