Maternal antibiotic prophylaxis during cesarean section has a limited impact on the infant gut microbiome.

Pregnant women undergoing a cesarean section (CS) typically receive antibiotics prior to skin incision to prevent infections. To investigate if the timing of antibiotics influences the infant gut microbiome, we conducted a randomized controlled trial (NCT06030713) in women delivering via a scheduled CS who received antibiotics either before skin incision or after umbilical cord clamping. We performed a longitudinal analysis on 172 samples from 28 infants at 8 post-birth time points and a cross-sectional analysis at 1 month in 79 infants from 3 cohorts.

Reversal of insulin resistance in people with obesity by lifestyle-induced weight loss does not impact the proportion of circulating 12α-hydroxylated bile acids.

Aim: Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome-related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non-12α-hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans.

Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials.

Introduction: Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients.

Areas Covered: Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors.

T cells with increased responsiveness cause obesity in mice without diet intervention.

Obesity is a complex multicausal disease that can cause morbidity and mortality, and there is need for improved knowledge on the underlying mechanisms. Using a mouse model of increased T cell responsiveness, we show that development of obesity can be driven by immune cells. This was confirmed with bone marrow transplantation and adoptive T cell transfer to several recipient mouse models.

Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice.

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes.

Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.

Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established.

Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Mice with a Human-like Bile Acid Composition.

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis.

Absence of gut microbiota reduces neonatal survival and exacerbates liver disease in Cyp2c70-deficient mice with a human-like bile acid composition.

Mice with deletion of Cyp2c70 have a human-like bile acid composition, display age- and sex-dependent signs of hepatobiliary disease and can be used as a model to study interactions between bile acids and the gut microbiota in cholestatic liver disease. In the present study, we rederived Cyp2c70-/- mice as germ-free (GF) and colonized them with a human or a mouse microbiota to investigate whether the presence of a microbiota can be protective in cholangiopathic liver disease associated with Cyp2c70-deficiency. GF Cyp2c70-/- mice showed reduced neonatal survival, liver fibrosis, and distinct cholangiocyte proliferation.

Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice.

Background: Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development.

Methods: Male APOE∗3-Leiden.

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development.

Combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonism attenuates atherosclerosis severity in APOE*3-Leiden.CETP mice.

Background And Aims: Combined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity and with or without type 2 diabetes mellitus. As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and lipid handling, two crucial players in atherosclerosis development, here we aimed to investigate the effects of combined GIPR/GLP1R agonism in APOE*3-Leiden.CETP mice, a well-established mouse model for human-like lipoprotein metabolism and atherosclerosis development.

A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding.

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.

Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition.

Cyp2c70 mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70 mice.

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles.

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism.

Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase.

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis.

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70 mice by reducing fat absorption.

Bile acids (BAs) play important roles in lipid homeostasis, and BA signaling pathways serve as therapeutic targets for nonalcoholic fatty liver disease (NAFLD). Recently, we generated cytochrome P450, family 2, subfamily C, polypeptide 70 (Cyp2c70) mice with a human-like BA composition lacking mouse-/rat-specific muricholic acids to accelerate translation from mice to humans. We employed this model to assess the consequences of a human-like BA pool on diet-induced obesity and NAFLD development.

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

Background And Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes.

Group IIA Secretory Phospholipase A Predicts Graft Failure and Mortality in Renal Transplant Recipients by Mediating Decreased Kidney Function.

The acute phase protein group IIA secretory phospholipase A (sPLA-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA-IIA was determined by ELISA.

Microbiome Modulation of the Host Adaptive Immunity through Bile Acid Modification.

The microbiome is well known to influence the immune response of the host. Song et al. now show that the microbiome modulates adaptive immunity in mice through formation of bile acid species acting on RORγ regulatory T cells via the Vitamin D Receptor, thereby lowering the vulnerability for chemically induced colitis.

A human-like bile acid pool induced by deletion of hepatic modulates effects of FXR activation in mice.

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data.