Abstract
The impact of dietary advanced glycation end products (dAGEs) on human health has been discussed in many studies but, to date, no consensual pathophysiological process has been demonstrated. The intestinal absorption pathways which have so far been described for dAGEs, the passive diffusion of free AGE adducts and transport of glycated di-tripeptides by the peptide transporter 1 (PEPT-1), are not compatible with certain pathophysiological processes described. To get new insight into the intestinal absorption pathways and the pathophysiological mechanisms of dAGEs, we initiated an in vivo study with a so-called simple animal model with a complete digestive tract, Caenorhabditis elegans. Dietary bacteria were chemically modified with glyoxylic acid to mainly produce Nε-carboxymethyllysine (CML) and used to feed the worms. We performed different immunotechniques using an anti-CML antibody for the relative quantification of ingested CML and localization of this AGE in the worms’ intestine. The relative expression of genes encoding different biological processes such as response to stresses and intestinal digestion were determined. The physiological development of the worms was verified. All the results were compared with those obtained with the control bacteria. The results revealed a new route for the intestinal absorption of dietary CML (dCML), endocytosis, which could be mediated by scavenger receptors. The exposure of worms to dCML induced a reproductive defect and a transcriptional response reflecting oxidative, carbonyl and protein folding stresses. These data, in particular the demonstration of endocytosis of dCML by enterocytes, open up new perspectives to better characterize the pathophysiological mechanisms of dAGEs.
Highlights
In order to reduce the diversity of the AGEs formed and to facilitate the interpretation of the results, glyoxylic acid was chosen as the glycating agent
The images clearly show the presence of endosomes containing CML epitopes in the worms. These endosomes presented distinct markers such as dynamin 1 or DYN-1, which is involved in the early stage of endocytosis, the lysosomal membrane protein lysosome-associated membrane protein homolog 1 (LMP-1) which confirms fusion with lysosomes and, for some, the RME-1 receptor which is involved in endosomal recycling. These results clearly demonstrate a new mechanism of intestinal absorption for dietary CML (dCML) which is endocytosis
Our study deserves additional analyses, in particular: 1—the quantification of the fate of dCML ingested by worms, 2—deciphering between endocytosed dCML and dCML transported by peptide transporter 1 (PEPT-1), 3—a demonstration of the health effect of glycated dietary proteins vs. glycated protein supplement which, as we have shown in this study, is endocytosed by enterocytes, 4—highlighting the mechanisms induced by the ingestion of dCML and the receptors involved
Summary
Given the number of alimentary products containing AGEs, many reports have rightly questioned the impact of dAGEs on human health [2,3]. DAGEs would be aggravating factors in older adults and in people with certain pathologies, in particular metabolic and hormonal disorders and chronic kidney diseases [4,5,6,7,8,9,10,11]. In these populations, a low-AGE diet can decrease plasma and urinary
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