Biosynthetic potential of the gut microbiome in longevous populations
Sheng Liu,
Zhao Zhang,
Xudong Wang,
Yan Ma,
Hengfang Ruan,
Xing Wu,
Baoxia Li,
Xiangyu Mou,
Tao Chen,
Zhengqi Lu,
Wenjing Zhao
Affiliations
Sheng Liu
Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
Zhao Zhang
Research and Development Center, Center of Human Microecology Engineering and Technology of Guangdong Province, Guangzhou, Guangdong, China
Xudong Wang
Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
Yan Ma
Research and Development Center, Center of Human Microecology Engineering and Technology of Guangdong Province, Guangzhou, Guangdong, China
Hengfang Ruan
Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China
Xing Wu
Research and Development Center, Center of Human Microecology Engineering and Technology of Guangdong Province, Guangzhou, Guangdong, China
Baoxia Li
Research and Development Center, Center of Human Microecology Engineering and Technology of Guangdong Province, Guangzhou, Guangdong, China
Xiangyu Mou
Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
Tao Chen
Research and Development Center, Center of Human Microecology Engineering and Technology of Guangdong Province, Guangzhou, Guangdong, China
Zhengqi Lu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China
Wenjing Zhao
Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
Gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species. Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts. We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of tri- and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.
