High-fat diet–induced colonocyte dysfunction escalates microbiota-derived trimethylamine <i>N</i> -oxide

Abstract

A Western-style, high-fat diet promotes cardiovascular disease, in part because it is rich in choline, which 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, we show that chronic exposure to a high-fat diet escalates <i>Escherichia coli</i> 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 <i>E. coli</i> In turn, <i>E. coli</i> choline catabolism increased levels of circulating trimethlamine <i>N</i>-oxide, which is a potentially harmful metabolite generated by gut microbiota.