Intestinal Epithelial Cells Adapt to Chronic Inflammation through Partial Genetic Reprogramming

Simple Summary Chronic inflammation, as observed in Crohn's disease and ulcerative colitis patients, damages the intestinal mucosa. We reasoned that if a subset of intestinal epithelial cells adapt to this inflammatory stress to survive, this adaptation could contribute to their malignant transformation. We show that human colonic epithelial cells escape chronic inflammation in vitro through a partial genetic reprogramming. By questioning data bases, we confirm that this reprogramming takes place in the inflamed mucosae of patients with Crohn's disease and ulcerative colitis, and that it is induced in vivo during the early stages of murine intestinal carcinogenesis. These data contribute to understanding the pathology and underline how orchestrators of cellular adaptation might contribute to intestinal homeostasis and, potentially, tumor initiation. Reactive oxygen species (ROS) are considered to be the main drivers of inflammatory bowel disease. We investigated whether this permanent insult compels intestinal stem cells to develop strategies to dampen the deleterious effects of ROS. As an adverse effect, this adaptation process may increase their tolerance to oncogenic insults and facilitate their neoplastic transformation. We submitted immortalized human colonic epithelial cells to either a mimic of chronic inflammation or to a chemical peroxide, analyzed how they adapted to stress, and addressed the biological relevance of these observations in databases. We demonstrated that cells adapt to chronic-inflammation-associated oxidative stress in vitro through a partial genetic reprogramming. Through a gene set enrichment analysis, we showed that this program is recurrently active in the intestinal mucosae of Crohn's and ulcerative colitis disease patients and evolves alongside disease progression. Based on a previously reported characterization of intestinal stem and precursor cells using tracing experiments, we lastly confirmed the activation of the program in intestinal precursor cells during murine colorectal cancer development. This adaptive process is thus likely to play a role in the progression of Crohn's and ulcerative disease, and potentially in the initiation of colorectal cancer.