Dietary fat and bile acids in the pathogenesis of gut barrier dysfunction
Year: 2013
Type: dissertation
Abstract: Gut barrier function is impaired in several disorders such as inflammatory bowel diseases, diabetes and steatohepatitis. It is suspected that this is related to increased permeability to bacterial endotoxins from the lumen through the gut epithelium. Recent studies have shown a link between high-fat diet and endotoxemia, but the underlying mechanisms are unknown. One possible explanation is the contribution of other luminal substances, such as bile acids. Fat ingestion induces bile flow to the duodenum to facilitate the absorption of fat. At high concentrations, bile acids especially very hydrophobic bile acids are cytotoxic. The aim of this study was to investigate whether dietary fat or obesity causes barrier dysfunction, and whether bile acids play a role in its pathogenesis. The role of bile acid hydrophobicity in their capability of inducing barrier dysfunction was given special attention. The effects of dietary fat and obesity on gut barrier function were investigated in the diet induced obesity and ob/ob -mouse models. Fecal bile acids were quantified and profiles calculated from these mice. The effects of bile acids on intestinal permeability were studied in an in vivo feeding trial with deoxycholic acid and in vitro in an Ussing chamber. In vitro, tissue preparations were incubated with deoxycholic acid and/or ursodeoxycholic acid - two bile acids greatly different in their hydrophobicity. Gut barrier function was impaired by a high-saturated fat diet in mice, but not in genetically obese mice that were fed normal low-fat chow. Barrier dysfunction by dietary fat was especially prominent in jejunum and colon - no significant difference was seen in the permeability of duodenum or ileum. Fecal bile acid hydrophobicity was increased only by dietary fat, not by genetic obesity, and was positively correlated with intestinal permeability. Deoxycholic acid alone increased gut permeability both in vivo and in vitro. The effect was more evident in colonic than jejunal tissue preparations, and the mechanism seemed not to be inflammation-dependent. Barrier impairment was reduced by the hydrophilic ursodeoxycholic acid, which was also reflected as improved tissue morphology. Deoxycholic acid -induced barrier dysfunction seemed to be aggravated by translocated lipopolysaccharides. The present results suggest that dietary fat, but not obesity itself, impairs gut barrier function. The data imply that luminal bile acids are one mechanism for barrier impairment, with hydrophobic bile acids initiating tissue disruption and lipopolysaccharides likely playing the role of a second hit.
Source: Työväentutkimus Vuosikirja
Author: Lotta K. Stenman
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1199784142