Identification of Akkermansia muciniphila as a candidate gut commensal involved in the pathogenesis of rheumatoid arthritis
- 1Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School , , ,
- 2Center for Biomedical Mass Spectrometry, Boston University Chobanian and Avedisian School of Medicine , , ,
- 3Department of Immunobiology, Yale University School of Medicine , , ,
Abstract
Objective: The “mucosal origins hypothesis” posits that mucosal sites, such as the gut, are initial sites where immune responses first develop that may, months to years later, result in clinical rheumatoid arthritis (RA). Our goal here was to conduct a discovery-based, hypothesis-generating study using samples from a relatively small number of patients to implicate previously unrecognized highly IgA-coated commensal flora that may have a role in RA pathogenesis (primary outcome). The secondary supporting outcomes were to determine whether HLA-DR-presented microbial peptides from such flora could be identified in synovial tissue and to determine T and B cell responses to these peptides and citrullinated proteins.
Methods: Highly IgA-coated bacteria taxa were identified in RA patients’ stool samples by 16s rRNA sequencing; HLA-DR-presented peptides derived from the most common, highly IgA-coated microbes were identified from synovial tissue by liquid chromatography–tandem mass spectrometry; T cell responses to the identified microbial and human mimic epitopes were determined by IFNγ ELISpot assays, and citrullinated IgG and IgA antibodies to implicated microbial and human proteins were measured by ELISA.
Results: Of 32 RA patients, 28 (88%) had highly IgA-coated Akkermansia muciniphila ( Am ) in stool samples. HLA-DR presentation of peptides derived from two Am proteins, including the molecular chaperone DnaK protein ( Am -cDnaK), was identified from RA synovial tissue, suggesting that the microbe or its components may reach the joints. Eight of 21 patients (38%) had T cell responses to the Am -cDnaK peptide and a human heat shock protein-mimic peptide (Hu-HSPA5) and/or IgG antibodies to citrullinated forms of these proteins. Reactivity was found primarily in pre-RA and early RA soon after transition to clinical RA and less commonly during later flares of arthritis.
Conclusions: These data implicate Am as a candidate gut commensal involved in RA pathogenesis and may serve as a compass for planning larger studies to test the hypothesis that Am , as well as certain other highly IgA-coated commensal flora or their components, may sometimes reach joints where they initiate or enhance autoimmune T cell responses via epitope mimicry and epitope spreading, leading to antibody responses to citrullinated host proteins in joints.
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BibTeX
@article{curham2026identification,
title = {{Identification of Akkermansia muciniphila as a candidate gut commensal involved in the pathogenesis of rheumatoid arthritis}},
author = {Lucy M. Curham and Korawit Kanjana and Cameron A. Deangelo and David E. Kling and Maissa M. Gaye and Yi Yang and Chaoshuang Xia and Sheila Arvikar and Noah W. Palm and Catherine E. Costello and James J. Moon and Allen C. Steere},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1917757},
url = {https://europepmc.org/article/PMC/PMC13669181},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of Akkermansia muciniphila as a candidate gut commensal involved in the pathogenesis of rheumatoid arthritis
AU - Lucy M. Curham
AU - Korawit Kanjana
AU - Cameron A. Deangelo
AU - David E. Kling
AU - Maissa M. Gaye
AU - Yi Yang
AU - Chaoshuang Xia
AU - Sheila Arvikar
AU - Noah W. Palm
AU - Catherine E. Costello
AU - James J. Moon
AU - Allen C. Steere
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1917757
UR - https://europepmc.org/article/PMC/PMC13669181
AB - Objective: The “mucosal origins hypothesis” posits that mucosal sites, such as the gut, are initial sites where immune responses first develop that may, months to years later, result in clinical rheumatoid arthritis (RA). Our goal here was to conduct a discovery-based, hypothesis-generating study using samples from a relatively small number of patients to implicate previously unrecognized highly IgA-coated commensal flora that may have a role in RA pathogenesis (primary outcome). The secondary supporting outcomes were to determine whether HLA-DR-presented microbial peptides from such flora could be identified in synovial tissue and to determine T and B cell responses to these peptides and citrullinated proteins. Methods: Highly IgA-coated bacteria taxa were identified in RA patients’ stool samples by 16s rRNA sequencing; HLA-DR-presented peptides derived from the most common, highly IgA-coated microbes were identified from synovial tissue by liquid chromatography–tandem mass spectrometry; T cell responses to the identified microbial and human mimic epitopes were determined by IFNγ ELISpot assays, and citrullinated IgG and IgA antibodies to implicated microbial and human proteins were measured by ELISA. Results: Of 32 RA patients, 28 (88%) had highly IgA-coated Akkermansia muciniphila ( Am ) in stool samples. HLA-DR presentation of peptides derived from two Am proteins, including the molecular chaperone DnaK protein ( Am -cDnaK), was identified from RA synovial tissue, suggesting that the microbe or its components may reach the joints. Eight of 21 patients (38%) had T cell responses to the Am -cDnaK peptide and a human heat shock protein-mimic peptide (Hu-HSPA5) and/or IgG antibodies to citrullinated forms of these proteins. Reactivity was found primarily in pre-RA and early RA soon after transition to clinical RA and less commonly during later flares of arthritis. Conclusions: These data implicate Am as a candidate gut commensal involved in RA pathogenesis and may serve as a compass for planning larger studies to test the hypothesis that Am , as well as certain other highly IgA-coated commensal flora or their components, may sometimes reach joints where they initiate or enhance autoimmune T cell responses via epitope mimicry and epitope spreading, leading to antibody responses to citrullinated host proteins in joints.
SN - 1664-3224
ER -