Br J Nutr. 2026 Mar 4:1-24. doi: 10.1017/S0007114526106734. Online ahead of print.

ABSTRACT

Tryptophan is an essential amino acid required for protein synthesis, immune regulation, and the production of serotonin, melatonin, and kynurenine. Its metabolism proceeds through three major pathways-the kynurenine, serotonin, and gut microbiota-derived indole pathways-which are influenced by diet, microbiota, and inflammation. The Mediterranean diet generally improves tryptophan bioavailability, enhances serotonin synthesis, and limits excessive kynurenine activation through anti-inflammatory and microbiota-mediated mechanisms. In contrast, Western diets promote systemic inflammation, increase kynurenine production, and reduce serotonin and beneficial indole metabolites. High-protein and ketogenic diets elevate substrate availability but may increase microbial production of indoles such as skatole and alter the balance of tryptophan utilization, while calorie-restricted diets appear to downregulate pro-inflammatory tryptophan degradation and improve serotonin-related satiety regulation. Collectively, these findings demonstrate that diet is a key regulator of tryptophan metabolism, with implications for mood, sleep, inflammation, cancer progression, and cardiometabolic health. Despite these advances, several knowledge gaps remain, including limited standardization of dietary assessment methods, insufficient databases on the tryptophan content of foods, and a lack of controlled comparative trials. Addressing these limitations may enable the development of nutritional strategies that optimize tryptophan metabolism and improve health outcomes.

PMID:41775650 | DOI:10.1017/S0007114526106734

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