Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes - PubMed (original) (raw)

Review

. 2020 Feb 9;4(4):493-503.

doi: 10.1002/hep4.1485. eCollection 2020 Apr.

Affiliations

Review

Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes

Michael J Weaver et al. Hepatol Commun. 2020.

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.

© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

PubMed Disclaimer

Figures

Figure 1

Figure 1

(A) The prevalence of obesity in the U.S. population is estimated at approximately 40% compared with NAFLD at 30% and IBS‐D at 10%‐15%. The estimated overlap between obesity and NAFLD is 75%‐90%, between obesity and IBS‐D is 10%‐20%, and between IBS‐D and NAFLD is 10%‐20%. There is a presumed overlap of obesity, NAFLD, and IBS‐D; these proportions are yet to be determined. (B) Data support that 25%‐50% of patients diagnosed with IBS‐D have BAD, and 10%‐20% will have concurrent NAFLD. There is a presumed overlap of IBS‐D, NAFLD, and BAD; these proportions are yet to be determined.

Figure 2

Figure 2

BAs are synthesized in the hepatocyte from free cholesterol by CYP7A1, generating C4 as an intermediate and surrogate of BA synthesis and exported through bile salt export pump into the biliary canaliculus. In response to a meal, BAs are secreted into the duodenum to aid in emulsification and absorption of dietary lipids. BAs are then reabsorbed in the terminal ileum by crossing the apical border of ileocytes through the ASBT and then the basolateral border through Ostα/β before entering the portal circulation. Following arrival to the hepatocyte, most BAs are taken up through NTCP and promote feedback inhibition of BA synthesis through FXR/RXR. BAs that escape first‐pass uptake by the hepatocyte will have peripheral effects on adipose and muscle tissue through Takeda G protein–coupled receptor 5, and promote energy expenditure through thyroxine and triiodothyronine. In healthy individuals, 5% of BAs do not get reabsorbed from the ileum and therefore promote luminal chloride secretion, including through the cystic fibrosis transmembrane regulator and subsequent osmotic force for fluid secretion in the colon. In BAD, reduced ileal secretion of FGF19 constrains negative feedback of hepatic BA synthesis, resulting in increased hepatic BA secretion, increased delivery of BA to the colon, and subsequent diarrhea. C4, an intermediate of hepatic BA synthesis from cholesterol and a surrogate of Cyp7a1 activity, is notably elevated in BAD and has been shown to be a reliable biomarker. In the process of passing through the ileocyte as part of this enterohepatic circulation, BAs also activate FXR through BA‐mediated liganding. FXR/RXR activation in the ileocyte up‐regulates SHP, FGF19, and Ostα/β. FGF19 is released into the portal vein and, following arrival to the hepatocyte, FGF19 binds to FGFR4/KLB. This signal also provides negative feedback of BA biosynthesis in the liver by promoting SHP and subsequent decreased CYP7A1 expression. Furthermore, FGF19 signaling through FGFR4/KLB has metabolic effects, which include increased hepatic fatty acid oxidation, decreased fatty acid synthase and lipid biosynthesis, and increased insulin sensitization. Abbreviations: CFTR, cystic fibrosis transmembrane regulator; ERK2, extracellular signal–related kinase 2; IBABP, ileal BA‐binding protein; MAPK, mitogen‐activated protein kinase; and T3, triiodothyronine; T4, thyroxine; TGR5, Takeda G protein–coupled receptor 5.

References

    1. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ III. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology 1991;101:927‐934. - PubMed
    1. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000;118:842‐848. - PubMed
    1. Simren M, Castedal M, Svedlund J, Abrahamsson H, Bjornsson E. Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)]. Dig Dis Sci 2000;45:2151‐2161. - PubMed
    1. Saito YA, Petersen GM, Locke GR III, Talley NJ. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol 2005;3:1057‐1065. - PubMed
    1. Kassinen A, Krogius‐Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 2007;133:24‐33. - PubMed

Publication types

Grants and funding

LinkOut - more resources