Project Summary
Human and mouse studies have identified changes in the gut microbiome associated with progression of
atherosclerosis. While gut microbes provide many benefits to the host (e.g. provide metabolic capabilities not
represented in our human genome), they also can be detrimental. Coexistence with our gut microbes is largely
enabled by the intestinal barrier—composed of a luminal mucus layer, epithelial cells and an inner functional
immunological barrier— which limits the entry of toxins and microbial pro-inflammatory molecules. Previous
studies have shown that diet and microbial metabolism modulate intestinal barrier function. Recent work from
our team and others has linked changes in the gut microbiome with alterations in intestinal barrier function and
cardiometabolic disease. However, the role of intestinal barrier function on atherosclerosis development and the
microbial, dietary and host factors that control this process remain largely unexplored. Defining these will open
new avenues for disease prevention and treatment, as both diet and the gut microbiome can be modified. We
have identified both microbial and host targets associated with intestinal homeostasis, inflammation, and
atherosclerosis. Briefly, we examined a panel of over 100 different genetically diverse inbred strains of mice
(known as the Hybrid Mouse Diversity Panel, HMDP) for both atherosclerosis susceptibility and gut microbiota
composition. In this screen, we identified several bacterial taxa associated with atherosclerosis protection and
experimentally validated one predicted protective microbe, Roseburia intestinalis, whose effect depends on the
availability of dietary substrates (i.e., fiber) that promote its growth and butyrate production. Moreover, we
showed that the beneficial effects of R. intestinalis are associated with improved intestinal barrier function and
lower plasma levels of LPS. Furthermore, these effects are mimicked by delivering butyrate to the distal gut.
Our HMDP studies also revealed a poorly understood protein expressed primarily in intestinal dendritic cells and
macrophages, ADAM-like Decysin-1 (Adamdec1), as a protein responsive to microbiome composition and
contributing to intestinal homeostasis, glucose homeostasis and systemic inflammation. In this application, we
propose to follow-up on these exciting observations to gain novel mechanistic insights into how modulation of
intestinal homeostasis via diet-butyrate-producing bacteria interactions and Adamdec1 affect progression of
atherosclerosis. We provide a strong validation for the overall approach, and the work will be done in two
laboratories with complementary skills: Dr. Rey (microbiology, gnotobiotic mouse models) and Dr. Lusis
(genetics, atherosclerosis). The investigators have worked together for several years. We anticipate discovery
of novel mechanisms by which gut bacteria modulate development of atherosclerosis, which should pave the
way for novel cardiovascular disease therapies that target the gut microbiome.