Estrogen-Related Receptor Alpha (Err Alpha) Is A Key Regulator Of Intestinal Homeostasis And Protects Against Colitis

The estrogen-related receptor alpha (ERR alpha) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERR alpha is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERR alpha in the intestine. We found that mice deficient in ERR alpha were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERR alpha lead to a reduction in microbiome alpha -diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERR alpha mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERR alpha in the gut and extends our current knowledge of nuclear receptors implicated in IBD.