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Page 4 of 23 Poznyak et al. Microbiome Res Rep. 2026;5:3

microbiome, particularly characterized by species of Prevotella - especially P. copri - may precede and
promote the onset of arthritis [40-42] .

The inflammatory role of P. copri extends beyond murine studies. Evidence shows that a peptide derived
from P. copri can bind to human leukocyte antigen – DR isotype (HLA-DR) molecules, triggering Th1-type
inflammatory responses in early RA patients. Both Immunoglobulin A (IgA) and Immunoglobulin G (IgG)
antibodies against P. copri have been identified in patients at both early and established stages of the
disease [43,44] . Additionally, there appears to be a correlation between antibodies against P. copri, levels of Th17
cytokines, and ACPAs. Furthermore, the 16S ribosomal RNA (16S rRNA) of P. copri has been detected in the
synovial fluid of some patients, suggesting that the gut microbiome may contribute to autoimmune
responses affecting the joints through microbial peptides . However, a direct link between intestinal levels
[45]
of P. copri and its proteins has not yet been established. Nevertheless, evidence for a causal relationship
remains limited; most available findings are observational and demonstrate association rather than
mechanistic proof. Only a few experimental studies using microbiota transfer into germ-free mice suggest a
contributory - but not definitive - causal role for P. copri in promoting inflammatory responses .
[46]
Interestingly, P. copri antigens share structural similarities with N-acetylglucosamine-6-sulfatase, an
autoantigen associated with RA that triggers T- and B-cell responses in approximately half of RA patients. It
is hypothesized that in genetically predisposed individuals, the immune system recognition of
Prevotella-derived epitopes might lead to T-cell activation in the gut, which could then migrate to the joints,
suggesting a possible mechanism for RA pathogenesis through molecular mimicry [47,48] .

Nevertheless, some Prevotella species, such as Prevotella histicola (P. histicola), have been found to reduce the
severity of arthritis in murine models, and the Prevotella genus is one of the most abundant groups of
beneficial commensal bacteria in healthy individuals. These conflicting findings highlight the intricate
interplay between various bacterial species and genetic factors in the development of RA. More
comprehensive longitudinal studies are needed to fully elucidate the role of Prevotella species in
autoantibody production and the pathogenesis of RA [49-51] .

Although P. copri has frequently been associated with a pro-inflammatory profile in early RA, emerging
evidence shows that not all Prevotella species exert similar effects. Mechanistic studies indicate that
strain-level differences within P. copri influence immunogenicity, including variation in carbohydrate-active
enzymes, LPS structure, and antigen presentation pathways . Some strains promote Th17-mediated
[52]
inflammation, whereas others appear to support mucosal immune tolerance. In contrast, P. histicola has been
shown to induce regulatory T cells (Tregs), enhance intestinal barrier integrity, and suppress
pro-inflammatory cytokines, resulting in protection against arthritis in murine models . Comparative
[53]
genomic and functional analyses confirm that distinct Prevotella species - and even different strains within a
species - possess divergent metabolic capacities and immunomodulatory properties. These findings suggest
that the ‘dual effect’ reflects underlying functional heterogeneity across Prevotella taxa rather than a
paradoxical behavior of a single organism .
[54]

Collinsella
Several bacterial genera, including Collinsella, Lactobacillaceae, Eggerthella, and Actinomyces, have been
associated with RA, suggesting that the disease development results from complex interactions among
various bacterial species, genetic factors, and environmental influences. Notably, Collinsella, especially the
species Collinsella aerofaciens (C. Aerofaciens), has been shown to increase intestinal permeability in RA
mouse models by reducing the expression of proteins that form tight junctions [55-57] . However, the evidence
supporting a causal role for Collinsella in intestinal permeability and inflammation remains limited. Much of