目的:胆汁酸(BA)是胃肠道的核心代谢产物,具有脂质吸收和细胞信号传导的双重功能。BAs在肝脏和远端小肠之间循环(即,回肠),然而,复杂的BA库在回肠中吸收并在体内与宿主肠细胞相互作用的动力学仍然知之甚少。由于回肠吸收在确定肠腔中哪些BAs可以进入宿主肠细胞和受体时是限速的,在什么浓度下,我们假设,定义回肠BA在体内吸收的速率和途径将产生对小鼠肠肝BA库的生理形式和功能的新见解。
方法:使用离体质谱,我们量化了个别野生型小鼠的肠腔和肠系膜上静脉中的88个BA物种和代谢物,以及缺乏回肠BA转运蛋白的笼子伴侣,Asbt/Slc10a2。
结果:使用这些数据,我们计算出通过回肠组织循环的BAs池(即,禁食C57BL/6J雌性小鼠的“回肠BA池”)为~0.3μmoles/g。Asbt介导的运输占这个池的80%,并扩大了大小。被动渗透率解释了剩余的20%,并产生了多样性。与野生型小鼠相比,Asbt缺陷小鼠的回肠BA池要小5倍,富含通常在结肠中发现的次级BA物种和代谢物,并在添加到离体培养的回肠外植体后引起独特的转录反应。
结论:这项研究定义了小鼠肝肠BA库的数量性状,并揭示了异常的BA代谢如何直接影响宿主的肠道生理。
OBJECTIVE: Bile acids (BAs) are core gastrointestinal metabolites with dual functions in lipid absorption and cell signaling. BAs circulate between the liver and distal small intestine (ie, ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with host intestinal cells in vivo remain poorly understood. Because ileal absorption is rate-limiting in determining which BAs in the intestinal lumen gain access to host intestinal cells and receptors, and at what concentrations, we hypothesized that defining the rates and routes of ileal BA absorption in vivo would yield novel insights into the physiological forms and functions of mouse enterohepatic BA pools.
METHODS: Using ex vivo mass spectrometry, we quantified 88 BA species and metabolites in the intestinal lumen and superior mesenteric vein of individual wild-type mice, and cage-mates lacking the ileal BA transporter, Asbt/Slc10a2.
RESULTS: Using these data, we calculated that the pool of BAs circulating through ileal tissue (ie, the ileal BA pool) in fasting C57BL/6J female mice is ∼0.3 mmol/g. Asbt-mediated transport accounted for ∼80% of this pool and amplified size. Passive permeability explained the remaining ∼20% and generated diversity. Compared with wild-type mice, the ileal BA pool in Asbt-deficient mice was ∼5-fold smaller, enriched in secondary BA species and metabolites normally found in the colon, and elicited unique transcriptional responses on addition to ex vivo-cultured ileal explants.
CONCLUSIONS: This study defines quantitative traits of the mouse enterohepatic BA pool and reveals how aberrant BA metabolism can impinge directly on host intestinal physiology.