Fig. 5

Proposed mechanism for imidazole propionate and bile acids in a CDAHFD fed Göttingen Minipig. CDAHFD indued change in the colon microbiota decrease SCFA production and increase the colonic pH. The increased pH activates bacterial produced enzymen urdA facilitating the production of imidazole propionate (ImP) which is subsequently absorbed into circulation with the minipig. Hereafter it reaches the liver and activates mTORC1 protein complex that in return starts a phosphorylation cascade resulting in degradation of IRS1 resulting in impaired hepatic insulin signalling. We suggest that glucagon hypersecretion potentially caused by imidazole propionate activation of mTOR in pancreatic a-cells causes a-cell hyperplasia resulting in secondary hyperglucagonemia. Furthermore, CDAHFD increased circulating and hepatic cholesterol alongside an increased total bile acid. This likely results in an increased production of primary bile acids (BAs) which are absorbed into the small intestine. The majority of the primary BAs will be reabsorbed into in distal small intestines. However, a proportion reaches the colon and are converted to secondary BAs by 7a-dehydroxylase containing bacteria. In addition to these events, there is a decrease in the abundance of species belonging to the Ruminococcus genus possibly resulting in a lower conversion of toxic bile acid. This changes the BA profile and may contribute to the severity of hepatic fibrosis in this NASH minipig model. Created with Biorender.com and appropriate copyright permission have been obtained (agreement number: ZV24LQR2TQ)