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.

中文翻译：

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肠道微生物组在长寿人群中的生物合成潜力。


肠道微生物组在对抗疾病和促进健康老龄化方面起着关键作用，源自人类微生物组生物合成基因簇 （BGC） 的天然产物表现出显着的生物活性。然而，人们对长寿人群中肠道微生物组的天然产物仍然知之甚少。在这里，我们整合了 6 个长寿人群队列，共包括 1029 个粪便宏基因组样本，并采用宏基因组单样本组装 BGC （MSSA-BGC） 分析管道来研究天然产物及其相关物种。我们的研究结果表明，在五个队列中，极长寿组的 BGC 组成与年轻老年人和年轻人的 BGC 组成显着不同。萜烯和 I 型 PKS BGCs 在极长寿的人群中富集，而环内酯自诱导剂 BGCs 在年轻人中更普遍。关联分析表明，萜烯 BGCs 与 Akkermansia muciniphila 的丰度密切相关，在至少三个队列中，嗜粘蛋白 Akkermansia 在长寿老年人中也更为丰富。我们使用来自六个队列中极长寿组的宏基因组数据组装了 18 个嗜粘蛋白不动杆菌基因组草案，发现它们都含有两类萜烯 BGC，这与从 NCBI 数据库中检索到的嗜粘蛋白不动杆菌菌株的 97 个完整基因组一致。这两类 BGC 的核心结构域是参与三萜和四萜生物合成的角鲨烯/八氢番茄红素合酶。此外，粪便嗜粘蛋白曲霉的丰度与 8 种类型的三萜类化合物显著相关。靶向萜类代谢组学分析显示，Holstinone C 和 colubrinic acid 两种三萜类化合物在 A 中富集。 嗜粘蛋白培养液与培养基相比，从而证实了嗜粘蛋白芽孢杆菌产生三萜类化合物。从长寿人群肠道中提取的天然产物提供了有趣的迹象，表明它们在调节健康方面具有潜在的有益作用。