Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.

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PubMed ID: 29519916

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Thaiss CA, Levy M, Grosheva I, Zheng D, Soffer E, Blacher E, Braverman S, Tengeler AC, Barak O, Elazar M, Ben-Zeev R, Lehavi-Regev D, Katz MN, Pevsner-Fischer M, Gertler A, Halpern Z, Harmelin A, Aamar S, Serradas P, Grosfeld A, Shapiro H, Geiger B, Elinav E

Science. 03 2018. doi: 10.1126/science.aar3318

COMMENT: In this work the authors discover a conection between hyperglycemia and systemic inflammation that involves microbial translocation trough altered intestinal barrier.

The authors detected elevated levels of microbial pattern recognition receptor (PRR) ligands in obese mouse models with genetic dysfunction of the leptin system. In these mice the authors detected that the tight junction integrity was compromised at the intestinal epithelium. The origin of these PRR appeared to be gut commensal-derived products. Hyperglycemia appeared to be the responsible for this alteration of the epithelial integrity that leaded to a high influx of immune-stimulatory microbial products. Using 16S sequencing they confirmed changes in the taxonomic profile of the gut microbiome in hyperglycemic mice.

In this study GLUT2 was discovered as the molecule involved in the intestinal epithelial cells metabolic and transcriptional alterations provoking barrier dysfunction after hyperglycemia. One of the most affected pathways by hyperglycemia was the N-glycosylation of proteins. In experiments con Caco-2 cells they demonstrated that glucose induced barrier alterations in a dose- and time-dependent manner causing alterations in of cell-cell junctions.

In summary the authors conclude that:

…hyperglycemia influences intestinal barrier permeability through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity.

One interesting consideration of the authors is that also the hyperglycemia by high intake of glucose could have similar consequences:

… similar effects might be caused by high-glucose diet, which may affect intestinal epithelial cells in a similar manner, potentially resulting in diet-induced alterations of barrier function.

They also suggest glucose metabolism and in general processes involved in the intestinal barrier integrity as new targets for the treatment of systemic inflammation:

… our results may present the starting point for harnessing glucose metabolism or other regulators of intestinal barrier integrity as potential therapeutic targets in the prevention and amelioration of enteric infection and gut-related systemic inflammation



Raquel Tobes