Metabolic shifts driven by host-microbial interactions

Host-microbe interactions within the gut have been extensively reviewed in the context of host immune response. Emerging evidence, however, highlights that these inflammatory and immune outcomes are often deeply intertwined with the microbiome-derived secondary metabolites. The gut microbiota functions in concert with the host by providing an extensive repertoire of metabolic enzymes that enhance digestion and capacity to assimilate a broad spectrum of ingested food sources. This symbiotic metabolism generates a diverse array of bioactive metabolites that shape local and systemic physiology, adaptive immune responses, and neuroimmune responses. Here, we focus on microbial metabolism as a central organizing principle of host-microbiota symbiosis. Microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, tryptophan-derived indoles, sphingolipids, and gaseous byproducts, signal through downstream molecular partners like nuclear receptors, transcriptional regulators, and redox-sensitive homeostatic pathways to regulate host energy homeostasis, but also alter immune functions like gut epithelial integrity, immune tolerance, and neuroimmune crosstalk. Finally, we discuss emerging therapeutic strategies that target microbial metabolic functions-including dietary interventions, engineered probiotics, postbiotics, and receptor-directed approaches-that position microbial metabolism as a tractable axis for modulating immunometabolism homeostasis and potentially mitigating metabolic and inflammatory diseases.