Transmission of Atherosclerosis and Thrombosis Susceptibility with Gut Microbial Transplantation

• Main Author: Gregory, Jill Christine
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2015
• Subjects: Biochemistry; Bioinformatics; Biology; Biomedical engineering; Ecology; Health sciences; Microbiology; Molecular biology; Nutrition
• ISBN: 9798662460621

The overall goal of my thesis research is to further the understanding of the link among dietary trimethylamine-containing nutrients, intestinal microbiome, and cardiovascular disease (CVD) by testing the hypothesis that disease susceptibility is a transmissible trait via cecal microbial transplant. The positive correlation discovered between plasma TMAO and lesion in a panel of inbred mouse strains permitted the identification of atherosclerosis prone (high TMAO-producing, large lesion; C57BL/6J) and resistant mice (low TMAO-producing, small lesion; NZW/LacJ) to be used as donor strains for cecal microbial transplant into intestinal microbiota-suppressed recipient C57BL/6J Apoe-/- female mice. Recipients of C57BL/6J microbes on the choline diet initially had statistically significantly higher plasma TMA and TMAO as compared to choline diet NZW/LacJ recipients, and at the study endpoint, choline diet-dependent enhancement of atherosclerotic lesion area was observed in the recipients of C57BL/6J microbes but not in recipients of NZW/LacJ microbes. Examination of microbial communities from 16S rRNA bacterial gene sequencing analysis showed distinct donor communities faithfully transferred to the respective recipient mouse groups. Several donor strain-characteristic taxa were identified in recipient groups whose proportional abundances correlated with plasma TMAO and/or lesion area. The second set of studies explores thrombosis potential and platelet reactivity, the proximal events in heart attack and stroke, for a relationship with the microbiome. Plasma TMAO is associated with a 2-fold increased risk for thrombotic events in a large cohort (n=4007). TMAO enhances agonist dependent platelet responsiveness by increasing the release of intracellular calcium stores. In mice, provision of TMAO or dietary choline (solely in the setting of an intact microbial community) enhances platelet aggregation ex vivo and shortens the time to cessation of blood flow in vivo. Cecal microbial transplant study showed that germ-free recipients of the disease-prone donor microbes were transmitted bacterial communities, choline diet-dependent enhanced TMA lyase activity, elevated plasma TMAO, and prothrombotic phenotypes as compared to recipients of disease-resistant donors. Collectively, the results of these studies suggest that the body and its microbial inhabitants interact to promote health or disease. Targeting microbial communities could be an adjunct treatment for the management of cardiometabolic disease in the future.