The loss of antioxidant activities impairs intestinal epithelium homeostasis by altering lipid metabolism

Abstract

ABSTRACTThe increase in reactive oxygens species (ROS) with aging could be at the origin of many diseases of the elderly. Here we investigated the role of ROS in the renewal of the intestinal epithelium in mice lacking catalase (CAT) and/or nicotinamide nucleotide transhydrogenase (NNT) activities.Cat-/-mice have delayed intestinal epithelium renewal and were prone to develop necrotizing enterocolitis upon starvation. Interestingly, crypts lacking CAT showed fewer intestinal stem cells (ISC) and lower stem cell activity than wild-type, together with less LYS in Paneth cells. In contrast, crypts lacking NNT showed a similar number of ISCs and amount of LYS as wild-type but increased stem cell activity, which was also impaired by the loss of CAT.Catdeficiency caused fat accumulation in crypts, and a fall in the remarkable high amount of adipose triglyceride lipase (ATGL) in PCs. Supporting a role of ATGL in the regulation of ISC activity, its inhibition halt intestinal organoid development. These data suggest that the reduction of the intestine renewal capacity along aging originates from fatty acid metabolic alterations caused by peroxisomal ROS.Summary statementMice with increased peroxisomal or mitochondrial reactive oxygen species develop intestinal phenotypes that are associated with aging and originate from a defective stem cell niche with impaired fatty acid metabolism.