LOSS OF EPITHELIAL DUOX2 SIGNALING IS ACCOMPANIED BY A REDUCTION IN AKKERMANSIACEAE AND PROMOTES THE DEVELOPMENT OF METABOLIC SYNDROME IN A MICROBIOME-DEPENDENT MANNER

Abstract

Dysbiosis, an imbalance in microbial composition or function, is a key player in the development of conditions associated with chronic inflammation. The gut epithelium regulates host-microbiome dynamics through a variety of mechanisms, including the release of reactive oxygen species by NADPH oxidases. Dual oxidase 2 (DUOX2) is an antimicrobial NADPH oxidase expressed in the thyroid gland and gut epithelium and its activity is associated with dysbiosis. Loss of function mutations in DUOX2 are linked to the development of metabolic and inflammatory conditions such as congenital hypothyroidism and inflammatory bowel disease. Metabolic syndrome (MetS) is a cluster of conditions characterized by dysbiosis, inflammation, obesity, glucose intolerance, and hepatic steatosis. Dysbiosis in MetS is associated with a reduction in Bacteroidaceae and Akkermansiaceae. Despite this association, the mechanism by which dysbiosis leads to chronic inflammation and MetS is poorly defined. Here, we investigate the relationship between impaired epithelial barrier function and the development of MetS by focusing for the first time on intestinal specific DUOX2 deficiency as a mechanistic link.