The intestinal microbiota acts as a dynamic biochemical factory producing metabolites that profoundly influence host immunity. These small molecules, derived from microbial processing of dietary and endogenous substrates, serve as signaling agents that maintain intestinal equilibrium and regulate inflammatory responses. Their immunomodulatory properties are increasingly recognized as central to both mucosal defense and the pathogenesis of chronic diseases.

Among the most extensively studied metabolites are short-chain fatty acids (SCFAs. Butyrate, acetate, and propionate extend far beyond energy supply to colonocytes. Reduced SCFA production, often observed during dysbiosis, is linked to heightened susceptibility to inflammatory bowel disease (IBD), allergies, and metabolic disorders. Another critical metabolite group includes Tryptophan metabolites, converted by gut microbes into indole derivatives, activate the aryl hydrocarbon receptor (AhR) to enhance epithelial integrity, drive IL-22 production, and boost antimicrobial defences. Dysregulated metabolism disrupts these processes, contributing to chronic intestinal inflammation and barrier dysfunction. Additionally, polyamines, produced by gut microbial activity, contribute to mucosal healing and regulation of innate immune pathways. These molecules enhance autophagy, modulate innate lymphoid cell responses, and support epithelial restitution during infection or injury.

In summary, metabolites produced by intestinal microbes are not passive byproducts but active immunological regulators. By reinforcing epithelial barriers, guiding immune cell differentiation, and restraining excessive inflammation, they serve as essential guardians of gut homeostasis. Understanding their mechanisms of action opens new directions for therapeutic innovation in infections and diseases. Harnessing the gut’s biochemical arsenal could pave the way for next-generation interventions aimed at restoring immune balance and intestinal health.

The human gastrointestinal tract hosts a dense and diverse community of microorganisms, collectively termed the gut microbiota, which plays a pivotal role in maintaining intestinal and systemic health. Beyond aiding digestion and nutrient absorption, these microbes produce a wide range of metabolites that act as signaling molecules, directly influencing host immune responses. Such metabolites, including short-chain fatty acids, tryptophan derivatives, bile acids, and polyamines—modulate immune cell function, reinforce epithelial barriers, and maintain intestinal homeostasis. Disruptions in microbial composition or metabolite production are increasingly linked to inflammatory bowel diseases, metabolic disorders, and systemic immune dysregulation. Understanding how microbiota-derived metabolites regulate immune pathways is therefore critical, as it provides insight into host microbe interactions and offers potential avenues for therapeutic interventions targeting gut-mediated immunity.

The gut microbiota generates diverse metabolites that critically regulate intestinal homeostasis and immune responses. Disrupted metabolite production is linked to chronic inflammation and diseases such as IBD. However, key challenges remain, including limited understanding of metabolite–immune interactions, sex- and age-specific effects, and barriers to therapeutic translation. Recent advances in metabolomics, organoid models, and engineered probiotics provide new opportunities to dissect mechanisms and design targeted interventions. This research aims to integrate current knowledge, identify universal metabolite-mediated pathways, and explore therapeutic strategies to harness microbiota-derived metabolites for restoring mucosal health and controlling intestinal inflammation.

We welcome the submission of Original Research, Review, Mini Review, and Perspective articles on themes including, but not limited to:

• Mechanistic insights into microbiota-derived metabolites

• Crosstalk between metabolites and innate/adaptive immune signaling in health and disease.

• Therapeutic potential of targeting metabolites

• Gender and age-dependent variations in metabolite-mediated immune regulation

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Immunomodulatory Effects of Microbiota-Derived Metabolites in Intestinal Homeostasis and Inflammation