The Impact of the Gut Microbiome on Intestinal Stem-Cells on a High Fat Diet

Obesity increases the risk for colorectal cancer. In mice, a pro-obesity high-fat-diet (HFD) leads to an intestinal phenotype characterized by enhanced proliferation, numbers, function and tumor-initiating capacity of stem cells, the cell-of-origin for many intestinal cancers. This phenotype is driven by a lipid metabolism program facilitated by an intrinsic Peroxisome Proliferator-Activated Receptor/Fatty Acid Oxidation (PPAR/FAO) axis that senses and utilizes cellular lipids. However, the microbiome is a known regulator of lipid metabolism in the gut, but little is understood about how the gut commensals affect access to the lipids and alter stem cell function. Here, we use the long term HFD-fed mouse model to analyze the phenotypic changes in the intestinal stem cells (ISCs) after depletion of the gut microbiota. We find that the loss of the gut microbiome after four weeks of antibiotic treatment imposes significant changes in ISC function leading to reduced HFD ISC regenerative potential. These results indicate that the gut microbiome plays a crucial role in the lipid metabolic process which regulates and maintains the HFD ISC phenotype, and further suggests that the gut microbiome may augment the diet-induced tumor initiating capacity by altering the stem cell function.