Mechanisms of Disruptive Inflammation in the Aging of the Intestinal Barrier

The intestinal barrier becomes leaky with age, allowing microbes and unwanted metabolites in the gut access to the body, where they will produce chronic inflammation and other harmful consequences. Ironically, it may be increased inflammatory signaling in the intestinal epithelium that causes dysfunction of the intestinal barrier and then later widespread, greater inflammation. Researchers here explore some of this inflammatory signaling and its downstream consequences, focusing in on IFNγ and its effects on a variety of mechanisms relevant to tissue dysfunction in the intestine.

The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium.

Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ signaling completely reverses these aging phenotypes and restores the regenerative capacity of the aged intestinal epithelium.