bims-liverm 2023-05-21 papers

Issue of 2023–05–21
six papers selected by

Eur J Immunol. 2023 May 12. e2250299

Exploiting the bile acid-activated receptors-specific innate and adaptive immune system: drug and agent approaches.

Kenneth C P Cheung, Jiao Ma, Rodrigo Azevedo Loiola, Xingxuan Chen, Wei Jia.

Bile Acid-Activated Receptors (BARs) such as a G-protein-coupled receptor (GPBAR1) and the farnesol X receptor (FXR) are activated by bile acids (BAs) and have been implicated in the regulation of microbiota-host immunity in the intestine. The mechanistic roles of these receptors in immune signaling suggest they may also influence the development of metabolic disorders. In this perspective, we provide a summary of recent literature describing the main regulatory pathways and mechanisms of BARs and how they affect both innate and adaptive immune system, cell proliferation, and signaling in the context of inflammatory diseases. We also discuss new approaches for therapy and summarizes clinical projects on BAs for the treatment of diseases. In parallel, some drugs that are classically used for other therapeutic purposes and BAR activity have recently been proposed as regulators of immune cells phenotype. Another strategy consists of using specific strains of gut bacteria to regulate BA production in the intestine. This article is protected by copyright. All rights reserved.

Keywords: Bile acid ⋅ Intestinal macrophage ⋅ GPBAR1 ⋅ FXR ⋅ RORγ

DOI: https://doi.org/10.1002/eji.202250299

Hepatol Commun. 2023 Jun 01. pii: e0151. [Epub ahead of print]7(6):

The influence of liver transplantation on the interplay between gut microbiome and bile acid homeostasis in children with biliary atresia.

Birgit Waldner, Denise Aldrian, Thomas Zöggeler, Herbert Oberacher, Rupert Oberhuber, Stefan Schneeberger, Franka Messner, Anna M Schneider, Benno Kohlmaier, Roland Lanzersdorfer, Wolf-Dietrich Huber, Andreas Entenmann, Thomas Müller, Georg F Vogel.

BACKGROUND: Biliary atresia (BA) causes neonatal cholestasis and rapidly progresses into cirrhosis if left untreated. Kasai portoenterostomy may delay cirrhosis. BA remains among the most common indications for liver transplantation (LT) during childhood. Liver function and gut microbiome are interconnected. Disturbed liver function and enterohepatic signaling influence microbial diversity. We, herein, investigate the impact of LT and reestablishment of bile flow on gut microbiome-bile acid homeostasis in children with BA before (pre, n = 10), 3 months (post3m, n = 12), 12 months (post12m, n = 9), and more than 24 months (post24 + m, n = 12) after LT.
METHODS: We analyzed the intestinal microbiome of BA patients before and after LT by 16S-rRNA-sequencing and bioinformatics analyses, and serum primary and secondary bile acid levels.
RESULTS: The gut microbiome in BA patients exhibits a markedly reduced alpha diversity in pre (p = 0.015) and post3m group (p = 0.044), and approximated healthy control groups at later timepoints post12m (p = 1.0) and post24 + m (p = 0.74). Beta diversity analysis showed overall community structure similarities of pre and post3m (p = 0.675), but both differed from the post24 + m (p < 0.001). Longitudinal analysis of the composition of the gut microbiome revealed the Klebsiella genus to show increased abundance in the post24 + m group compared with an age-matched control (p = 0.029). Secondary bile acid production increased 2+ years after LT (p = 0.03). Multivariable associations of microbial communities and clinical metadata reveal several significant associations of microbial genera with tacrolimus and mycophenolate mofetil-based immunosuppressive regimens.
CONCLUSIONS: In children with BA, the gut microbiome shows strongly reduced diversity before and shortly after LT, and approximates healthy controls at later timepoints. Changes in diversity correlate with altered secondary bile acid synthesis at 2+ years and with the selection of different immunosuppressants.

DOI: https://doi.org/10.1097/HC9.0000000000000151

JPGN Rep. 2023 May;4(2): e301

Odevixibat Treatment of Alagille Syndrome: A Case Report.

Rainer Ganschow, Christof Maucksch.

A male pediatric patient with elevated liver enzyme and bile acid levels, bile duct hypoplasia, mild liver fibrosis, and pruritus was initially diagnosed with progressive familial intrahepatic cholestasis. The patient did not respond to treatments of ursodeoxycholic acid and naltrexone. Subsequent treatment with odevixibat resulted in improvements in serum bile acid levels and pruritus within a few weeks of initiation. During the course of odevixibat treatment, genetic testing results and additional clinical findings indicated a diagnosis of Alagille syndrome, a condition that shares some clinical features with progressive familial intrahepatic cholestasis. Odevixibat treatment was continued off label, during which time the patient's serum bile acid levels dropped to within the normal limit and pruritus was completely ameliorated. This report suggests odevixibat may be an effective treatment option for Alagille syndrome.

