Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways

Abstract

Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRα) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure.

Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

“…Moreover, BA-induced down-regulation of adhesion proteins like N-cadherin and connexin 43 (CX43) was shown to alter the BTB, leading to its disruption [ 162 ], making way for more BAs to access the apical compartment and to induce male reproductive dysfunctions by amplifying germ cell degeneration. As observed for male rat fed high-fat diets [ 163 ], it cannot be excluded that BA overload causes persistent alteration in the male germ cell epigenome with an impact on offspring, in accordance with recent studies that have reported generational inheritance of metabolic defects in the offspring of CA-fed fathers [ 164 , 165 ]. Unbiased whole-genome approaches should help to address how BAs code transgenerationally-inherited traits, and complementary studies are still needed to tease out the complex relationship between BAs, their receptors, and male germ cell-derived epigenetic inheritance.…”

Methylation signatures in peripheral blood are associated with marked age acceleration and disease progression in patients with primary sclerosing cholangitis

“…Indeed, prior studies have observed direct effects of bile acids on DNA methylation. 36,37 The composition of specific bile acid species may also contribute to the inflammation-related senescent phenotype. A previous study found that bile acids such as deoxycholic acid contribute to the senescent and inflammatory characteristics of hepatic stellate cells, which combined with high fat feeding leads to fibrosis and hepatocarcinogenesis.…”

Retracted: The protective effects of TGR5 against ultraviolet B irradiation in epidermal stem cells

“…DNA damage has been linked with impairment of cellular capacities and genetic unreliability of ESCs by causing aberrant changes in the stem cell niche . Interestingly, activation of TGR5 by bile acids has a protective effect on germ cell DNA integrity . The protective effects of TGR5 in maintaining the capacities of ESCs implicate that TGR5 is important for protecting the DNA of ESCs against UV‐B‐induced insults.…”