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Poznyak et al. Microbiome Res Rep. 2026;5:3 Page 11 of 23

alpha (TNF-α)] and increased levels of anti-inflammatory cytokines (IL-2, IL-10). However, classifying
cytokines strictly as “pro-” or “anti-inflammatory” oversimplifies the highly dynamic and context-dependent
nature of immune signaling, which varies according to disease stage, tissue microenvironment, and
interactions with other immune and microbial cues . After FMT, the gut microbiota was normalized at the
[160]
phylum level, particularly with an increase in Firmicutes from 52.50% to 75.01%. Notably, at the genus level,
there was a decrease in Muribaculum and a significant increase in Lactobacillaceae, from 31.51% to 59.16%,
in mice that received FMT from those treated with tuna elastin peptides. Correlation analyses indicated a
negative association between the abundance of Prevotella sp., Helicobacter typhlonius, and Lentilactobacillus
hilgardii and levels of SCFAs such as valeric acid, butyric acid, and acetic acid [160,161] . In contrast, a positive
correlation was noted between Clostridium aerotolerans and valeric acid production.

Certain studies have demonstrated promising results for the use of FMT in RA treatment, highlighting
reductions in arthritis severity and RF levels in patients with refractory RA. However, careful screening of
FMT donors is essential due to reported cases of infectious complications following treatment [162,163] . An
evaluation of FMT long-term safety for patients with C. difficile infection confirmed its overall safety, despite
one case indicating a potential increase in myocardial infarction risk. Additionally, a recent cross-sectional
study found that individuals with prevalent autoimmune conditions such as RA, systemic lupus
erythematosus, and psoriasis were less familiar with FMT compared to those with ulcerative colitis or Crohn
disease (P < 0.001) [164,165] . Furthermore, general awareness of FMT was identified as the primary factor
influencing acceptance of the treatment (P < 0.001), underscoring the urgent need for educational efforts by
healthcare providers to improve patient understanding and address misconceptions about FMT [166,167] . The
authors of these studies have proposed several explanations for why this approach did not yield the expected
therapeutic effect, including insufficient microbial engraftment, high inter-individual variability in baseline
microbiota composition, and the possibility that the targeted taxa do not play a causal role in disease
progression [166,167] . Some studies also note that host immune activation or metabolic context may override
microbiota-directed interventions, limiting their efficacy .
[168]

Therefore, ongoing research in this area is essential.

AUTOPHAGY REGULATION
Autophagy plays a crucial role in maintaining intestinal mucosal homeostasis through intestinal epithelial
cells (IECs) and in regulating the balance of gut microbiota. Dysfunction in IEC autophagy has been
identified as a significant factor in RA. Thus, enhancing autophagy in IECs may strengthen the intestinal
barrier and optimize gut microbiota composition, presenting a potential therapeutic approach for early-stage
RA [169,170] .

Research indicates that modifying gut microbiota alongside regulating autophagy can effectively reduce gut
inflammation. For instance, altering the microbiota in mice deficient in the autophagy related 7 (Atg7) gene
within IECs led to a marked increase in the presence of Dubosiella and Turicibacter, which correlated with
more severe dextran sodium sulfate-induced colitis. In contrast, promoting autophagy has been shown to
create a more balanced bacterial composition in the gut and prevent intestinal inflammation [171,172] .
Preliminary studies have explored the protective effects of autophagy enhancers in an IBD mouse model. The
addition of spermidine, a natural autophagy promoter, increased the abundance of Firmicutes in the gut and
potentially influenced microbial functions related to amino acid, nucleotide, and lipid metabolism. This
modulation was associated with positive outcomes, including enhanced expression of genes linked to tight
junction integrity [Tight junction protein ZO-1 (Tjp1), Claudin-7 (Cldn7), Claudin-1 (Cldn1), and Tight
junction protein ZO-3 (Tjp3)] [173,174] . Additionally, galangin, another natural autophagy enhancer,
demonstrated protective effects against colon mucosal inflammation by promoting the growth of