TY - JOUR
T1 - Gut microbe-derived aromatic trace amines mediate individual variability in response to herbal medicine CDD-2101 for functional constipation
AU - Ruan, Shifa
AU - Li, Yaqi
AU - Ning, Ziwan
AU - Li, Yunlyu
AU - Liu, Qin
AU - Fang, Wenyu
AU - Jiang, Xuanting
AU - Luo, Jingyuan
AU - Gao, Hetong
AU - To, Wing Lam Wendy
AU - Zhu, Lin
AU - Lin, Chengyuan
AU - Yuan, Chunsu
AU - Xiao, Haitao
AU - Zhai, Lixiang
AU - Bian, Zhaoxiang
N1 - This research was funded by the Health@InnoHK Initiative Fund provided by the Hong Kong SAR Government (ITC RC/IHK/4/7 to Zhaoxiang Bian), the General Research Fund (12100323 to Zhaoxiang Bian), the Guangdong Basic and Applied Basic Research Foundation (2414050003325 to Lixiang Zhai) and the Young Collaborative Research Grant (C2004-23Y to Lixiang Zhai) for the following purposes: research design, conduct, analysis, and manuscript production (Health@InnoHK Initiative Fund); data analysis (General Research Fund); and conduct (manpower) (Guangdong Basic and Applied Basic Research Foundation and Young Collaborative Research Grant). The authors would also like to express profound gratitude to Vincent and Lily Woo Foundation for their support of this work.
Publisher Copyright:
© 2025
PY - 2025/7
Y1 - 2025/7
N2 - 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.
AB - 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.
KW - Aromatic trace amines
KW - CDD-2101
KW - Functional constipation
KW - Gut microbiota
KW - Ruminococcus gnavus
KW - Serotonin
KW - TAAR1
UR - http://www.scopus.com/inward/record.url?scp=105007004016&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2025.107810
DO - 10.1016/j.phrs.2025.107810
M3 - Journal article
AN - SCOPUS:105007004016
SN - 1043-6618
VL - 217
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 107810
ER -
