Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis

Figures & data

Figure 1. Structures of common AGEs. Modified from Akıllıoğlu and Gökmen (2019).

Figure 2. Dietary advanced glycation end-products (AGEs) induce toxicological effects by activating RAGE, modulating gut microbiota and inducing collagen crosslinking – potential roles in severity of COVID-19, aging, obesity and Type 2 diabetes. ADME: Absorption, distribution, metabolism, and excretion.

Figure 3. Schematic representation of paradoxical control of pro- and anti-inflammation by RAGE activation.

Figure 4. Differential immunomodulating capabilities of EGPs and AGEs. (A) Structure of glucose-derived Amadori compounds (early glycation products). R = protein/peptide/amino acid. (B) Comparison of EGPs and AGEs in modulating cytokine/chemokine production. Modified from Chen and Guo (2019). No: no significant change when compared to non-reacted control. ^aValue significantly different from EGPs but not from non-reacted control.

Table 1. Summary of human and lab animal microbiome studies on Maillard reaction products (AGE and EGP).

Disease model	Population/ animal model	Exposure windows	MRP/dose/ concentration	Routes of administration	Diet	Effects	Reference
Autoimmune prostatitis	Male NOD mice	Feeding (6 months) starting at ≈4-months-of-age	600 mg EGPs/kg	Gavage	Diet 5053, PicoLab	Increased Anaerostipes, Parabacteroides, Prevotella, Allobaculum and Bacteroides and decreased Adlercreutzia and Roseburia in terms of relative abundance.	Chen, et al. 2019
Not specified	Weanling Wistar rats	Feeding for 88 days	Diets containing bread crust or its soluble high molecular weight, soluble low molecular weight or insoluble fractions	In food	AIN-93G purified diet	Low and high MW fractions rich in Amadori compounds down-regulated Lactobacillus spp.; the insoluble fraction abundant in HMF and CML down-regulated E. rectale/C. coccoides and C. leptum	Delgado-Andrade et al. 2017
Not Specified	Sprague–Dawley rats	Feeding for 2 weeks	High in furosine (Amadori compound-derived marker for initial stage of Maillard reaction), CML, and CEL	In food		Increases in Akkermansia, Allobaculum and Lachnospiraceae_UCG-006, and a decrease in Erysipelatoclostridium at genus level compared to in hosts fed heated control	Han et al. 2018
Atherosclerosis	Male ApoE^−/− mice	Feeding (8 weeks) starting at 8-weeks-of-age	Plasma CML and CEL increased 1.7- and 2.5-fold, respectively	In food	Heat-treated high-fat diet	Decreased α diversity accompanied by increases in Allobaculum and unclassified genus of Clostridiales and decreases in Bacteroides, unclassified genera of Lachnospiraceae, Rikenellaceae and Ruminococcaceae at genus level	Marungruang et al. 2016
Inflammatory bowel diseases	Male BALB/c mice	Feeding (3 weeks) starting at 7-weeks-of-age	N^ε-Carboxymethyllysine; 1.6 mg/kg/day	Per os	Standard chow	Bacteroidaceae increased, Lachnospraceae decreased	Al Jahdali et al. 2017
Not specified	Male Sprague–Dawley rats	Fed for 6, 12, or 18 weeks	Fluorescent AGE (968 v. 2148 AU/g), CML (272 v. 143 μg/g), CEL (6.26 v. 0.97 μg/g), GO (49.1 v. 12.1 mg/kg), and MGO (28.7 v. 1.1 mg/kg) were higher in the H-AGE diet	In food	AIN-93G diet enriched with AGEs	Decreased α diversity, Alloprevotella and Ruminococcaceae, while increasing Allobaculum and Bacteroides	Qu et al. 2017
Not specified	Male C57BL/6 mice	Feeding (8 months) starting at 6-weeks-of-age	Same as above	In food	Same as above	Decreased α diversity, increased Alloprevotella, Helicobacter, Parabacteroides, Ruminococcaceae_UCG-014 and unclassified genus of Rhodospirillaceae, and decreased Alistipes, Desulfovibrio, Lachnospiraceae_ NK4A136_group and Rikenellaceae_RC9_gut group.	Qu et al. 2018
Not specified	Adolescent men	2-weeks randomized two-period crossover trial	Diets high or low in hydroxy-methylfurfural (HMF; 5-fold) and CML (2-fold)	In food	Prepared by a local catering firm	Negative correlations between Lactobacilli numbers and dietary advanced MRP (e.g. AGEs); Bifidobacteria counts negatively correlated with Amadori compound intake (e.g. EGPs).	Seiquer et al. 2014
Not specified	Male weanling Wister rats	Feeding (87 days) starting at weanling	High in Amadori compounds, HMF and CML	In food	AIN 93 G diet	Total bacteria and Lactobacilli were negatively-correlated with MRP intake; no correlations were found with Bifidobacteria.	Seiquer et al. 2014
End stage renal disease (ESRD) patients	Undergoing peritoneal dialysis	One-month dietary AGEs restriction	Dietary AGEs restriction resulted in decreases in serum CML (29.6 vs. 23.3 u/ml) and methylglyoxal-derivatives (5.6 vs. 4.0)	In food	Habitually consuming a high AGE diet	Dietary AGE restriction significantly decreased Prevotella copri and Bifidobacterium animalis relative Abundance, and increased Alistipes indistinctus, Clostridium citroniae, Clostridium hathewayi and Ruminococcus gauvreauii relative abundance	Yacoub et al. 2017

