Endocrine Abstracts

Metabolic syndrome (MS) is an important etiologic risk factor for the development and progression of certain cancers, including colorectal. Bile acids (BA) are potent antimicrobials that support gastrointestinal health and the dysregulation of BA homeostasis is thought to contribute to gut dysbiosis and drive endotoxemia. Furthermore, an increase in the cytotoxicity ofintestinal BA species can directly damage enterocytes and promote carcinogenesis. We have previously shown that expression of bile acid synthesis enzyme, 5β-reductase (AKR1D1), is decreased in patients with non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MS and here we demonstrate the impact of AKR1D1 deletion on gastrointestinal health in C57BL/6 mice. Female and male wildtype (WT) and AKR1D1 knockout (KO) mice were maintained on a control diet until 52-weeks of age. In both sexes, AKR1D1 deletion decreased BA levels and altered composition, as determined by LC-MS/MS analysis, leading to a more cytotoxic BA profile. Although 16s rRNA analysis ofcecal chyme showed no change in total bacterial counts there were family level changes in bacterial composition.

Consistent with ileal damage, female AKR1D1KO mice had decreased villi lengthand increased crypt depth. Suggesting increased intestinal permeability and endotoxemia the expression of the tight junction genes Claudin 1, ZO-1 and Occludin were reduced and the presence of bacterial DNA in the liver increased, as was hepatic mRNA and protein levels of TLR4 along with expression of TLR4 mediated genes, Nfkb1 and Tnfa. In the colon female AKR1D1 KO mice had decreased crypt depth and greater numbers of cells stained for the proliferation marker Ki-67. Furthermore, there was increased incidence of abnormal growths (tumours and polyps) in the proximal colon; 20% of female AKR1D1 KO mice compared to 0% of WT. Interestingly, male AKR1D1 KO mice had a much milder intestinal phenotype with decreasedexpression of Claudin 1, ZO-1 and Occludin but without signs of damage in the ileum or colon or of endotoxemia in the liver. No abnormal growths were found in either WT or AKR1D1 KO male mice. Collectively, our results suggest that reduced AKR1D1 activity, as that seen in patients with NAFLD, has a sex specific impact on intestinal health, driving intestinal damage and gut permeability and potentially contributing to the risk of colon cancer in females.