A study of Yanjun. et al

Although the benefits of vertical sleeve gastrectomy surgery (VSG) are clear, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. In addition to observing increasedthat circulating bile acid (BA) levels are increased after VSG in mice, here we found that the expression of sterol 12α-hydroxylase (CYP8B1), a key enzyme in controlling the ratio of 12α-hydroxylated (12α-OH) BAs to non-12α-OH BAs, is strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout, we demonstrated that VSG-induced alterations to the enterohepatic BA circulation and BA composition depend on CYP8B1. As a consequence of these alterations, intestinal lipid absorption is restricted and the gut microbiome (GM) is shifted, which contributes to the metabolic effects of VSG. These results suggest that CYP8B1 is a critical downstream target of VSG. Therefore, modulation of BAbile acid composition and GMgut microbiota profile may be a promising strategy for the development of therapies that non-invasively mimic bariatric surgery to treat obesity and its complications.尽管袖状胃切除术（vertical sleeve gastrectomy, VSG）的临床益处已得到广泛认可，但其缓解肥胖及其并发症的分子机制仍未明确。本研究在观察到小鼠接受VSG后循环胆汁酸（bile acid, BA）水平升高的基础上，进一步发现：作为调控12α-羟化胆汁酸（12α-hydroxylated BA, 12α-OH BA）与非12α-羟化胆汁酸比例的关键酶，固醇12α-羟化酶（sterol 12α-hydroxylase, CYP8B1）的表达在VSG术后显著下调。本研究通过构建CYP8B1过表达、敲低及敲除的基因工程小鼠模型，证实VSG诱导的肠肝胆汁酸循环及胆汁酸组成改变依赖于CYP8B1。上述改变可导致肠道脂质吸收受限，并重塑肠道微生物组（gut microbiome, GM），进而介导VSG的代谢效应。上述结果表明，CYP8B1是VSG发挥作用的关键下游靶点。因此，调控胆汁酸组成与肠道微生物组谱，有望开发出无创模拟减重手术的新型疗法，用于治疗肥胖及其并发症。