Chen Y, Guo T. 2019. Dietary early glycation products promote the growth of prostate tumors more than advanced glycation end-products through modulation of macrophage polarization. Mol Nutr Food Res. 63(4):e1800885.

 PubMed Web of Science ®Google Scholar

Chen Y, Nagy T, Guo T. 2019. Glycated whey proteins protect NOD mice against Type 1 diabetes by increasing anti-inflammatory responses and decreasing autoreactivity to self-antigens. J Funct Foods. 56:171–181.

 PubMed Web of Science ®Google Scholar

Delgado-Andrade C, de la Cueva S, Peinado M, Rufian-Henares J, Navarro M, Rubio L. 2017. Modifications in bacterial groups and short chain fatty acid production in the gut of healthy adult rats after long-term consumption of dietary Maillard reaction products. Food Res Intl. 100:134–142.

 PubMed Web of Science ®Google Scholar

Han K, Jin W, Mao Z, Dong S, Zhang Q, Yang Y, Zeng M. 2018. Microbiome and butyrate production are altered in gut of rats fed glycated fish protein diet. J Funct Foods. 47:423–433.

 Web of Science ®Google Scholar

Marungruang N, Fak F, Tareke E. 2016. Heat-treated high-fat diet modifies gut microbiota and metabolic markers in apoe-/- mice. Nutr Metab. 13:22.

 Google Scholar

Al Jahdali N, Gadonna-Widehem P, Delayre-Orthez C, Marier D, Garnier B, Carbonero F, Anton P. 2017. Repeated oral exposure to Nε-carboxymethyllysine, a Maillard reaction product, alleviates gut microbiota dysbiosis in colitic mice. Dig Dis Sci. 62(12):3370–3384.

 PubMed Web of Science ®Google Scholar

Qu W, Yuan X, Zhao J, Zhan Y, Hu J, Wang J, Li J. 2017. Dietary advanced glycation end-products modify gut microbial composition and partially increase colon permeability in rats. Mol Nutr Food Res. 61(10):201700118.

 Web of Science ®Google Scholar

Qu W, Nie C, Zhao J, Ou X, Zhang Y, Yang S, Bai X, Wang Y, Wang J, Li J. 2018. Microbiome-metabolomics analysis of the impacts of long-term dietary advanced glycation end-product consumption on C57BL/6 mouse fecal microbiota and metabolites. J Agric Food Chem. 66(33):8864–8875.

 PubMed Web of Science ®Google Scholar

Seiquer I, Rubio L, Peinado M, Delgado-Andrade C, Navarro M. 2014. Maillard reaction products modulate gut microbiota composition in adolescents. Mol Nutr Food Res. 58(7):1552–1560.

 PubMed Web of Science ®Google Scholar

Yacoub R, Nugent M, Cai W, Nadkarni GN, Chaves LD, Abyad S, Honan AM, Thomas SA, Zheng W, Valiyaparambil SA, et al. 2017. Advanced glycation end-products dietary restriction effects on bacterial gut microbiota in peritoneal dialysis patients; a randomized open label controlled trial. PLoS One. 12(9):e0184789.

 PubMed Web of Science ®Google Scholar