Hankir Mohammed K, Langseder Theresa, Bankoglu Ezgi Eyluel, Ghoreishi Yalda, Dischinger Ulrich, Kurlbaum Max, Kroiss Matthias, Otto Christoph, le Roux Carel W, Arora Tulika, Seyfried Florian, Schlegel Nicolas
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany.
Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Bavaria 97080, Germany.
iScience. 2020 Nov 5;23(12):101777. doi: 10.1016/j.isci.2020.101777. eCollection 2020 Dec 18.
Regional changes to the intestinal microenvironment brought about by Roux-en-Y gastric bypass (RYGB) surgery may contribute to some of its potent systemic metabolic benefits through favorably regulating various local cellular processes. Here, we show that the intestinal contents of RYGB-operated compared with sham-operated rats region-dependently confer superior glycemic control to recipient germ-free mice in association with suppression of endotoxemia. Correspondingly, they had direct barrier-stabilizing effects on an intestinal epithelial cell line which, bile-exposed intestinal contents, were partly farnesoid X receptor (FXR)-dependent. Further, circulating fibroblast growth factor 19 levels, a readout of intestinal FXR activation, negatively correlated with endotoxemia severity in longitudinal cohort of RYGB patients. These findings suggest that various host- and/or microbiota-derived luminal factors region-specifically and synergistically stabilize the intestinal epithelial barrier following RYGB through FXR signaling, which could potentially be leveraged to better treat endotoxemia-induced insulin resistance in obesity in a non-invasive and more targeted manner.
Roux-en-Y胃旁路术（RYGB）手术引起的肠道微环境区域变化可能通过有利地调节各种局部细胞过程，对其强大的全身代谢益处起到一定作用。在此，我们表明，与假手术大鼠相比，RYGB手术大鼠的肠道内容物区域依赖性地赋予无菌受体小鼠更好的血糖控制，并伴有内毒素血症的抑制。相应地，它们对肠上皮细胞系具有直接的屏障稳定作用，而暴露于胆汁的肠道内容物部分依赖法尼醇X受体（FXR）。此外，在RYGB患者的纵向队列中，循环成纤维细胞生长因子19水平（肠道FXR激活的指标）与内毒素血症严重程度呈负相关。这些发现表明，RYGB术后各种宿主和/或微生物群衍生的腔内因子通过FXR信号通路区域特异性地协同稳定肠上皮屏障，这有可能被用于以非侵入性和更有针对性的方式更好地治疗肥胖症中内毒素血症诱导的胰岛素抵抗。
