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Poznyak et al. Microbiome Res Rep. 2026;5:3 Page 9 of 23

challenge this idea, revealing that rigorous oral hygiene does not affect disease activity in patients with
established RA, although this approach has yet to be tested in individuals with early-stage RA [119,120] . The
relationship between gut dysbiosis and the intestinal immune system is especially critical during the early
phases of inflammation, which, once initiated, may not be reversible through approaches targeting dysbiosis.
Investigating modifications of dysbiosis in the early or preclinical stages of the disease, or among individuals
at high risk for RA, could significantly enhance our understanding of its role in the onset of the disease [121,122] .

Several randomized controlled trials have assessed the impact of probiotics on RA by examining disease
activity and cytokine profiles. However, a meta-analysis of four trials found no significant benefit in using
probiotics as a supplementary treatment for RA. This conclusion is tentative due to the small sample sizes
and varying study designs. Among the dietary interventions studied in RA, only the Mediterranean and
vegetarian diets have shown a reduction in disease activity [123-125] . However, the long-term effects and patient
adherence to these dietary interventions remain unclear. Further research is needed to explore strategies for
optimizing these diets, enhancing patient compliance, and assessing their sustainability and impact on
long-term disease outcomes in RA .
[126]
SCFAs, such as butyrate, produced through the fermentation of dietary fibers by gut bacteria, play an
essential role in modulating the immune system. They exert their influence on immune cells primarily
through direct interaction with FFAR2 receptors located on colonic T cells and type 3 innate lymphoid cells
(ILC3s). In mouse models, the absence of FFAR2 is associated with a pro-inflammatory gut state, increasing
susceptibility to inflammation and infections [127,128] . SCFAs and FFAR2-activating compounds enhance the
proliferation of ILC3s and the secretion of IL-22 in mice, providing local protection against colonic
inflammation. Similarly, SCFA activation of free fatty acid receptor 2 (FFAR2) in T cells promotes the
expansion of regulatory Treg cells both locally and systemically. The therapeutic potential of SCFAs was also
investigated in CIA mice, where they were found to alleviate arthritis severity by modulating IL-10
levels [129,130] .

Fiber serves as the primary substrate for SCFA production by the gut microbiota. Given the established role
of SCFAs in maintaining gut health and their potential to reduce systemic inflammation in RA, it is
reasonable to propose that a fiber-rich diet could protect the gut and lower systemic inflammation in RA
patients [131,132] . Additionally, fiber may play a significant role in the health benefits associated with vegetarian
and Mediterranean diets, both known for their high fiber content. Supporting this hypothesis, a pilot study
involving 36 RA patients provided a high-fiber diet supplement for 28 days. Post-treatment blood tests
indicated an increase in circulating Treg cells, an improved T helper 1 (TH1) to T helper 17 (TH17) cell
ratio, a reduction in markers of bone erosion, and patients reported feeling better overall [133-135] .

An intriguing hypothesis suggests that the beneficial effects of the natural flavonoid resveratrol on arthritis
may be mediated through its positive impact on the gut microbiome. Resveratrol is recognized for its
anti-inflammatory properties and has demonstrated potential in alleviating RA symptoms in both animal
and human studies [136-138] . A 2019 study suggested that resveratrol may influence intestinal microbiota, though
it remains unclear whether this interaction contributes to its effects against RA. While many of these
research avenues are still in early stages, the evidence gathered thus far could serve as a foundation for
comprehensive double-blind randomized controlled trials exploring microbiota-focused dietary
interventions for RA [139,140] .

Inhibiting immune cell trafficking
Discussions regarding the movement of immune cells from the intestines to the joints suggest that
strategically manipulating the migration of T effector cells from the gut to other areas of the body may