Background

Obesity and inflammatory bowel disease (IBD) represent chronic inflammatory conditions. Bariatric surgery improves some obesity-related co-morbidities, but the effects of bariatric surgery on IBD have not been well studied.

Objectives

To examine if bariatric surgery may attenuate colitis in an obese murine model of IBD and study the mechanisms underlying the postsurgical amelioration of intestinal inflammation.

Setting

University of California Irvine, Department of Surgery and Microbiology laboratories.

Methods

Obese mice were assigned to one of 2 bariatric procedures [Duodenojejunal Bypass (DJB n = 6), Sleeve Gastrectomy (SG n = 8)]. Sham-operated mice were (Sham n = 8) were used as a control. After recovering from surgery, IBD was induced by administration of 2% dextran sodium sulfate. Fecal samples were collected before and after IBD induction for microbiome analysis. Pathologic analyses and immunohistochemical staining were performed on colon.

Results

Survival after DJB and SG was higher relative to Sham mice. Histologically, DJB mice had significantly less intestinal inflammation. The observed improvements were not related to a difference in weight among the groups. Farnesoid X receptor staining in the colon was observed quantitatively more in DJB than in SG and sham mice. A statistically significant increase in the number of Lactobacillales was observed in the stool of mice after DJB.

Conclusion

These results suggest that bariatric surgery, in particular DJB, reduces the severity of colitis in a chemically-induced IBD murine model. The anticolitis effects of DJB may be associated with Farnesoid X receptor regulation and gut microbiome rearrangements.

Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (Fxr) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific Fxr knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (Bsep) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat absorption. These findings were verified in sterol 27-hydroxylase (Cyp27a1) knockout mice, which exhibited low intestinal BAs and fat absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and lipid absorption contribute to the metabolic benefits of VSG.

Unlabelled

Vertical sleeve gastrectomy (VSG) is one of the most commonly performed clinical bariatric surgeries used for the remission of obesity and diabetes. However, the precise molecular mechanism by which VSG exerts its beneficial effects remains elusive. We report that the membrane-bound G protein-coupled bile acid receptor, GPBAR-1 (also known as TGR5), is required to mediate the effects of anti-obesity, anti-hyperglycemia, and improvements of fatty liver of VSG in mice. In the absence of TGR5, the beneficial metabolic effects of VSG in mice are lost. Moreover, we found that the expression of TGR5 increased significantly after VSG, and VSG alters both BA levels and composition in mice, resulting in enhancement of TGR5 signaling in the ileum and brown adipose tissues, concomitant with improved glucose control and increased energy expenditure.

Conclusion

Our study elucidates a novel underlying mechanism by which VSG achieves its postoperative therapeutic effects through enhanced TGR5 signaling. (Hepatology 2016;64:760-773).