Genetics and diet influence bile acid homeostasis

Genetics and diet influence bile acid homeostasis

EPFL scientists used a systems genetics approach to unravel novel genetic and environmental modulators of bile acid homeostasis. Their findings provide new insights into the mechanisms regulating bile acid homeostasis and may have implications for the treatment of metabolic diseases.

Bile acids are a large group of cholesterol derivatives that are well known for their role in facilitating the intestinal absorption of fats. Once reabsorbed by the intestine, bile acids circulate in the blood, where they can function as powerful hormones. The concentration and composition of bile acids in the blood changes after each meal, allowing them to inform other organs that energy is available.

Despite this knowledge of their function, genetic and environmental modulators of bile acids are not fully deciphered and understanding of how specific bile acid entities are produced and function is lacking.

In a new study led by the groups of Kristina Schoonjans and Johan Auwerx at EPFL, with colleagues from UNIL and ETHZ, researchers used a “genetic reference population” of mice (the BXDs), which resembles the genetic variation of a small human population to gain new insights into bile acid homeostasis. By combining environmental changes (high-fat diet), ‘omics’ data, bioinformatics and molecular biology analyses, the team mapped hundreds of potential genetic and environmental determinants of bile acids, defining their impact on health. and disease. The study is published in Cell metabolism.

The researchers also measured the abundance and composition of bile acids in the liver, feces, and plasma (the major tissues for bile acid synthesis, metabolism, and signaling, respectively) in 36 strains of BXD mice fed with normal food or a high-fat diet. The data showed that bile acid levels were strongly influenced by diet.

Bile acids play a critical role in metabolic diseases, and researchers have confirmed that they are strongly correlated with physiological traits, including body weight, fat mass, glucose, and insulin levels. They also identified several genetic loci linked to bile acid levels, tauro-ursodeoxycholic acid (TUDCA) being the most prominent example. TUDCA is known to relieve multiple diseases, but its receptor and modulators remain unknown. Scientists identified carboxylesterase 1C (CES1C) as a novel modulator of plasma TUDCA levels through systems bioinformatics and genetics approaches, and validated its role using an in vivo loss-of-function mouse model.

“The reference population of BXD mice is a perfect model to study the genetic basis of complex traits and allows the establishment of a controlled environment, a key prerequisite for this analysis”, explains Hao Li, the first author of the study. “This approach allowed us to identify CES1C as a modulator of plasma TUDCA levels and to discover many other links between genes, bile acids and phenotypes,” adds co-first author Alessia Perino. “This work, largely sponsored by the Kristian Gerhard Jebsen Foundation, lays the foundation for identifying new approaches to increasing health-promoting bile acids, which could pave the way for the development of promising therapies for human metabolic diseases. »