Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host-gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but it remains largely unknown how the highly variable genomes of gut bacteria interact with host BA metabolism. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete clusters showed correlations with BA metabolism. Metagenome-wide association analysis identified 809 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the largest microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and it highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.

胆汁酸 (BA) 促进肠道脂肪吸收，并在宿主-肠道微生物群串扰中充当重要的信号分子。已经确定了微生物群落中的 BA 代谢途径，但在很大程度上仍不清楚肠道细菌的高度可变基因组如何与宿主 BA 代谢相互作用。我们对来自两个队列的 1,437 个人的肠道微生物组中的 55 种细菌物种的 8,282 种结构变异 (SV) 进行了表征，并对 39 个血浆 BA 参数进行了系统的关联研究。基于 SV 的连续基因组成和离散簇的变化都显示出与 BA 代谢的相关性。宏基因组关联分析确定了细菌 SV 和 BA 和 SV 调节剂之间的 809 个可复制关联，这些关联介导生活方式因素对 BA 代谢的影响。