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

Abstract

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 βdiversity. 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.

Advanced Glycation End-Products and Their Effects on Gut Health

“…To date, the current literature has questioned many findings from animal and human studies due to the unreliability of the methods used for AGEs measurements. Most studies in the past predominantly measured AGE levels in foods using ELISA [ 61 , 62 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ] instead of ultraperformance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), which is currently considered the gold standard for AGE measurements [ 19 , 104 ]. In addition, many studies focused on producing high-AGE and low-AGE diets using high and low baking (heat-treated) methods or changing the cooking technique (boiling, poaching instead of grilling, frying) to adjust the AGE concentrations in foods.…”

“…Yacoub et al [ 101 ] conducted a randomised open-label-controlled trial, looking at the association between the gut microbiota and the consumption of dietary AGEs in patients with end-stage renal disease. Their study indicated that a one-month dietary AGE restriction was associated with a decline in the relative abundance of Prevotella copri and Bifidobacterium animalis and with an increase in the relative abundance of Alistipes indistinctus, Clostridium citroniae, Clostridium hathewayi , and Ruminociccus gauvreauii [ 101 , 102 , 151 , 152 ]. The increase in Alistipes indistinctus is not likely beneficial, as it is recognised to be highly pathogenic due to its strong association with colitis and tumorigenesis in mice [ 153 ].…”

“…The increase in Alistipes indistinctus is not likely beneficial, as it is recognised to be highly pathogenic due to its strong association with colitis and tumorigenesis in mice [ 153 ]. Further, the decrease in Prevotella copri may also be detrimental, as this is known to generate high levels of short-chain fatty acids (SCFAs) [ 102 , 124 , 149 , 150 , 154 , 155 , 156 ]. SCFAs are recognised to exert multiple health benefits, in particular improved intestinal barrier function [ 155 , 156 , 157 ].…”

The Intake of Dicarbonyls and Advanced Glycation Endproducts as Part of the Habitual Diet Is Not Associated with Intestinal Inflammation in Inflammatory Bowel Disease and Irritable Bowel Syndrome Patients

“…The most well studied AGEs include Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and methylglyoxal-derived hydroimidazolone-1 (MG-H1). In vitro and in vivo studies show that ingested AGEs can induce an inflammatory response [ 2 , 3 , 4 , 5 ] and affect microbial growth [ 5 , 6 , 7 , 8 , 9 , 10 ]. Furthermore, previous human studies showed that a diet high in dietary AGEs is associated with low-grade inflammation, endothelial dysfunction and insulin resistance [ 11 ].…”

Microbiome-Targeted Therapies as an Adjunct to Traditional Weight Loss Interventions: A Systematic Review and Meta-Analysis

“…Dietary changes can have a considerable and sustained effect on the composition of the microbiome, and alterations in the microbiome, in turn, may influence the absorption, breakdown, and storage of nutrients. 11 , 18 , 20 Additionally, compositional differences in gut microbiota contribute to individual differences in the metabolic responses to specific foods. 21 , 22 These differences have been associated with differential weight loss in response to certain diets.…”