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Progetto vincitore della Borsa di Studio "Andrea Mezzetti" 2016 - M. Busnelli

Effect of apolipoprotein A-I on microbiota: a new mechanism of HDL-mediated atheroprotection?

Marco Busnelli

Abstract:

Background. The small intestine, together with the liver, is responsible for the synthesis of apoA-I, the most abundant protein of HDL. Moreover, the intestine harbors trillions of microbes, the so-called gut microbiota, that play a crucial role in host metabolic processes and, in particular, can influence cholesterol and bile acids metabolism. Interestingly, inflammatory conditions of the small intestine are associated with a downregulation of the APOA1 gene and lead to an altered microbiota composition.

Objectives. The proposed project is aimed at demonstrating, for the first time, that apoA-I can modulate intestinal homeostasis and microbiota composition and notably, that an apoA-I deficiency-driven dysbiosis can predispose to atherosclerosis development. This hypothesis is supported by two independent observations that have never been merged so far: i) apoA-I deficient mice have an altered microbiota composition, enriched in choline-degrading bacteria; ii) the gut microbiota can influence atherosclerosis development by processing dietary choline to trimethylamine, further metabolized to trimethylamine N-oxide (TMAO) by hepatic flavin mono-oxygenase.

Methods. The research strategy will be based on the use of both conventional and germ-free, atherosclerosis prone mice. In conventional genetically modified mice, lacking or overexpressing apoA-I, the effects of apoA-I and dietary choline on: i) atherosclerosis development; ii) TMAO production; iii) gut/liver homeostasis; iv) microbiota composition, will be evaluated. In addition, microbiota transfer from those mice to atherosclerosis-prone germ-free animals will be used to assess to what extent a deficit of apoA-I makes the gut microbiota harmful for atherosclerosis development.

Expected results. i) To demonstrate whether apoA-I deficiency promotes the presence of TMAO-producing bacteria in the gut that worsen atherosclerosis development; ii) to clarify how apoA-I modulates gut microbiota composition.

Presentazione del progetto vincitore della Borsa di Studio “Andrea Mezzetti” - 2016