Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure

Abstract

Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = −0.50, p < 0.05). In ileum, the inflammation grades were inversely associated with farnesoid X receptor (FXR) expression (r = −0.55, p < 0.05). In liver, the expression of induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients.

Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling

“…Although previous studies have linked cholestasis to liver disease in patients with IF 3 , 31 – 34 , the underlying mechanisms are still not fully understood. In this study, we first describe a potential mechanism by which antibiotic administration contributes to the development of cholestasis in IF patients via the alteration of intestinal bacteria.…”

“…Intestinal failure (IF)-associated liver disease (IFALD) is a serious complication in pediatric patients with IF 1 , 2 . We and others previously showed that cholestasis could cause liver injury in pediatric IF patients 3 – 5 . However, the mechanisms underlying the development of cholestasis are poorly understood.…”

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients

“…Hence, diminished propagation of anterograde pressure waves in the biliary‐digestive system could lead to slow delivery of bile salts to the distal part of the small intestine . Furthermore, intestinal inflammation is related to low ileal FXR expression and therefore low FGF19 production, in pediatric intestinal failure . In critical illness, bile salt malabsorption likely caused by inflammation of the intestinal epithelium could contribute to reduced FXR activation.…”

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine

“…Bile acids have been suggested as a mediator for organ dysfunction [69]. Altered bile acid homeostasis in paediatric patients with intestinal failure has been postulated to contribute to liver dysfunction via increased hepatic bile acid synthesis due to a failing feedback mechanism [70]. Intrahepatic cholestasis of the critically ill is a consequence of alterations of bile acid signalling and transportation at the hepatocellular level.…”