Abstract
The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα 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 ERRα in the intestine. We found that mice deficient in ERRα 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 ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα 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 ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.
Highlights
The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation
~ 90% of the colon tissue was damaged or eroded in Esrra−/− mice on day 8 post-dextran sodium sulfate (DSS) treatment compared to ~ 30% in WT mice (Fig. 1g). These results suggested that estrogen-related receptor α (ERRα) expression protects against DSS-induced colitis
ERRα controls a wide transcriptional network pertaining to cellular energy metabolism, mitochondrial function, autophagy and wound healing, among others[32,33,39]
Summary
The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. 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 ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD. Mitochondrial unfolded protein response (mt-UPR), and the autophagy-dependent degradation of damaged mitochondria, known as m itophagy[5] Defects in these pathways are linked to IBD in genetic-association and functional studies[6,7]. Defects in autophagy and mitophagy are associated with IBD, by impacting IEC survival and function, antimicrobial peptide production, bacterial handling, reactive oxygen species (ROS) levels and immune responses to the microbiota. Its levels are reduced in IBD and in experimental models of colitis, and its IEC-specific deletion in mice (PGC-1α ΔIEC) results in increased susceptibility to experimental colitis induced by dextran sodium sulfate (DSS)[12]
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