CirculAting Bile Acids as biomarkers of metabolic health - Linking microbiotA, Diet and Health

ERA-HDHL (Healthy Diet for Healthy Life) Cofund (H2020 and MIUR for Italy), “Biomarkers for Nutrition and Health”: grant for 3-yrs project ‘ Bile acids (BA) through G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5) and nuclear receptors like Farnesoid X receptor (FXR) regulate mammalian inflammation, and lipid, glucose, energy, and xenobiotic metabolism. The gut microbiota modulates the enterohepatic circulation of BA and microbially produced secondary BA appear to be more potent receptor agonists than primary BA, providing a mechanistic link between microbiome structure/function and regulation of host physiology. Evidence mainly from animal studies shows that dietary fibers and polyphenols can bind BA driving them into the colon and modifying their absorption and/or excretion and importantly, that exercise can impact on BA metabolism. Similarly, certain bile salt hydrolyzing (BSH) probiotic bacteria modulate circulating bile acid (CBA) profiles and strongly influence cholesterol uptake. However, human data confirming dietary modulation of CBA profiles and subsequent regulation of physiological homeostasis remains elusive. CABALA_DIET&HEALTH aims to establish circulating BA profiles as biomarkers of health, modulated by diet and exercise which reflect a change in metabolic health. This project will establish whether dietary modulation of BA profiles indicate a change in health status. Using samples from the RoCAV cohort and existing randomised control trials (RCT), we will correlate CBA profiles with adherence to the Mediterranean diet, intake of fiber/polyphenol rich foods and measures of metabolic health (BMI, insulin/glucose and lipid homeostasis). In a bespoke short-term RCT we will measure the ability of probiotics, prebiotics and polyphenols to modulate post-prandial BA profiles and in a long term (18 month), large-scale (n=300) existing dietary and lifestyle intervention, we will measure how polyphenol rich whole foods and exercise promote metabolic health in susceptible individuals through modulation of BA signalling. Finally, we will link BA profiles or metabotype with microbiome signatures and BA biotransformation potential using high-resolution metagenomics and establish the molecular basis of BA regulation of immune and metabolic homeostasis by measuring the relative BA-metabotype receptor activation potential. CABALA_DIET&HEALTH will provide direct evidence in humans that diet:gut microbiota interactions, as indicated by CBA profiles, determine metabolic disease risk providing at once a validated biomarker of health and a unifying molecular basis for efficacious probiotics, prebiotics and polyphenols.