TGR5 signaling mitigates parenteral nutrition-associated liver disease

Abstract

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5−/−). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5−/− mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5−/−. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5−/− mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5−/− mice. However, the gut microbiota of TGR5−/− mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5−/− animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN. NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

The gut mycobiome of healthy mice is shaped by the environment and correlates with metabolic outcomes in response to diet

“…Our understanding role of BAs has evolved from simple detergents to hormones intimately related to multiple metabolic processes, revealing important roles of BAs in dyslipidemia and type 2 diabetes 36 . BAs are a significant source of host–microbiome interaction via cellular receptors such as TGR5 ( Gpbar1 ) 37 and FXR ( Nrlh4 ) 36 . Therefore, BA composition is interrelated with metabolic hormones such as leptin 38 , 39 , resistin 40 , ghrelin, GLP-1 (glucose-like peptide-1), and peptide YY 41 .…”

Reply to “Letter to Editor: Takeda-G Protein Receptor-5 signaling mitigates parenteral nutrition-associated liver disease: public health impact”

“…We acknowledge the recent Letter to the Editor of Am J Physiol Gastrointestinal Liver Physiol by Dr. Saumya Pandey, which emphasized the need for deeper understanding of the underpinning mechanisms of parenteral nutrition (PN)-associated liver disease (PNALD) and Takeda-G protein receptor-5 (TGR5) signaling. This letter highlighted our recently published work that employed human and murine samples provided PN alimentation to define the role of TGR5 signaling upon hepatic stress and homeostasis (1). The letter also highlighted the insightful findings of Zhan et al 2, which identified additional changes in hepatic retinoid acid-related orphan receptor-␣ (ROR␣), hepatic nuclear and transmembrane receptors, and sterol-exporters as potential influencers of PNALD development.…”

The gut mycobiome of healthy mice is shaped by the environment and shapes metabolic outcomes in response to diet

“…Our understanding role of BAs has evolved from simple detergents, to hormones intimately related to multiple metabolic processes, revealing important roles of BAs in dyslipidemia and type 2 diabetes. 40 BAs are a significant source of host-microbiome interaction via cellular receptors such as TGR5 41 and FXR. 40 Therefore, BA composition is interrelated with metabolic hormones such as leptin, 42,43 resistin, 44 ghrelin, GLP-1 (glucose-like peptide-1) and peptide YY.…”