Final Report Summary - MIBIOANDCMD (Gut microbiota, choline metabolites and cardiometabolic diseases.)
The human gastrointestinal tract is home to trillions of bacteria that tremendously impact human health. Recent studies have convincingly linked gut microbiota to traits relevant to cardio-metabolic disease including atherosclerosis and obesity. These are complex diseases where both genetic and environmental factors act together in complex relationships. Gut microbiota appear to influence host metabolism and disease in large part by producing metabolites that enter the host circulation.
In the Marie Curie IOF-project MIBIOandCMD we studied a novel pathway affecting atherosclerosis and other cardiometabolic traits. In the setting of specific dietary nutrients characterized by a trimethylamine group (e.g. choline, phosphatidylcholine (PC), and carnitine), gut microbiota are shown to participate in the formation of a pro-atherogenic compound called trimethylamine-N-oxide (TMAO). TMAO is produced in a two-step process, starting with degradation of dietary trimethylamines like free choline, PC, or carnitine by specific intestinal bacterial strains into the precursor trimethylamine (TMA), whish is subsequently metabolized by several enzymes to generate circulating TMAO. Carnitine is an abundant nutrient in red meat and we showed that gut microbiota also play a role in TMAO production from dietary l-carnitine. The enhanced atherosclerosis seen with dietary choline or L-carnitine supplementation is entirely dependent on gut microbiota, given that antibiotic treatment or germ-free conditions abolished dietary choline-driven TMAO generation and atherosclerosis development. We aimed to extend our knowledge about the phenotypes associated with elevated plasma levels of TMAO and identify specific gut microbes that contribute to dietary choline and L-carnitine metabolic production.
Using metabolically well-characterized mouse and human cohorts we showed that elevated TMAO levels enhance platelet hyperreactivity and thrombosis risk and are strongly associated with different kidney parameters. We identified a group of bacteria associated with TMA/TMAO production in response to choline or carnitine administration. Moreover, we also demonstrated that transplanting gut microbiota from mouse strain with high TMAO levels into a strain with low TMAO levels resulted elevated TMAO and increased atherosclerosis.
Our group was also interested in dissecting genetic and environmental interactions between host-gut microbiota relationships. We addressed these questions by analyzing gut microbiota composition in panel of 110 diverse inbred strains of mice. We showed that different inbred strains differ strikingly in the composition of gut microbiota and provided evidence that the variation is determined in part by the host genetic background. We showed that a common anaerobe Akkermansia muciniphila has striking effects on weight gain, adiposity, plasma lipids and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes using system/genetics. Finally, we also provided evidence of sex-by-gene interactions, showing that different genders have profound differences in gut microbiota composition and this in turn affects dietary response.
Our study provides new insight into cardiometabolic diseases and highlights the central role of gut microbiota in these traits. TMAO has potential to become a prognostic marker for predicting cardiovascular risk in early stages. The knowledge gained from this project holds potential to improve diagnosis, therapy and prevention in future cardiovascular patients.
In the Marie Curie IOF-project MIBIOandCMD we studied a novel pathway affecting atherosclerosis and other cardiometabolic traits. In the setting of specific dietary nutrients characterized by a trimethylamine group (e.g. choline, phosphatidylcholine (PC), and carnitine), gut microbiota are shown to participate in the formation of a pro-atherogenic compound called trimethylamine-N-oxide (TMAO). TMAO is produced in a two-step process, starting with degradation of dietary trimethylamines like free choline, PC, or carnitine by specific intestinal bacterial strains into the precursor trimethylamine (TMA), whish is subsequently metabolized by several enzymes to generate circulating TMAO. Carnitine is an abundant nutrient in red meat and we showed that gut microbiota also play a role in TMAO production from dietary l-carnitine. The enhanced atherosclerosis seen with dietary choline or L-carnitine supplementation is entirely dependent on gut microbiota, given that antibiotic treatment or germ-free conditions abolished dietary choline-driven TMAO generation and atherosclerosis development. We aimed to extend our knowledge about the phenotypes associated with elevated plasma levels of TMAO and identify specific gut microbes that contribute to dietary choline and L-carnitine metabolic production.
Using metabolically well-characterized mouse and human cohorts we showed that elevated TMAO levels enhance platelet hyperreactivity and thrombosis risk and are strongly associated with different kidney parameters. We identified a group of bacteria associated with TMA/TMAO production in response to choline or carnitine administration. Moreover, we also demonstrated that transplanting gut microbiota from mouse strain with high TMAO levels into a strain with low TMAO levels resulted elevated TMAO and increased atherosclerosis.
Our group was also interested in dissecting genetic and environmental interactions between host-gut microbiota relationships. We addressed these questions by analyzing gut microbiota composition in panel of 110 diverse inbred strains of mice. We showed that different inbred strains differ strikingly in the composition of gut microbiota and provided evidence that the variation is determined in part by the host genetic background. We showed that a common anaerobe Akkermansia muciniphila has striking effects on weight gain, adiposity, plasma lipids and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes using system/genetics. Finally, we also provided evidence of sex-by-gene interactions, showing that different genders have profound differences in gut microbiota composition and this in turn affects dietary response.
Our study provides new insight into cardiometabolic diseases and highlights the central role of gut microbiota in these traits. TMAO has potential to become a prognostic marker for predicting cardiovascular risk in early stages. The knowledge gained from this project holds potential to improve diagnosis, therapy and prevention in future cardiovascular patients.