Ecophysiology of trimethylamine-producing bacterial communities of human gut microbiota

• Applicant: Dr. Marius Vital
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Microbial Ecology and Applied Microbiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456214861

Extensive research on gut microbiota in the last decade has broadened our view on the role of bacteria for host health extending beyond traditional pathogens. The specific factors and mechanisms involved in disease etiology are, however, only recently discovered and interventions to precisely manipulate host microbiota are in its infancy. An altered microbiota composition can lead to an increase of metabolites that harm the host and cause disease, which is exemplified by trimethylamine (TMA), an atherosclerotic and thrombotic compound produced by gut bacteria from diet-derived substrates. TMA is absorbed by the host and subsequently oxidized to trimethylamine-N-oxide (TMAO). Despite the fact that multiple studies linked TMAO with a risk for developing cardiovascular disease (CVD), very little is known on specific bacteria that produce TMA.We have shown that a myriad of taxonomically distinct commensal bacteria are involved in TMA-formation, constituting, however, only a small fraction of all gut bacteria. The approach outlined in the present proposal will provide comprehensive insights into TMA-forming bacterial communities and specify their ecophysiological key features by combining in silico, in vitro and in vivo experiments. Publicly available metagenomic data will be screened in silico to expose bacteria harbouring TMA-forming pathways, including uncultured members, followed by in-depth analyses to specify their ecological niches in the gut environment. Results will be complemented by defined in vitro cultivation experiments. Based on our recent study indicating that TMA-formation of Enterobacteriaceae from choline is a major route for the production of TMA in CVD patients, we will specifically perform in-depth culturing experiments revealing underlying bacterial physiological mechanisms and assess differences between taxa in their efficiencies to produce TMA via this pathway. Additionally, we will establish quantitative mathematical models on global interactions between substrate intake (diet), abundance/composition of TMA-producing bacteria, and TMA(O) plasma concentrations in vivo based on samples derived from dialysis patients, a group highly affected by CVD. Due to a lack of renal clearance, TMAO accumulates in those individuals and serves as a predictor for coronary atherosclerosis burden and long-term mortality. Furthermore, the influence of a fibre-rich diet on TMA-producing bacteria and formation of TMA(O) will be closely monitored in a longitudinal manner in those patients.The results of the present proposal will provide crucial new insights into microbiota functioning related to TMA formation and will start building a framework for risk assessment and for guiding the development of precision treatment to restrict the production of this harmful compound.

• DFG Programme: Research Grants