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 hydrolysing (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. 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 (DIRECT-PLUS study). 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. We aim to 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. Using data from existing trials, we have already correlated CBA profiles with gut microbiota, shown that in a dietary intervention with apples the observed cholesterol lowering effect may be linked to CBA regulatory processes in sex dependent manner and have developed advanced reporter systems for BA cell signalling. We have also completed measurements for the DIRECT-PLUS study and the CABALA-diet&health study in the UK. Early setbacks due to the Italian funding agency MIUR have been largely overcome and remaining analyses will be completed by project end. 

CABALA_DIET&HEALTH aims to provide direct evidence that diet-microbiome interactions in the gut determine circulating bile acid (CBA) profiles and their physiological effects. In this second year, the project has published new analytical methodologies, analyzed data and samples from existing/ongoing studies, including the DIRECT-PLUS study in Israel, advanced in vitro models for measuring CBA cell signaling and progressed the CABALA_diet&health dietary intervention in Reading, UK.