Dietary Advanced Glycation End Products Shift the Gut Microbiota Composition and Induce Insulin Resistance in Mice

Abstract

Jiao Wang,1– 3,* Wei Cai,4,* Jiao Yu,1 Honghong Liu,1 Shasha He,1 Lingyan Zhu,1– 3 Jixiong Xu1– 3 1Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People’s Republic of China; 3Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, 330006, People’s Republic of China; 4Department of Medical Genetics and Cell biology, Medical College of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jixiong Xu, Email [email protected]: This study aimed to explore the associations between gut microbiota characteristics and glycometabolic profiles in mice fed diets high in advanced glycation end products (AGEs).Methods: C57BL/6 mice were exposed to a heat-treated diet or exogenous AGEs for 24 weeks, and glucose metabolism was assessed via the intraperitoneal glucose-tolerance test (IPGTT). Serum AGE and lipopolysaccharide-binding protein (LBP) levels were quantified using ELISA kits. 16S rDNA sequencing was performed to analyze the changes in gut microbiota according to α- and β-diversity. Key operational taxonomic units (OTUs) were evaluated, and co-abundance groups (CAGs) were delineated using weighted correlation network analysis. Associations between CAGs and clinical parameters were analyzed using Spearman correlation; predictive functional analysis of gut microbiota was performed using Kyoto Encyclopedia of Genes and Genomes data.Results: We identified significant increases in fasting blood glucose (FBG) and fasting insulin levels, as well as homeostatic model assessment insulin resistance (HOMA-IR) and glucose area under the receiver operating characteristic curve from IPGTT, in the high-AGE diet groups relative to controls at week 24. Serum AGE and LBP levels were elevated, and the α- and β-diversity of gut microbiota reduced in high-AGE diet groups. We identified 92 key OTUs that clustered into six CAGs, revealing positive correlations between CAG2/3/5 and insulin levels and mice weight and negative correlations between CAG1/3/4/5 and AGE, FBG, and LBP levels and HOMA-IR in mice fed high-AGE diets. We observed a reduced abundance of butyrate-producing bacteria, including Bacteroidales_S24-7, Ruminococcaceae, and Lachnospiraceae, in mice fed high-AGE diets, with pathway analysis of gut microbiota revealing significantly enriched fructose and mannose metabolism.Conclusion: High-AGE diets altered the gut microbiota composition and structure, and induced insulin resistance in mice. In the pathogenesis of insulin resistance, the loss of butyrate-producing bacteria might impair the colonic epithelial barrier, thereby triggering chronic low-grade inflammation.Keywords: diet, advanced glycation end products, gut microbiota, insulin resistance

Keywords

• diet
• advanced glycation end products
• gut microbiota
• insulin resistance