Project name: Marked gut microbiota dysbiosis and increased imidazole propionate are associated with a NASH Göttingen Minipig model

Description: Gut microbiota contributes to the development of NASH through modulation of gut barrier, inflammation, altered lipid metabolism, bile acid signaling and short-chain fatty acids (SCFA). We describe the impact of a choline-deficient amino acid defined high fat diet (CDAHFD) on the gut microbiota in a male Göttingen Minipig model and on selected pathways involved in the development of NASH.Eight weeks of CDAHFD resulted in a significantly altered colon microbiota mainly driven by the bacterial families Lachnospiraceae and Enterobacteriaceae, being decreased and increased in abundance, respectively. CDAHFD decreased colon content of SCFA and increased colonic pH. In addition, serum imidazole propionate was significantly elevated as a consequence of CDAHFD feeding. Hepatic gene expression analysis indicated upregulation of ras homolog enriched in brain and mechanistic target of rapamycin (mTOR) and downregulation of insulin receptor substrate 1 and insulin receptor substrate 2 in CDAHFD fed minipigs. Furthe consequences of CDAHFD was increased serum cholesterol, increased serum bile acids (BA) and hyperglucagonemia, but not hyperaminoacidemia.: In Göttingen Minipigs, CDAHFD introduced a shift in the colon microbiota resulting in a bacterial community with a decreased capacity for SCFA production. Consequently, the pH rises creating an environment with the potential to activate the bacterial enzymes urocanate reductase facilitating production imidazole propionate. We speculate that imidazole propionate activates hepatic mTORC1 resulting in impaired insulin sensitivity in the liver. Moreover, we suggest that imidazole propionate has the ability to activate mTOR in α-cells and contribute to an hyperglucagonemic state through α-cell hyperplasia. Additionally, the changed colon microbiota could be linked to a changed BA profile and hepatic fibrosis, further contributing to the NASH development.

Data type: Other

Sample scope: Monoisolate

Last updated: 2022-07-07