Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes

Abstract

Irritable bowel syndrome with diarrhea (IBS‐D) and NAFLD are both common conditions that may be influenced by shared pathways of altered bile acid (BA) signaling and homeostatic regulation. Pathophysiological links between IBS‐D and altered BA metabolism include altered signaling through the ileal enterokine and fibroblast growth factor 19 (FGF19) as well as increased circulating levels of 7α‐hydroxy‐4‐cholesten‐3‐one, a metabolic intermediate that denotes increased hepatic BA production from cholesterol. Defective production or release of FGF19 is associated with increased BA production and BA diarrhea in some IBS‐D patients. FGF19 functions as a negative regulator of hepatic cholesterol 7α‐hydroxylase; therefore, reduced serum FGF19 effectively de‐represses hepatic BA production in a subset of IBS‐D patients, causing BA diarrhea. In addition, FGF19 modulates hepatic metabolic homeostatic response signaling by means of the fibroblast growth factor receptor 4/klotho beta receptor to activate cascades involved in hepatic lipogenesis, fatty acid oxidation, and insulin sensitivity. Emerging evidence of low circulating FGF19 levels in subsets of patients with pediatric and adult NAFLD demonstrates altered enterohepatic BA homeostasis in NAFLD. Conclusion: Here we outline how understanding of shared pathways of aberrant BA homeostatic signaling may guide targeted therapies in some patients with IBS‐D and subsets of patients with NAFLD.

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver

“…Serum levels of primary bile acids such as CA and CDCA were higher in individuals with slow motility compared to those with fast motility. In brief, we assume that gut motility affects the clearance and effects of the intestinal bile acid pool and its activation of intestinal FXR, as previously shown in BA-induced diarrhea [28]. Again, none of the CeD patients suffered from diarrhea in our cohort, and given the fact that we recruited adults with CeD in clinical remission under gluten-free diet, it might be an expectable result that total bile acid levels were not changed.…”

Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection

“…Moreover, diabetes, a component of metabolic syndrome which may cause vasculopathies and neuropathies in the intestines, also contributes to dysmotility[ 60 ]. Additionally, diverticular disease, irritable bowel disease[ 61 ] and inflammatory bowel disease[ 62 ], together with SIBO and dysmotility have all been shown to have increased prevalence in NAFLD patients. Not surprisingly, the structural and functional abnormalities in the gut associated with NAFLD and metabolic dysfunction further increase the risk of CDI and its complications.…”