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Poznyak et al. Microbiome Res Rep. 2026;5:3 Page 13 of 23

underscore the capacity of miRNAs to modulate gut microbial communities and thereby help preserve
intestinal immune homeostasis [194,195] .

Conversely, some researchers propose that miRNAs may help foster an anti-inflammatory state and enhance
the integrity of the gut barrier by directly interacting with the ycnE gene of L. rhamnosus monooxygenase,
which is believed to stimulate the production of IL-22 - an important molecule for gut health [196-198] . IL-22
aids in the regeneration of the intestinal epithelium, enhances the expression of chemokines and cytokines
for pathogen clearance, and promotes the growth of goblet cells. This theory was supported by observations
that the ycnE gene was suppressed following treatment with ginger-derived mdo-miR7267-3p, resulting in a
significant decrease in indole-3 acetamide (I3AM), a compound that inhibits the precursor to
indole-3-carboxaldehyde (I3CA), ultimately increasing I3CA production [199,200] . Interestingly, IL-22 levels
remained unchanged in aryl hydrocarbon receptor (AhR)-deficient mice treated with I3AM, underscoring
the crucial role of AhR in suppressing the L. rhamnosus I3CA-induced IL-22 expression by I3AM. Thus,
miRNAs could serve as effective mechanisms for preserving intestinal barrier function and regulating
immune responses by modulating metabolites produced by specific gut bacteria [201,202] .

miRNAs also contribute to the preservation of gut barrier function by reinforcing epithelial architecture. In
mouse models of IBD, marked upregulation of miRNA-602 resulted in clear symptomatic improvement -
most notably reduced diarrhea—and was accompanied by elevated expression of barrier-supporting genes
such as Zonula Occludens-1 (ZO-1), Mucine-2 (MUC2), and MUC3 [203,204] . Consistent with these findings,
treatment of colonic injury with mesenchymal stem cell-derived miRNA-181a restored the expression of key
tight junction components, including claudin-1 and ZO-1. Moreover, plant-derived miRNAs provide
another layer of protection: ginger-associated miRNAs were shown to suppress both transcription and
protein levels of the L. rhamnosus pilus adhesin SpaC, thereby limiting the organism’s ability to accumulate
within the mucosal layer. These observations suggest that host or dietary miRNAs can directly modulate
bacterial behavior, contributing to enhanced resistance against pathogenic or excessive microbial
colonization [205,206] .

Overall, the findings indicate that altering gut microbiota using miRNAs could be a promising strategy to
enhance the stability of the microbial symbiont community, reduce intestinal inflammation, and improve gut
barrier function in individuals with pre-clinical RA. Further clinical research is essential to assess the
effectiveness and safety of miRNA-based therapies and to provide additional evidence regarding the benefits
of this approach [207-209] .

FUTURE PERSPECTIVES
Dysbiosis of the gut microbiota occurs during the pre-clinical stage of RA and significantly contributes to the
disease development. Various mechanisms have been identified that link microbiota imbalance with RA
progression, including molecular mimicry, the effects of microbiome-produced metabolites, impaired
intestinal barrier function, immune responses triggered by the microbiome, autophagy in IECs, and
alterations in miRNA expression [210,211] .

Current RA treatments are typically initiated only after the disease has manifested, and their long-term use
can result in numerous side effects. Therefore, addressing gut microbiota during the pre-clinical stage may
represent a considerable advancement in RA management. Interventions such as dietary modifications and
prebiotics - including a high-fiber diet, fish oil supplementation, and inulin consumption - have the potential
to correct microbiota imbalances and restore immune balance in individuals at this early stage of RA [212] .
However, extensive research in pre-clinical populations is essential to confirm the effectiveness of these