Gut microbe-derived aromatic trace amines mediate individual variability in response to herbal medicine CDD-2101 for functional constipation.

Functional constipation (FC), a common gastrointestinal disorder, poses significant therapeutic challenges due to the limited efficacy and durability of current therapies. A novel strategy for addressing FC involves the targeting of gut dysbiosis. Our previous study demonstrated that the botanical drug CDD-2101 alleviated bowel movement disorders in FC patients. Nevertheless, whether the alterations in gut microbiota composition affected by CDD-2101 are associated with improved bowel movements and the gut microbiota-mediated mechanisms of action of CDD-2101 are not yet fully comprehended. Here, we showed that CDD-2101 enriched aromatic trace amines and aromatic trace amines-producing gut bacteria in FC patients, which correlated with enhanced bowel function and increased peripheral serotonin levels. In preclinical studies, treatment with tyramine, one of the aromatic trace amines, improved constipation-like symptoms and upregulated serotonin production in mice. Consistent with these findings, the colonization of mice with tyramine-enriched fecal microbiota from CDD-2101-treated patients or administration of an aromatic trace amines-producing engineered Lactobacillus casei alleviated constipation-like symptoms and enhanced serotonin production. Mechanistically, we showed that aromatic trace amines improved gastrointestinal motility by activating the trace amine-associated receptor 1 (TAAR1)-serotonin biosynthesis axis. Our study provides mechanistic and therapeutic insights into aromatic trace amines as microbial-derived TAAR1 ligands that regulate serotonin production to improve defecation in FC. These results not only support the therapeutic potential of targeting gut microbiota for the treatment of FC but also identify the aromatic trace amines-serotonin axis, as promoted by CDD-2101, as a pivotal therapeutic target for the improvement of FC. Chinese Clinical Trial Registry (ChiCTR) no: ChiCTR2100043211.