Abstract
BACKGROUND AND AIMSMetabolic syndrome (MetS) is characterized by obesity, glucose intolerance, and hepatic steatosis. Alterations in the gut microbiome play important roles in the development of MetS. However, the mechanisms by which this occurs are poorly understood. Dual oxidase 2 (DUOX2) is an antimicrobial NADPH oxidase expressed in the gut epithelium. Here we posit that epithelial DUOX2 activity provides a mechanistic link between the gut microbiome and the development of MetS. METHODSMice carrying an intestinal epithelial-specific deletion of DUOXA1/2 (DA IEC-KO), and wild-type (WT) littermates were fed a standard diet and euthanized at 24 weeks. Metabolic alterations were determined by glucose tolerance, lipid tests, and body and organ weight measurements. DUOX2 activity was determined by Amplex Red. Intestinal permeability was determined by FITC-dextran, microbial translocation assessments, and portal vein (PV) lipopolysaccharides (LPS) measurements. Metagenomic analysis of the stool microbiome was performed. The role of the microbiome was assessed in antibiotic-treated mice. RESULTSDA IEC-KO males exhibited increased body and organ weights accompanied by glucose intolerance and elevated plasma lipids and liver enzymes, and increased adiposity in the liver and adipose tissue. Expression of F4/80, CD68, UCP1, ChREBP, leptin, and adiponectin was altered in the liver and adipose tissue of DA IEC-KO males. DA IEC-KO males produced less epithelial H2O2, had altered relative abundance of Akkermansiaceae and Lachnospiraceae in stool, and showed increased PV LPS and intestinal permeability. Females were protected from barrier defects and MetS, despite producing less H2O2. Antibiotic depletion abrogated all MetS phenotypes observed. CONCLUSIONIntestinal epithelial inactivity of DUOX2 promotes MetS in a microbiome-dependent manner.
