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

Abstract

Objective

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

Abbreviations

AGE, advanced glycation end product; ANOVA, analysis of variance; AUC, area under the receiver operating characteristic curve; BSA, bovine serum albumin; CAG, co-abundance group; FBG, fasting blood glucose; HOMA-IR, homeostatic model assessment insulin resistance; IPGTT, intraperitoneal glucose-tolerance test; KEGG, Kyoto Encyclopedia of Genes and Genomes; LBP, lipopolysaccharide-binding protein; MG, methylglyoxal; OTU, operational taxonomic unit; PCoA, principal coordinate analysis; ROC, receiver operating characteristic; WGCNA, weighted correlation network analysis.

Data Sharing Statement

The 16S rDNA sequencing set of this article has been deposited in the Genome Sequence Archive (GSA) under the BioProject accession code PRJCA006137.

Ethics Approval and Consent to Participate

Animal experiments were performed in accordance with the Guidelines on the Ethical Treatment of Experimental Animals issued by the Ministry of Science and Technology of China and approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (No. 2021-5-073).

Acknowledgments

The authors would like to thank BGI Company (Shenzhen, China) for performing the fecal microbiota 16S rDNA sequencing.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study was supported by grants from the National Natural Science Funds of China [grant no. 81760168] and Natural Science Foundation of Jiangxi Province [grant no. 20192BAB205031].