Fermentable Fibers Induce Rapid Macro and Micronutrient Depletion in Toll-like Receptor 5 Deficient Mice.

Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 months. In particular, a subset of toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the current study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies. Here, we measured hepatic fatty acids and serum vitamin A and D levels from WT, T5KO low bilirubin (LB) and T5KO-HB mice fed ICD for 4 weeks. Additionally, hepatic RNAseq and proteomics were performed to ascertain other metabolic alterations. Compared to WT and T5KO-LB, T5KO-HB mice exhibited steatorrhea, i.e. ~50% increase in fecal lipids. This could contribute to the significant reduction of linoleate in hepatic neutral lipids in T5KO-HB mice. Alongside, serum vitamins A and D were ~50% reduced in T5KO-HB mice, which was associated with metabolic compromises. Overall, our study highlights that fermentable fiber-induced cholestasis is further characterized by depletion of macro and micronutrients.