Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2023 Jan 31;14(1):512. doi: 10.1038/s41467-023-36138-3.
The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.
人类肠道微生物群产生数十种在血液中循环的小分子，其积累水平可与药物相媲美，并影响宿主的生理机能。尽管这些代谢物对人类健康和疾病至关重要，但大多数微生物产生的分子的来源及其在宿主中的命运在很大程度上仍是未知的。在这里，我们揭示了一种宿主-微生物共代谢途径，用于生成马尿酸，这是哺乳动物尿液中最丰富的有机酸之一。我们结合稳定同位素示踪和细菌及宿主遗传学，证明了肠道细菌将苯丙氨酸还原为苯丙酸；然后，宿主通过中链酰基辅酶 A 脱氢酶（MCAD）重新氧化苯丙酸。生成无菌雄性和雌性 MCAD 小鼠，使定植共生成为可能，再结合非靶向代谢组学，鉴定出 MCAD 在宿主循环中处理的其他微生物代谢物。我们的研究结果揭示了一种丰富、无毒的苯丙氨酸代谢物马尿酸的宿主-微生物途径，并确定了通过 MCAD 的β-氧化是哺乳动物代谢微生物衍生代谢物的一种新机制。
