Advanced glycation end products (AGEs) in metabolic disease: linking diet, inflammation and microbiota

Introduction: High sugar consumption promotes endogenous formation of advancedglycation end-products (AGEs), a heterogeneous class of molecules originated from nonenzymaticglycation between reducing sugars and free amino groups of proteins, nucleicacids, or lipids. AGEs accumulation in tissues has been linked to aging and diabetescomplications. AGEs might also play an independent role in inflammation and developmentof cardiovascular disease (CVD). Exogenous dietary AGEs, due to excess intake of modernheat-treated foods, might act synergistically with endogenous AGEs, thus contributing toincrease inflammation and CVD. A large amount of ingested AGEs reaches the colon, wherethey might affect gut microbial metabolism, for example, by acting as substrate for colonicbacterial fermentation, driving alterations of microbiota composition and of intestinalpermeability. However in vitro and in vivo studies (animal and human) on the impact of AGEson the gut microbiota are discordant. This study on mice aims to link the modulation of gutmicrobiota by AGEs-enriched diet (AGE-D) with metabolic and inflammatory markers.Materials and methods: C57BL/6 mice were randomly allocated into the following dietaryregimens: Control (n=24) and AGE-D (n=20) for 22 weeks. AGE-D was prepared replacingcasein (200 g/kg diet) by an equal amount of modified casein where 10% of arginine wasglycated with MG-H1 (methylglyoxal 5-hydro-5-methylimidazolone) for a total of 4 μmol ofMG-H1 per g of diet. Faeces were collected using metabolic cages (18 h starving) at week 0,11 and 22 for fecal DNA extraction and 16SrRNA analysis through Illumina MiSeq using V3-V4 targeted primers. After 22 weeks of dietary manipulation, mice were sacrificed, plasmaand organ lipid profiles and serum metabolic and inflammatory profiles were determined.Results and discussion: AGE-D caused a significant reduction in the blood levels of twoimportant components of the incretin system, GIP and GLP-1, when compared to control diet,suggestive of unbalance in the incretin-insulin axis. AGE-D exposure was associated with asignificant increase in systemic concentrations of inflammatory cytokines, e.g. IL-1β and IL-17, and PAI-1, which has been suggested as both reliable marker and critical mediator ofcellular senescence. We will present how AGEs impact on microbiome community structureand correlate changes in gut microbiota with GIP and GLP-1 levels.Conclusions: AGEs, characteristic of modern processed foods, appear to impact on theincretin-insulin axis, a key regulator of metabolic disease risk. Diets rich in AGEs may mediatethese physiological effects at least in part, by reshaping intestinal microbiota structure.