SFEBES2019 ORAL POSTER PRESENTATIONS Metabolism and Obesity (4 abstracts)
1Oxford Brookes University, Oxford, UK; 2University of Oxford, Oxford, UK; 3MRC Harwell Institute, Oxford, UK; 4University of Basel, Basel, Switzerland
Disruption of the gut-liver axis contributes to metabolic syndrome and the progression of non-alcoholic fatty liver disease (NAFLD). Bile acids (BAs) are potent antimicrobials that support gastrointestinal health and dysregulation of BA homeostasis in NAFLD is thought to contribute to gut dysbiosis. Furthermore, an increase in hydrophobic (cytotoxic) BA species may directly affect gut health. We have previously shown that bile acid synthesis enzyme, 5β-reductase (AKR1D1), is downregulated in NAFLD patients. Here we demonstrate the impact of AKR1D1 deletion on intestinal health in female mice. Female wildtype (WT) and AKR1D1-Knockout (KO) mice were maintained on a control diet until 52-weeks of age. Fecal BAs were reduced (WT 2.56±0.49; KO 1.35±0.28 pmol/ng, P< 0.05) and LC-MS/MS analysis of serum BAs showed increased hydrophobicity of BA pool (hydrophobicity index: WT −54.9±8.3; KO −23.6±7.1, P<4*10-4). Although there was no change in total caecal bacterial counts, bacterial composition was altered, with changes seen for species associated with inflammatory status, Alkaliphilus crotonatoxidans (WT 0.6%; KO 1.2%, P<5*10-5) and Mucispirillum schaedleri (WT 6.5%; KO 3.7%, P<1*10-6). Consistent with ileum damage, KOs had decreased villi length (WT 275±11; KO 227±15 um, P<0.05) and increased crypt depth (WT 61±4; KO 71±2 um, P<0.05) as well as increased DNA damage (TUNEL). Key tight junction genes, ZO-1 (WT 0.88±0.05; KO 0.64±0.04, P<0.005), claudin-1 (WT 0.17±0.02; KO 0.09±0.01, P<0.05) and occludin (WT 0.66±0.05; KO 0.38±0.03, P<1*10-4) were downregulated in ileum, suggestive of increased intestinal permeability. Endorsing our intestinal data, toll-like receptor (TLR4) expression was increased in the liver (WT 0.39±0.01; KO 0.45±0.02, P<0.05). Our results strongly propose that AKR1D1 deletion and disruption of BA synthesis has a negative impact on intestinal health, putatively increasing intestinal damage and gut permeability, with the potential to drive pathogenesis of NAFLD.