Simulating the Post-gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR
Mohammed K. Hankir,
Theresa Langseder,
Ezgi Eyluel Bankoglu,
Yalda Ghoreishi,
Ulrich Dischinger,
Max Kurlbaum,
Matthias Kroiss,
Christoph Otto,
Carel W. le Roux,
Tulika Arora,
Florian Seyfried,
Nicolas Schlegel
Affiliations
Mohammed K. Hankir
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany; Corresponding author
Theresa Langseder
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
Ezgi Eyluel Bankoglu
Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Bavaria 97080, Germany
Yalda Ghoreishi
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
Ulrich Dischinger
Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
Max Kurlbaum
Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
Matthias Kroiss
Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
Christoph Otto
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
Carel W. le Roux
Diabetes Complications Research Centre, University College Dublin, Dublin 4, Ireland
Tulika Arora
Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark
Florian Seyfried
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
Nicolas Schlegel
Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany; Corresponding author
Summary: 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, for 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.
