Format

Send to

Choose Destination
Science. 2018 Mar 23;359(6382):1376-1383. doi: 10.1126/science.aar3318. Epub 2018 Mar 8.

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.

Author information

1
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
2
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
3
Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, affiliated with the Hebrew University and Hadassah School of Medicine, Jerusalem, Israel.
4
The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.
5
Sackler Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
6
Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
7
Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
8
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
9
Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
10
INSERM Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Cités, UPD Univ. Paris 05, CNRS, IHU ICAN, Paris, France.
11
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. eran.elinav@weizmann.ac.il.

Abstract

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.

PMID:
29519916
DOI:
10.1126/science.aar3318
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center