bims-liverm 2023-08-13 papers

Issue of 2023–08–13
six papers selected by

World J Gastroenterol. 2023 Jul 21. 29(27): 4252-4270

Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease.

Xiong-Quan Long, Ming-Zhu Liu, Zi-Hao Liu, Lv-Zhou Xia, Shi-Peng Lu, Xiao-Ping Xu, Ming-Hao Wu.

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

Keywords: Bile acid metabolism; Bile acid receptors; Bile acids; Gut microbiota; Inflammatory bowel disease; Intestinal immunology

DOI: https://doi.org/10.3748/wjg.v29.i27.4252

Drug Metab Dispos. 2023 Aug 07. pii: DMD-AR-2023-001358. [Epub ahead of print]

CYP2D6 activity is correlated with changes in plasma concentrations of taurocholic acid during pregnancy and postpartum in CYP2D6 extensive metabolizers.

Lindsay C Czuba, Karan Malhotra, Luke Enthoven, Emily E Fay, Sue L Moreni, Jennie Mao, Yuanyuan Shi, Weize Huang, Rheem A Totah, Nina Isoherranen, Mary F Hebert.

Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of > 20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women (n=47) during mid-pregnancy (25-28 weeks gestation) and {greater than or equal to} 3 months postpartum, and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid), and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan / dextromethorphan. At 25-28 weeks gestation, taurine conjugated bile acids comprised 23% of the quantified serum bile acids compared to 7% {greater than or equal to} 3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan / dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy. Significance Statement Bile acid homeostasis is altered in pregnancy and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of FXR ligands, such as bile acids, may contribute to the high interindividual variability in CYP2D6 expression and activity.

Keywords: CYP induction; CYP2D6; bile acids; human/clinical; metabolomics

DOI: https://doi.org/10.1124/dmd.123.001358

Front Physiol. 2023 ;14 1213757

Revisited role of the placenta in bile acid homeostasis.

Edgar Ontsouka, Mariana Schroeder, Christiane Albrecht.

To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100 μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only "detergent molecules" required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle "not too much, not too little" applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.

Keywords: bile acid signaling; bile acid synthesis; fetal development; placenta; pregnancy

DOI: https://doi.org/10.3389/fphys.2023.1213757

Molecules. 2023 Aug 04. pii: 5870. [Epub ahead of print]28(15):

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome.

Xianmei Gou, Lin Qin, Di Wu, Jian Xie, Yanliu Lu, Qianru Zhang, Yuqi He.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.

Keywords: TGR5; Takeda G protein-coupled receptor 5; bile acids; metabolic syndrome

DOI: https://doi.org/10.3390/molecules28155870

Int J Mol Sci. 2023 Jul 28. pii: 12123. [Epub ahead of print]24(15):

The Potential of Bile Acids as Biomarkers for Metabolic Disorders.

Chang Yin, Ruqing Zhong, Weidong Zhang, Lei Liu, Liang Chen, Hongfu Zhang.

Bile acids (BAs) are well known to facilitate the absorption of dietary fat and fat-soluble molecules. These unique steroids also function by binding to the ubiquitous cell membranes and nuclear receptors. As chemical signals in gut-liver axis, the presence of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and even tumors have been reported to be closely related to abnormal levels of BAs in the blood and fecal metabolites of patients. Thus, the gut microbiota interacting with BAs and altering BA metabolism are critical in the pathogenesis of numerous chronic diseases. This review intends to summarize the mechanistic links between metabolic disorders and BAs in gut-liver axis, and such stage-specific BA perturbation patterns may provide clues for developing new auxiliary diagnostic means.

Keywords: bile acid metabolism; diagnostic biomarker; dysbiosis; enterohepatic circulation; gut microbiota; metabolic disorders

DOI: https://doi.org/10.3390/ijms241512123

Front Pharmacol. 2023 ;14 1226448

Inulin ameliorates metabolic syndrome in high-fat diet-fed mice by regulating gut microbiota and bile acid excretion.

Shaoxiong Huang, Shiliang Dong, Lizhen Lin, Qiming Ma, Mengping Xu, Limei Ni, Qitong Fan.

Background: Inulin is a natural plant extract that improves metabolic syndrome by modulating the gut microbiota. Changes in the gut microbiota may affect intestinal bile acids. We suggest that inulin may improve metabolism by inducing bile acid excretion by gut microbes. Methods: Male C57/BL mice were fed either a high-fat diet (60% calories) or a regular diet for 16 weeks, with oral inulin (10% w/w). At the end of the experiment, the gene expression levels (FGF15, CD36, Srebp-1c, FASN, and ACC) in the liver and intestines, as well as the serum levels of triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, total cholesterol, and free fatty acids, were collected. The expression of FGF15 was examined using Western blot analysis. The fat distribution in the liver and groin was detected by oil red and hematoxylin and eosin staining. Simultaneously, the levels of serum inflammatory factors (alanine aminotransferase and aspartate aminotransferase) were detected to explore the side effects of inulin. Results: Inulin significantly improved glucose tolerance and insulin sensitivity, and decreased body weight and serum TG and LDL levels, in mice fed normal diet. Furthermore, inulin increased the α-diversity of the gut microbiota and increased the fecal bile acid and TG excretion in inulin-treated mice. In addition, inulin significantly reduced lipid accumulation in liver and inguinal fat, white fat weight, and hepatic steatosis. Western blot analysis showed that inulin reduced the expression of FGF15, a bile acid reabsorption protein. Conclusion: Inulin ameliorates the glucose and lipid metabolic phenotypes of mice fed a normal diet, including decreased intestinal lipid absorption, increased glucose tolerance, increased insulin sensitivity, and decreased body weight. These changes may be caused by an increase in bile acid excretion resulting from changes in the gut microbiota that affect intestinal lipid absorption.

Keywords: Intestine; bile acids; gut microbes; high-fat diet; inulin

DOI: https://doi.org/10.3389/fphar.2023.1226448