Journal
SCIENCE
Volume 359, Issue 6382, Pages 1376-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aar3318
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Funding
- Boehringer Ingelheim Fonds PhD Fellowship
- Leona M. and Harry B. Helmsley Charitable Trust
- Adelis Foundation
- Gurwin Family Fund for Scientific Research
- Crown Endowment Fund for Immunological Research
- estate of J. Gitlitz
- estate of L. Hershkovich
- Benoziyo Endowment Fund for the Advancement of Science
- French National Center for Scientific Research (CNRS)
- V. R. Schwartz Research Fellow Chair
- European Research Council
- Marie Curie Integration grant
- German-Israeli Foundation for Scientific Research and Development
- Israel Science Foundation
- Helmholtz Foundation
- European Foundation for the Study of Diabetes
- European Foundation for the Study of Diabetes [Lilly 2015_7] Funding Source: researchfish
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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.
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