Page 60 - Read Online

Poznyak et al. Microbiome Res Rep. 2026;5:3 Page 7 of 23

Table 2. Therapeutic strategies targeting gut microbiota in preclinical RA
Intervention Mechanism Evidence Future directions References

Modulates gut microbiota Mediterranean and vegetarian Investigate long-term effects and
Dietary changes [116-119,124-128]
composition diets reduce RA activity specific dietary components
Restores microflora Mixed results; some studies show Explore specific strains beneficial for
Probiotics [78-80,116-118]
balance symptom relief RA prevention
Restores gut microbiome Show promise in animal models; Protocol standardization and
FMT [144-156]
from healthy donors variable human results long-term safety assessments
MicroRNA Alters gut immune Emerging research linking miRNAs Clinical trials to assess efficacy in [180-202]
modulation responses to microbiome composition RA prevention
RA: Rheumatoid arthritis; FMT: fecal microbiota transplantation.

Limosilactobacillus fermentum ME-3, have been shown to enhance regulatory T-cell responses, improve
epithelial barrier integrity, and increase short-chain fatty acid (SCFA) production in experimental systems.
These divergent effects highlight that functional outcomes cannot be inferred at the genus level. Instead,
biological activity is highly dependent on strain-level genomic and metabolic properties and their interaction
with host immune networks. Rigorous strain-level characterization is therefore essential for interpreting
reported effects and for the rational design of microbiota-based interventions in RA [63,89] .

TRANSFORMING THE GUT-JOINT AXIS
Multiple microbiota-targeted interventions, including dietary modification, probiotics, FMT, and
miRNA-based approaches, have been investigated for their potential roles in preclinical RA, with proposed
mechanisms of action, current evidence, and research gaps summarized in Table 2.

Anti-rheumatic drugs and the gut microbiota
The alterations in the gut microbiome associated with RA, both in terms of composition and abundance,
prompt an investigation into how existing RA treatments affect patients’ gut bacteria. Anti-rheumatic
medications, including chemical agents, can disrupt microbial balance by influencing immune responses and
directly interacting with microbes as foreign entities [90-92] . Minocycline, an antibiotic from the tetracycline
class, has been used as a DMARD for RA treatment and continues to be prescribed for a limited number of
patients in certain areas. The rationale for using antibiotics in RA was initially based on the hypothesis of an
infectious cause, particularly targeting Mycoplasma. However, the therapeutic effects of minocycline in RA
are now attributed to its anti-inflammatory and immune-modulating properties rather than its antimicrobial
activity [93,94] .

As research progresses in understanding the role of gut and other microbiota in inflammatory arthritis, there
is increasing interest in how tetracyclines such as minocycline might influence RA through changes to the
gut microbiome. Although direct evidence of minocycline’s effect on gut microbiota is limited, studies
indicate that a single dose can significantly alter fecal microbiota composition in healthy individuals. This
observation raises the possibility that minocycline’s therapeutic effects in RA are mediated, at least in part,
via shifts in the gut microbiota that alter host immunity or microbial metabolite profiles. Antibiotic-induced
decreases in taxa linked to pro-inflammatory phenotypes (e.g., some Actinobacteria including Collinsella)
and concurrent changes in SCFA producers could plausibly reduce systemic inflammation and modify drug
pharmacokinetics . However, the evidence is currently indirect: most human data are short-term and
[95]
descriptive. Therefore, the contribution of microbiota modulation to minocycline’s clinical efficacy remains a
testable hypothesis rather than a proven mechanism. Importantly, long-term antibiotic exposure could also
induce persistent dysbiosis, select for antibiotic resistance genes, or impair beneficial microbial functions,
which underscores the need to evaluate chronic effects in RA populations . Notably, minocycline treatment
[96]