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Poznyak et al. Microbiome Res Rep. 2026;5:3 Page 5 of 23

the current literature is based on correlations between increased Collinsella abundance and inflammatory
markers. Experimental support comes primarily from a single mechanistic study showing that C. Aerofaciens
reduced tight junction protein expression and increased IL-17A production in vitro, suggesting a potential
causal effect .
[58]

Yet, alternative interpretations exist: Collinsella may increase in abundance because it can utilize Maillard
reaction products (MRPs) and advanced glycation end products (AGEs), which are themselves
pro-inflammatory . MRPs and AGEs accumulate in inflammatory and metabolically stressed environments
[59]
and are strongly associated with oxidative stress, immune activation, and epithelial dysfunction. Several gut
microbial taxa, including members of the Actinobacteria phylum to which Collinsella belongs, possess
metabolic capacities that enable the utilization of complex glycated substrates [60,61] . In this context,
enrichment of Collinsella may represent a secondary ecological response to increased availability of MRPs
and AGEs rather than a primary pathogenic driver of inflammation . In such a scenario, Collinsella
[62]
expansion could reflect an adaptive or compensatory response rather than a driver of disease.

Importantly, direct in vivo evidence demonstrating that Collinsella independently initiates intestinal barrier
disruption or systemic inflammation in humans is currently lacking. To date, evidence that C. Aerofaciens
drives intestinal barrier loss in humans is indirect and largely inferential, relying on associations rather than
causative demonstrations . Mechanistic evidence that Collinsella causes permeability defects primarily
[63]
comes from in vitro and animal experiments (e.g., reduced tight-junction protein expression and increased
IL-17A after exposure to Collinsella or its products) [64,65] . Human studies, by contrast, report associations
between increased Collinsella abundance and RA or with biomarkers of gut barrier disruption (e.g., elevated
zonulin, LPS/LPS-binding protein, and soluble CD14), but these are observational and cannot establish
causality. Importantly, experimental targeting of intestinal barrier regulators such as zonulin has
demonstrated that barrier dysfunction can precipitate arthritis in murine models, supporting the biological
plausibility of a gut → joint pathway. However, this still does not prove that expansion of Collinsella is a
primary initiating event in humans .
[66]
In short, the current human evidence links Collinsella to RA and to indirect markers of permeability;
however, direct, longitudinal or interventional human data demonstrating that Collinsella alone initiates
barrier breakdown and subsequent RA onset are lacking. This bacterium elevates levels of inflammatory
chemokines such as IL-17A, C-X-C motif chemokine ligand 1 (CXCL1), C-X-C motif chemokine ligand 5
(CXCL5), and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), exacerbating
both the incidence and severity of arthritis. These findings indicate that increased intestinal permeability may
be a crucial mechanism through which gut dysbiosis affects RA .
[67]

The proliferation of C. Aerofaciens is believed to induce intestinal inflammation and compromise the
integrity of the epithelial barrier, allowing bacterial antigens to enter the bloodstream [68-70] . This translocation
can trigger immune responses at distant sites, including the joints. Additionally, studies have identified a
reduction in the genera Roseburia and Faecalibacterium in individuals with RA. These bacteria are known for
their butyrate production and anti-inflammatory properties, playing a vital role in maintaining intestinal
barrier health. This supports the hypothesis that a compromised intestinal barrier contributes to the onset of
RA and suggests potential avenues for treatment.

However, interpretation of these findings is complicated by the compositional nature of most
high-throughput microbiome datasets. Because sequencing-based approaches primarily generate relative
abundance data, apparent decreases in butyrate-producing genera such as Roseburia and Faecalibacterium
may not reflect true biological depletion but instead result from proportional shifts driven by expansion of