Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Christoph A. Thaiss; Maayan Levy; Inna Grosheva; Danping Zheng; Eliran Soffer; Eran Blacher; Sofia Braverman; Anouk C. Tengeler; Oren Barak; Maya Elazar; Rotem Ben-Zeev; Dana Lehavi-Regev; Meirav N. Katz; Meirav Pevsner-Fischer; Arieh Gertler; Zamir Halpern; Alon Harmelin; Suhail Aamar; Patricia Serradas; Alexandra Grosfeld; Hagit Shapiro; Benjamin Geiger; Eran Elinav

doi:10.1126/science.aar3318

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Christoph A. Thaiss, Maayan Levy, Inna Grosheva, Danping Zheng, Eliran Soffer, Eran Blacher, Sofia Braverman, Anouk C. Tengeler, Oren Barak, Maya Elazar, Rotem Ben-Zeev, Dana Lehavi-Regev, Meirav N. Katz, Meirav Pevsner-Fischer, Arieh Gertler, Zamir Halpern, Alon Harmelin, Suhail Aamar, Patricia Serradas, Alexandra GrosfeldHagit Shapiro, Benjamin Geiger, Eran Elinav^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

607 Scopus citations

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.

Original language	English
Pages (from-to)	1376-1383
Number of pages	8
Journal	Science
Volume	359
Issue number	6382
DOIs	https://doi.org/10.1126/science.aar3318
State	Published - 23 Mar 2018
Externally published	Yes

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Thaiss, C. A., Levy, M., Grosheva, I., Zheng, D., Soffer, E., Blacher, E., Braverman, S., Tengeler, A. C., Barak, O., Elazar, M., Ben-Zeev, R., Lehavi-Regev, D., Katz, M. N., Pevsner-Fischer, M., Gertler, A., Halpern, Z., Harmelin, A., Aamar, S., Serradas, P., ... Elinav, E. (2018). Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science, 359(6382), 1376-1383. https://doi.org/10.1126/science.aar3318

@article{564ba9339a364e5aa2aa1eb0a49e6f6b,

title = "Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection",

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.",

author = "Thaiss, {Christoph A.} and Maayan Levy and Inna Grosheva and Danping Zheng and Eliran Soffer and Eran Blacher and Sofia Braverman and Tengeler, {Anouk C.} and Oren Barak and Maya Elazar and Rotem Ben-Zeev and Dana Lehavi-Regev and Katz, {Meirav N.} and Meirav Pevsner-Fischer and Arieh Gertler and Zamir Halpern and Alon Harmelin and Suhail Aamar and Patricia Serradas and Alexandra Grosfeld and Hagit Shapiro and Benjamin Geiger and Eran Elinav",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors.",

year = "2018",

month = mar,

day = "23",

doi = "10.1126/science.aar3318",

language = "אנגלית",

volume = "359",

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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 2018, 'Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection', Science, vol. 359, no. 6382, pp. 1376-1383. https://doi.org/10.1126/science.aar3318

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T1 - Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

AU - Thaiss, Christoph A.

AU - Levy, Maayan

AU - