Key microbial metabolites regulating gut inflammation: sources, host targets, and pathophysiological relevance.
| Metabolite | Primary microbial producers | Host receptors/Targets | Major immunological & epithelial effects | Alterations in IBD/Inflammation | References |
|---|---|---|---|---|---|
| Butyrate | Faecalibacterium prausnitzii, Roseburia spp., Eubacterium rectale | GPR41 (FFAR3), GPR43 (FFAR2), GPR109A; HDAC inhibition | Enhances epithelial ATP metabolism; strengthens tight junctions (ZO-1, occludin); induces FOXP3+ Tregs; suppresses NF-κB, TNF-α, IL-6 | Significantly reduced in active UC and CD; correlates with barrier dysfunction and disease severity | [52–54] |
| Propionate | Bacteroides spp., Veillonella spp. | GPR41, GPR43; partial HDAC inhibition | Modulates dendritic cell maturation; suppresses Th17 polarization; supports mucin production | Reduced in IBD; systemic immunomodulatory effects are less pronounced than butyrate | [55, 56] |
| Acetate | Broad range including Bifidobacterium spp. | GPR43; central metabolic pathways | Supports epithelial metabolism; influences peripheral immune cell energy balance | Decrease in IBD stool samples; altered systemic availability | [57, 58] |
| Indole-3-propionic acid (IPA) | Clostridium spp., Peptostreptococcus spp. | AhR; PXR | Enhances IL-22 production; promotes epithelial repair; antioxidant effects | Reduced in IBD; loss associated with impaired mucosal healing | [59, 60] |
| Indole-3-aldehyde (IAld) | Lactobacillus spp. | AhR | Induces antimicrobial peptides and mucins; maintains barrier integrity | Depleted in dysbiosis; impaired AhR-IL-22 signaling in IBD | [60, 61] |
| Kynurenine (Kyn) | Host-driven (IDO1 induction), microbiota-modulated | AhR; NMDA receptors (indirect) | Immune tolerance at low levels; chronic elevation drives oxidative stress and immune dysregulation | Elevated Kyn/Trp ratio in IBD; correlates with disease activity | [62] |
| Quinolinic acid | Host Kyn pathway | NMDA receptor agonist | Neurotoxicity; oxidative stress; promotes chronic inflammation | Increased in inflammatory and neuroimmune conditions | [63] |
| Serotonin (5-HT) | Enterochromaffin cells (TPH1), microbiota-regulated | 5-HT receptors; SERT | Regulates gut motility; modulates macrophage and T-cell responses | Dysregulated in IBD; contributes to motility disorders and immune activation | [64, 65] |
| Succinate | Dysbiotic taxa (Prevotella, Enterobacteriaceae) | SUCNR1 (GPR91) | Activates macrophages; primes inflammasome; destabilizes Tregs | Elevated in IBD; promotes NF-κB signaling and Th17 skewing | [66] |
5-HT: 5-hydroxytryptamine; AhR: aryl hydrocarbon receptor; ATP: adenosine triphosphate; CD: Crohn’s disease; FOXP3: forkhead box P3; HDAC: histone deacetylase; IBD: inflammatory bowel disease; IDO1: indoleamine-2,3-dioxygenase-1; Kyn/Trp: kynurenine/tryptophan; NF-κB: nuclear factor kappa-B; NMDA: N-methyl-D-aspartate; PXR: pregnane X receptor; SERT: serotonin transporter; SUCNR1: succinate receptor 1; Th17: T helper 17 cell; TPH1: tryptophan hydroxylase-1; Tregs: regulatory T-cells; UC: ulcerative colitis; ZO-1: zonula occludens-1.
We, the authors, sincerely acknowledge REVA University for providing an opportunity and platform for research.
NSK: Conceptualization, Writing—original draft, Resources, Data curation, Writing—review & editing, Visualization. AH: Data curation, Writing—review & editing, Visualization, Supervision. AC: Conceptualization, Writing—review & editing, Visualization, Supervision. All authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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