Gut-derived metabolites regulate immune cells in complex ways

Published on March 23, 2026, in Volume 2, article number 18 of the journal Immunity & Inflammation, the review begins by systematically outlining the sources and synthetic pathways of immune-relevant microbial metabolites, including bile acids, short-chain fatty acids, amino acid derivatives, vitamins, trimethylamine/trimethylamine N-oxide, and odd-chain fatty acids. The authors then explore how these metabolites influence disease progression through actions on specific immune cell populations.

In the innate immune compartment, short-chain fatty acids can suppress dendritic cell antigen presentation while simultaneously promoting IL-10 and retinoic acid production, favoring an immune-tolerant phenotype. The secondary bile acid, deoxycholic acid (DCA), alleviates autoimmune uveitis by activating the TGR5 receptor on dendritic cells. Conversely, trimethylamine N-oxide enhances type I interferon secretion from tumor-associated macrophages, improving responses to pancreatic cancer immunotherapy.

For innate lymphoid cells, taurodeoxycholic acid promotes their intestinal retention to ameliorate colitis, while glycodeoxycholic acid improves polycystic ovary syndrome symptoms by inducing IL-22 secretion, illustrating how microbial metabolites orchestrate functional connections between the gut and distant organs.

In the adaptive immune compartment, the review highlights the bidirectional regulation of CD4⁺ T cell differentiation. On the tolerogenic side, 3-oxolithocholic acid binds RORγt to inhibit Th17 differentiation, while isolithocholic acid and isodeoxycholic acid promote regulatory T cell (Treg) differentiation through NR4A1 or the FXR receptor on dendritic cells. Short-chain fatty acids increase Treg numbers by inhibiting histone deacetylases or activating GPR43, thereby alleviating colitis.

On the pro-inflammatory side, indoxyl sulfate enters the skin and exacerbates psoriasis by enhancing Th17 cell chromatin plasticity via the aryl hydrocarbon receptor (AhR). Inosine activates Th1 cells through the adenosine A2A receptor, enhancing the efficacy of immune checkpoint inhibitors.

For CD8⁺ T cells, secondary bile acids again display context-dependent effects: DCA suppresses CD8⁺ T cell function by inhibiting calcium signaling, promoting colorectal cancer progression, while 3-oxo-Δ4,6-lithocholic acid activates the androgen receptor to enhance CD8⁺ T cell infiltration and improve anti-PD-1 therapy responses.

In the B cell compartment, short-chain fatty acids modulate antibody class switching and secretion in a concentration-dependent manner by regulating B cell energy metabolism and histone deacetylase activity, while also promoting IL-10⁺ regulatory B cell differentiation. The tryptophan metabolite indole-3-acetic acid promotes IL-35⁺ B cell accumulation in the colon via AhR, helping to combat high-fat diet-induced obesity. Together, these findings paint a comprehensive picture of how microbial metabolites fine-tune immune cell functions through multiple targets and pathways.

A key theme throughout the review is that "the same metabolite can exert opposing effects depending on the immune cell type, concentration, and disease context." Short-chain fatty acids, for example, can both enhance CD8⁺ T cell anti-tumor function and suppress dendritic cell antigen presentation, potentially weakening immune responses. This duality and complexity represent the central challenge in moving the field from correlative observations to mechanism-based interventions.

The review provides clear guidance for future research. The authors highlight how emerging metabolomics technologies-including reverse metabolomics and click chemistry-based approaches-combined with AI-assisted enzyme function prediction are accelerating the discovery and functional characterization of novel metabolites. Given the challenge that targeting a single metabolite may perturb multiple others, "future studies should focus on holistic regulation of the metabolite profile rather than isolated intervention on single molecules," the authors point out.

Establishing quantitative relationships between metabolite concentrations and immune cell functions will be critical for achieving precision interventions. Finally, the authors call for advancing basic discoveries toward clinical translation: "Although clinical applications targeting microbial metabolites remain limited, the convergence of synthetic biology, microbial engineering, and AI-powered predictive modeling is poised to make metabolite-targeted precision immunotherapy a promising direction for next-generation therapeutic strategies," the authors prospect.