Bile Acids group - Dr Simon Peschard

Prensation of research topics

The objective of the team is to investigate the pathophysiological role of bile acids (BAs) in cardiometabolic diseases (insulin resistance, type 2 diabetes, obesity, metabolic dysfunction-associated steatotic liver disease [MASLD], atherosclerosis, etc.) in humans and preclinical models (mouse and pig models).To this end, the qualitative and quantitative composition of the bile acid pool is determined in different biological matrices (systemic and portal blood, caecal contents, bile, faeces, milk, etc.) and analysed in relation to metabolic, clinical, and biological phenotypic characteristics. These analyses help identify the role of bile acids as contributors to and/or biomarkers of the pathophysiology of cardiometabolic diseases.

What are bile acids?

Bile acids are a large family of steroid molecules derived from cholesterol. They are found at high concentrations in the enterohepatic circulation and, to a lesser extent, in the systemic circulation. Approximately 25 major bile acid species are found in humans and 35 in mice

What is the pathophysiological role of bile acids?

Bile acids (BAs) have been known for centuries for their detergent role in the intestinal absorption of fat-soluble molecules (lipids, vitamins, etc.). However, over the past two decades, these molecules have attracted renewed interest following the discovery of their role in regulating metabolic homeostasis. Indeed, BAs act as cell-signalling molecules that regulate carbohydrate and lipid metabolism, inflammation, and other physiological processes by binding to specific receptors. These include the nuclear receptor FXR (Farnesoid X receptor) and the G protein-coupled receptor TGR5 (Takeda G protein-coupled receptor 5), which are expressed in various metabolic tissues, including the intestine, liver, adipose tissue, and heart. Not all BAs activate these two receptors with the same potency or affinity. For example, CDCA is a potent activator of FXR, whereas TGR5 is activated by LCA. Thus, the qualitative and quantitative composition of the bile acid pool is a key determinant of metabolic homeostasis. Alterations in bile acid pool composition and disruptions in receptor-mediated signalling are associated with the development of cardiometabolic diseases, including obesity, insulin resistance, atherosclerosis, heart failure, and MASLD. Conversely, pharmacological modulation of bile acid signalling pathways has demonstrated therapeutic potential. Bile acids play a key role in inter-organ communication and are emerging as promising therapeutic targets for cardiometabolic diseases.

How is the bile acid pool determined?

The different bile acid (BA) species that make up the bile acid pool are quantified using targeted metabolomics by liquid chromatography–tandem mass spectrometry (LC-MS/MS), following extraction from the biological matrix. These specialized analyses are performed in collaboration with the Mass Spectrometry Core Facility (PSM) – GRITA (Prof. JF Goossens), within the Department of Pharmacy, UFR3S. We quantify conventional bile acids (CA, CDCA, DCA, etc.), as well as bile acids produced by the gut microbiota and conjugated to amino acids (e.g., Phe-CA, Leu-CA, and Trp-CA) or LCA-derived bile acids (e.g., iso-alloLCA). These measurements are complemented by the quantification of C4 (7α-hydroxy-4-cholesten-3-one), a biomarker of hepatic bile acid biosynthesis.