18/11/2025
Gut Microbiota–Derived Metabolites Modulate Treg/Th17 Balance: in a review of emerging literature discussing emerging mechanistic insights in autoimmune disease.
“…As we examine the current evidence, it has become increasingly clear to us that dysregulation of the homeostasis between regulatory T cells and T helper 17 cells represents a pivotal mechanism underlying the development and progression of autoimmune diseases…”
“…We have observed that gut microbiota-derived metabolites - including short-chain fatty acids, secondary bile acids, and aromatic compounds -exert profound effects on immune-cell differentiation and function, and may therefore represent promising therapeutic targets…”
“…In this review, we synthesize recent clinical and experimental findings to clarify how microbial communities and their metabolic products influence the regulatory T cell–T helper 17 cell axis across a spectrum of autoimmune diseases…”
‘…The gut microbiota functions as a major regulator of host immunity, and microbial metabolites have emerged as key modulators of immune-cell differentiation and function…’
‘…Across autoimmune diseases, multiple studies indicate that loss of microbial diversity and altered metabolite abundance correlate inversely with disease severity, while rebalancing the microbiota can restore regulatory T cell and T helper 17 cell proportions and mitigate inflammation…’
‘…We highlight that the translation of these mechanistic insights into therapeutic strategies remains challenging due to heterogeneity in microbiome signatures, variability in metabolite responsiveness, and the pressing need for integrated multi-omic analysis…’
‘…We further emphasise that autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, autoimmune hepatitis, and myasthenia gravis show distinct but convergent patterns of microbial–immune interaction, with regulatory T cell–T helper 17 cell imbalance acting as a shared mechanistic thread…’
In conclusion and taken together…
“…The balance between regulatory T cells and T helper 17 cells, critical in autoimmune disease, is influenced by gut microbiota-derived metabolites…”
Figure Key: Gut microbiota and microbial metabolites regulate the Th17–Treg balance. Specific taxa influence T-cell fate: Clostridium, Bacteroides fragilis and Lactobacillus promote Treg development and function, whereas SFB, Bacteroides fragilis, Lactobacillus and Bifidobacterium stimulate Th17 differentiation and cytokine production.
Microbial metabolites are key effectors: SCFAs (acetate, propionate, butyrate) act mainly via HDAC inhibition and modulation of the mTOR–S6K pathway; BA derivatives signal through TGR5 and FXR to promote Treg differentiation and/or suppress Th17 polarization; Trp-derived ligands (IAA, IPA, I3C) function as AhR agonists that favor Treg generation and restrain Th17 responses, whereas I3AA may antagonize AhR and impair Treg function.
Microbial components and secreted factors — including LPS, flagellin (from SFB), exopolysaccharides (from Lactobacillus casei), EVs and BFT - promote Th17 differentiation.
Conversely, EVs, PSA (from Bacteroides fragilis) and cell-surface β-glucan/galactan polysaccharides enhance Treg activity.
Abbreviations: Treg, regulatory T cell; Th17, T helper 17 cell; SFB, segmented filamentous bacteria; SCFAs, short-chain fatty acids; BA, bile acid; Trp, tryptophan; HDACs, histone deacetylases; TGR5, G-protein-coupled bile acid receptor; FXR, farnesoid X receptor; IAA, indole-3-acetic acid; IPA, indole-3-propionic acid; I3C, indole-3-carbinol; AhR, aryl hydrocarbon receptor; I3AA, indole-3-acetaldehyde; LPS, lipopolysaccharide; EVs, bacterial extracellular vesicles; BFT, Bacteroides fragilis toxin; PSA, polysaccharide A. (By Figdraw, ID: ATTYS1c1c0).
�“…Therapeutic strategies targeting microbial metabolites and microbiome composition represent promising but still emerging opportunities in autoimmune disease management…”
�“…Future research must integrate metagenomics, metabolomics, immunology and clinical trials to deliver safe and effective microbiota-based therapies…"
As we interpret the totality of this evidence, it becomes clear that…
‘…The gut microbiota exerts immunological influence far beyond the intestinal environment, shaping systemic immune tone through metabolite-driven regulation…’
‘…Microbial metabolites - particularly short-chain fatty acids and secondary bile acids - emerge as mechanistic links between microbial ecosystems and autoimmune pathophysiology, influencing regulatory T cell differentiation, inflammatory cytokine networks, and peripheral tolerance…’
‘…Interventions that restore microbial symbiosis or enhance beneficial metabolite production may shift immune homeostasis away from autoimmunity, positioning the microbiota as a clinically actionable axis in immunological therapy…’
Full text: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710733/full