Keywords: bile acids and salts; cholestasis; pruritus

DOI: https://doi.org/10.1097/PG9.0000000000000301

Front Cell Neurosci. 2023 ;17 1161930

Bile acid interactions with neurotransmitter transporters.

Tiziana Romanazzi, Daniele Zanella, Manan Bhatt, Angela Di Iacovo, Aurelio Galli, Elena Bossi.

Synthesized in the liver from cholesterol, the bile acids (BAs) primary role is emulsifying fats to facilitate their absorption. BAs can cross the blood-brain barrier (BBB) and be synthesized in the brain. Recent evidence suggests a role for BAs in the gut-brain signaling by modulating the activity of various neuronal receptors and transporters, including the dopamine transporter (DAT). In this study, we investigated the effects of BAs and their relationship with substrates in three transporters of the solute carrier 6 family. The exposure to obeticholic acid (OCA), a semi-synthetic BA, elicits an inward current (IBA) in the DAT, the GABA transporter 1 (GAT1), and the glycine transporter 1 (GlyT1b); this current is proportional to the current generated by the substrate, respective to the transporter. Interestingly, a second consecutive OCA application to the transporter fails to elicit a response. The full displacement of BAs from the transporter occurs only after exposure to a saturating concentration of a substrate. In DAT, perfusion of secondary substrates norepinephrine (NE) and serotonin (5-HT) results in a second OCA current, decreased in amplitude and proportional to their affinity. Moreover, co-application of 5-HT or NE with OCA in DAT, and GABA with OCA in GAT1, did not alter the apparent affinity or the Imax, similar to what was previously reported in DAT in the presence of DA and OCA. The findings support the previous molecular model that suggested the ability of BAs to lock the transporter in an occluded conformation. The physiological significance is that it could possibly avoid the accumulation of small depolarizations in the cells expressing the neurotransmitter transporter. This achieves better transport efficiency in the presence of a saturating concentration of the neurotransmitter and enhances the action of the neurotransmitter on their receptors when they are present at reduced concentrations due to decreased availability of transporters.

Keywords: GABA transporter 1; SLC6; bile acids; dopamine transporter; glycine transporter; obeticholic acid (OCA); two-electrode voltage clamp

DOI: https://doi.org/10.3389/fncel.2023.1161930

Eur J Pharmacol. 2023 May 12. pii: S0014-2999(23)00301-1. [Epub ahead of print]951 175790

Gentamicin alleviates cholestatic liver injury by decreasing gut microbiota-associated bile salt hydrolase activity in rats.

Yanrong Ma, Huan Wang, Jinru Yang, Mingyan Xin, Xinan Wu.

Intrahepatic cholestasis lacks effective therapeutic drugs. The gut microbiota-associated bile salt hydrolases (BSH) may be a potential therapeutic target. In this study, oral administration of gentamicin (GEN) decreased the serum and hepatic levels of total bile acid in 17α-ethynylestradiol (EE)-induced cholestatic male rats, significantly improved the serum levels of hepatic biomarkers and reversed the histopathological changes in the liver. In healthy male rats, the serum and hepatic levels of total bile acid were also decreased by GEN, the ratio of primary to secondary bile acids, and conjugated to unconjugated bile acids was significantly increased, and the urinary excretion of total bile acid was elevated. 16S rDNA sequencing of the ileal contents revealed that GEN treatment substantially reduced the abundance of Lactobacillus and Bacteroides both of which expressed BSH. Consistently, BSH activity analysis by the generation of d5-chenodeoxycholic acid from d5-taurochenodeoxycholic acid in situ showed BSH was significantly inhibited in the ileal contents of rats treated with GEN. This finding led to an increased proportion of hydrophilic conjugated bile acids and facilitated the urinary excretion of total bile acids, thereby decreasing serum and hepatic total bile acids and reversing liver injury related to cholestasis. Our results provide important evidence that BSH can be a potential drug target for treating cholestasis.

Keywords: Bile acids; Bile salt hydrolases; Gentamicin; Gut microbiota; Liver injury

DOI: https://doi.org/10.1016/j.ejphar.2023.175790

Hepatol Commun. 2023 May 01. pii: e0138. [Epub ahead of print]7(5):

Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling.

Sabita Pokhrel, Matthew Dilts, Zachary Stahl, Shannon Boehme, Gabrielle Frame, John Y L Chiang, Jessica M Ferrell.

BACKGROUND: Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury.
METHODS: Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways.
RESULTS: Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet.
CONCLUSIONS: Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

DOI: https://doi.org/10.1097/HC9.0000000000000138