Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro mechanistic study with correlational human biomarker measurements
PubMed 34296202 · doi:10.1016/j.medj.2021.04.013
What was done
Analyzed peripheral blood and serum markers of gut permeability, intestinal damage, and gut-homing leukocytes in patients with rheumatoid arthritis (RA). In parallel, evaluated gut permeability, bacterial translocation, and immune infiltration in spontaneous (K/BxN) and induced mouse models of arthritis, including IL-10R-/- and claudin-8-/- knockout strains, as well as in mouse intestinal organoids exposed to interferon-gamma (IFNγ). Tested the effect of the gut-permeability inhibitor AT-1001 on arthritis severity in mice.
What was found
RA patients demonstrated elevated serum markers of gut permeability, damage, and gut-homing cells that correlated positively with disease severity (no numerical values or correlation coefficients reported in the abstract). Arthritic mice showed early gut hyperpermeability, bacterial translocation, increased IFNγ+ and decreased IL-10+ intestinal leukocytes, and downregulated epithelial IL-10R. Mice with increased baseline permeability (claudin-8-/- or epithelial IL-10R-/-) developed worse arthritis, while pharmacological treatment with AT-1001 reduced arthritis severity in mice.
Why it matters
Provides a mechanistic link between gut barrier integrity and joint inflammation, suggesting that therapeutic approaches targeted at restoring gut permeability could represent a novel strategy for rheumatoid arthritis.
Limits
Human findings are limited to correlational circulating biomarker data with sample size not specified in the abstract. All mechanistic, genetic, and pharmacological intervention experiments were conducted in mice and organoids, meaning clinical efficacy and translatability to human RA remain unproven. No exact quantitative values or effect sizes are provided.
Cited by
- supports Intestinal hyperreactivity driven by an immune response causes intestinal permeability, which can exacerbate autoimmune conditions.