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Page 12 of 23 Poznyak et al. Microbiome Res Rep. 2026;5:3

Lactobacillaceae and boosting SCFA production, particularly acetic and butyric acids [175,176] .

From a mechanistic standpoint, boosting autophagy in the gut may mitigate early inflammatory processes in
individuals who are still in the preclinical phase of RA. This enhancement can help restore microbial balance,
support the synthesis of anti-inflammatory metabolites, and strengthen epithelial barrier integrity [177,178] .
Alterations in specific bacterial groups - most notably increases in Bifidobacterium dentium and members of
Verrucomicrobia such as Akkermansia - appear capable of triggering autophagy through pathways involving
toll-like receptor 4 (TLR4) and mechanistic target of rapamycin (mTOR). Activation of these mechanisms
may, in turn, reduce intestinal inflammation by increasing mucus thickness, enhancing goblet cell activity,
and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, oxidative
injury, and downstream cytokine production. As a result, therapeutic strategies that combine probiotic
administration with microbial species known to directly induce autophagy in IECs may offer a means of
slowing or preventing the transition from preclinical to clinical RA [179-181] . Nevertheless, emerging evidence
indicates that excessive or dysregulated autophagy activation in the gut could drive M1 macrophage
polarization, a process potentially intensified by shifts in the microbiome and by Paneth cell metaplasia. Such
outcomes raise the concern that high autophagy levels - particularly in individuals exposed to substantial
psychosocial stress - may aggravate IBD rather than provide protection [182,183] .

Given the complexity of the downstream pathways in IEC autophagy and the intricate interactions between
autophagy and the gut microbiome, extensive research is needed to assess the potential benefits and
drawbacks of moderating IEC autophagy as a strategy for treating preclinical RA. Furthermore, enhancing
the screening processes for autophagy inducers is essential to identify those that provide optimal
anti-inflammatory effects while curbing RA progression and minimizing the risk of triggering IBD [184-186] .

THE CASE OF MIRNAS
Recent studies suggest that miRNAs may play a role in the onset of early RA. Several miRNAs, including
miRNA-449, miRNA-27b-3p, miRNA-495, miRNA-34a-3p, miRNA-340-5p, and miRNA-17-5p, have been
shown to inhibit the proliferation of RA synovial fibroblasts by targeting the signal transducer and activator
of transcription 3 (STAT3)/β-catenin signaling pathway, reducing the expression of cell cycle proteins, and
decreasing histone deacetylase 1 production [187-189] . Despite these findings, research on miRNA-based
therapies for pre-clinical RA is still in its early stages. However, insights from treatments for other
dysbiosis-related diseases may inform future strategies for managing pre-clinical RA. In the context of IBD,
studies investigating the use of exogenous miRNAs have shown promising results, indicating that miRNA
treatments can reduce intestinal inflammation by modifying gut microbiota composition and modulating the
intestinal immune response [190,191] .

In experimental colitis models receiving mesenchymal stem cell-derived miRNAs, investigators observed
distinct shifts in gut microbial structure. Treatment with miRNA-181a led to increased alpha diversity,
reflected in higher values of observed operational taxonomic units, Chao1, and the Abundance-based
Coverage Estimator [192,193] . At the genus level, administration of the miRNA elevated the relative abundance of
Enterorhabdus, Lactobacillaceae, and Akkermansia, while reducing Bacteroides. Family-level profiling further
showed that miRNA-181a promoted expansion of Lactobacillaceae and Bacteroidales S24-7, accompanied by
a decline in Clostridiaceae. Immunologically, treatment enhanced the proportion of Interleukin-10 (IL-10 )
+
forkhead box P3 (Foxp3 ) Tregs and lowered the frequency of Th17 cells within the intestinal mucosa, along
+
with broad suppression of pro-inflammatory mediators such as IL-1β, IL-6, IL-2, IL-18, IL-17, and TNF-α.
Conversely, enrichment of taxa including Enterococcus, Turicibacter, Helicobacter, Desulfovibrionaceae,
unclassified Desulfovibrionaceae, and Mogibacteriaceae showed positive associations with elevated
inflammatory cytokine levels and activation of immune-inflammatory pathways. Collectively, these results