Chenodeoxycholic acid stimulates glucagon‐like peptide‐1 secretion in patients after Roux‐en‐Y gastric bypass

Abstract

Postprandial secretion of glucagon‐like peptide‐1 (GLP‐1) is enhanced after Roux‐en‐Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP‐1 secretion through activation of TGR5‐receptors. We aimed to evaluate GLP‐1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB‐operated participants. Eleven participants (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo‐controlled, crossover‐study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral intake of CDCA increased plasma concentrations of GLP‐1, C‐peptide, glucagon, peptide YY, neurotensin, total bile acids, and fibroblast growth factor 19 significantly compared with placebo (all P < 0.05 for peak and positive incremental area‐under‐the‐curve (piAUC)). All plasma hormone concentrations were unaffected by UDCA. Neither UDCA nor CDCA changed glucose, cholecystokinin or glucose‐dependent insulinotropic polypeptide (GIP) concentrations. In conclusion, our findings demonstrate that the primary bile acid chenodeoxycholic acid is able to enhance secretion of gut hormones when administered orally in RYGB‐operated patients—even in the absence of nutrients.

Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents

“…In line with this, inhibition of BA absorption by resin drugs with BA sequestering properties (such as cholesevelam), lead to an acute blockage of GLP-1 secretion (9, 25), however, prolonged resin administration is also found to increase GLP-1 secretion (22,26) and improve glucose tolerance (41), which may be due to increased colonic BA delivery and thus colonic TGR5 activation. Absent peptide responses to the poor TGR5 receptor ligand, TUDCA (28,34), further support the importance of the receptor, which again is similar to a human study where no gut hormone responses were seen upon oral ingestion of UDCA, whereas the primary BA, CDCA, increased secretion of GLP-1, PYY, neurotensin, C-peptide, and glucagon (42). Finally, GLP-1 responses to intra-arterial as well as intra-luminal BA stimulation remained unchanged in TGR5 knockouts (opposite to TGR5 +/+ mice), clearly demonstrating that TGR5 is essential for BA-mediated GLP-1 secretion from the colon.…”

“…Accordingly, the BA concentrations measured directly in perfusion effluents (before retention in the liver) were found to reach ∼30 µM (= almost 100 nmol/min, figure 1), whereas the in vivo data would be consistent with near complete BA uptake by the liver. The dependence of BA absorption on BA-induced secretion is in line with the relatively smaller magnitude of GLP-1 secretion obtained in humans upon proximal BA delivery (25) compared to studies investigating distal BA delivery either by rectal infusions (a rather unphysiological stimulus) (1,2) or by oral delivery to gastric bypass operated individuals where the upper part of the gut is surgically shunted away from intestinal continuity (42). The significantly larger responses reported here, suggest that response size depends on site of stimulation and absorption as also pointed out by Nielsen et al (42).…”

“…Recent in vitro as well as in vivo studies have already pointed to BAs as potent stimulators of GLP-1 and PYY secretion (1,2,8,19,23,34,42,46,50,51), but exactly where in the intestine BAs particularly act to stimulate L-cell secretion is unknown. Once absorbed, BAs are returned to the liver trough the enterohepatic circulation (13,38), where they interact with the nuclear farnesoid X receptor (FXR), which regulates hepatic BA synthesis and also appear to be involved in lipid and glucose metabolism (29,35,66).…”

Mechanisms for the metabolic success of bariatric surgery

“…In mice, VSG also results in a change in the composition of BA also towards CA, although there is also an increase in tauroursodeoxycholic acid, a particular BA that has been found to have potent metabolic effects in a diabetic mouse model . Interestingly, ursodeoxycholic acid, a hydrophilic secondary BA utilised pharmacologically to treat cholestasis, has no additional impact on gut peptide or glucose levels when administered to RYGB patients . Thus, the differences in the impact of obesity and bariatric surgery are important because different types of BA have differing metabolic properties and differing affinities (including antagonistic properties) for the two receptors thought to be critical for BA signalling.…”

“…120 Interestingly, ursodeoxycholic acid, a hydrophilic secondary BA utilised pharmacologically to treat cholestasis, has no additional impact on gut peptide or glucose levels when administered to RYGB patients. 121 Thus, the differences in the impact of obesity and bariatric surgery are important because different types of BA have differing metabolic properties and differing affinities (including antagonistic properties) for the two receptors thought to be critical for BA signalling.…”