[초청강연] Gut pathogen’s last breath and diseases: High-fat diet-induced intestinal inflammation links gut dysbiosis and cardiovascular disease.

A Western-style obesogenic diet, high in simple carbohydrates and saturated fatty acids, is
associated with obesity, a condition that has reached epidemic proportions world-wide. A
Western-style high-fat diet has been known to be associated with low-grade intestinal
inflammation, gut dysbiosis and an increased risk for atherosclerosis. However, our knowledge
about the pathways producing each of these different disease manifestations is incomplete,
which makes it difficult to see connections. In my recent study, the question of which
mechanisms drive changes in the gut microbiota composition during high-fat diet and
whether the consequent dysbiosis increases the risk for cardiovascular disease was solved.
Choline which is abundant substrate in high-fat diet is converted to trimethylamine (TMA) by
the gut microbiota. However, whether diet-induced changes in intestinal physiology can alter

the metabolic capacity of the microbiota remains unknown. Using a mouse model of diet-
induced obesity, I found that chronic exposure to a high-fat diet escalates Escherichia coli (E.

coli) choline catabolism by altering intestinal epithelial physiology. A high-fat diet impaired
the bioenergetics of mitochondria in the colonic epithelium to increase the luminal
bioavailability of oxygen and nitrate, thereby intensifying respiration-dependent choline
catabolism of E. coli. In turn, E. coli choline catabolism increased levels of circulating
trimethylamine N-oxide (TMAO), which is a potentially harmful metabolite generated by gut
microbiota. This research provides innovation by establishing for the first time the molecular
pathways connecting different major disease manifestations associated with high-fat diet.