Integrating host-microbiota metabolic networks: how aromatic amino acids shape immune homeostasis and affect disease...

Gut microbial metabolism is intimately linked to host immune homeostasis. Aromatic amino acids (AAAs) serve as substrates for both host and microbial enzymes, yielding a diverse array of metabolites that shape immune responses at local and systemic sites. In this review, an integrated framework is provided for understanding how AAA metabolites orchestrate immune cell function. The journey of AAAs from dietary intake through intestinal absorption and microbial utilization is traced, emphasizing the cooperative metabolic networks that generate immunomodulatory compounds. How these metabolites act on dendritic cells, macrophages, T cells, and B cells through membrane receptors, nuclear receptors, and epigenetic modifications to achieve cell‑type‑specific effects is subsequently examined. Drawing on recent discoveries, including cooperative microbial interactions in tryptophan metabolism, AAA metabolism is best understood as an integrated network rather than separate host and microbial compartments. How the dysregulation of these pathways contributes to inflammatory bowel disease and infectious diseases is further discussed, and emerging therapeutic strategies targeting the microbiota‑metabolite‑immune axis are highlighted. By synthesizing molecular mechanisms, cellular targets, and disease contexts, this review offers a conceptual roadmap for precision interventions that leverage the intricate metabolic connections between the host and microbiota.