Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels... Show moreTrimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population. Show less
Cardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases... Show moreCardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases, indicating inter-organ cross-talk as a therapeutic target. Herein, I explored the therapeutic potential of targeting inter-organ communication in cardiometabolic diseases, including obesity, atherosclerotic cardiovascular disease and non-alcoholic steatohepatitis, based on which I proposed novel therapies to tackle these diseases. On one hand, strategies can focus on regulating the gut microbiota-centered inter-organ cross-talk. We demonstrated that dietary interventions are efficient to modulate the gut microbiota composition and function, thereby regulating the gut microbial metabolite production. In particularly, we showed that dietary supplementation of butyrate, a gut microbial metabolite, and choline, a nutrient enriched in red meat, can beneficially modulate the gut microbiota to alleviate adiposity. On the other hand, therapies can also focus on liver-centered inter-organ cross-talk. We showed that improving hepatocyte mitochondrial function by γ hydroxybutyric acid not only improves liver metabolic function, but also reverses obesity and its associated metabolic diseases. Besides, cardiometabolic health can be improved by regulating systemic levels of hepatokines (e.g. FGF21). We showed that FGF21-based pharmacotherapies can regulate the cross-talk between the liver and adipose tissue to improve cardiometabolic diseases, especially fibrotic non-alcoholic steatohepatitis and atherosclerotic cardiovascular disease. Thus, the findings described in this thesis emphasize the importance of inter-organ cross-talk for cardiometabolic diseases, and have improved our knowledge on the mechanisms that underlie the risk in the ever-increasing population of individuals who suffer from cardiometabolic diseases. Show less