Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH, USA.
Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH, USA.
Endocrinology. 2021 Feb 1;162(2). doi: 10.1210/endocr/bqaa235.
Historically, the focus of type II diabetes mellitus (T2DM) research has been on host metabolism and hormone action. However, emerging evidence suggests that the gut microbiome, commensal microbes that colonize the gastrointestinal tract, also play a significant role in T2DM pathogenesis. Specifically, gut microbes metabolize what is available to them through the host diet to produce small molecule metabolites that can have endocrine-like effects on human cells. In fact, the meta-organismal crosstalk between gut microbe-generated metabolites and host receptor systems may represent an untapped therapeutic target for those at risk for or suffering from T2DM. Recent evidence suggests that gut microbe-derived metabolites can impact host adiposity, insulin resistance, and hormone secretion to collectively impact T2DM progression. Here we review the current evidence that structurally diverse gut microbe-derived metabolites, including short chain fatty acids, secondary bile acids, aromatic metabolites, trimethylamine-N-oxide, polyamines, and N-acyl amides, that can engage with host receptors in an endocrine-like manner to promote host metabolic disturbance associated with T2DM. Although these microbe-host signaling circuits are not as well understood as host hormonal signaling, they hold untapped potential as new druggable targets to improve T2DM complications. Whether drugs that selectively target meta-organismal endocrinology will be safe and efficacious in treating T2DM is a key new question in the field of endocrinology. Here we discuss the opportunities and challenges in targeting the gut microbial endocrine organ for the treatment of diabetes and potentially many other diseases where diet-microbe-host interactions play a contributory role.
从历史上看，2 型糖尿病（T2DM）的研究重点一直集中在宿主代谢和激素作用上。然而，新出现的证据表明，肠道微生物组——定植在胃肠道中的共生微生物——在 T2DM 发病机制中也起着重要作用。具体来说，肠道微生物通过宿主饮食代谢它们所获得的物质，产生小分子代谢物，这些代谢物可以对人类细胞产生类似激素的影响。事实上，肠道微生物产生的代谢物与宿主受体系统之间的元生物体相互作用，可能代表了一种针对 T2DM 高危人群或患者的未开发治疗靶点。最近的证据表明，肠道微生物衍生的代谢物可以影响宿主肥胖、胰岛素抵抗和激素分泌，从而共同影响 T2DM 的进展。在这里，我们回顾了目前的证据，表明结构多样的肠道微生物衍生代谢物，包括短链脂肪酸、次级胆汁酸、芳香族代谢物、氧化三甲胺、多胺和 N-酰基酰胺，可以以类似激素的方式与宿主受体相互作用，促进与 T2DM 相关的宿主代谢紊乱。尽管这些微生物-宿主信号通路不如宿主激素信号通路那么被充分理解，但它们作为新的可药物靶点具有未被开发的潜力，可以改善 T2DM 并发症。选择性靶向元生物体内分泌的药物在治疗 T2DM 方面是否安全有效，是内分泌学领域的一个关键新问题。在这里，我们讨论了针对肠道微生物内分泌器官治疗糖尿病和其他可能因饮食-微生物-宿主相互作用而发挥作用的疾病的机会和挑战。
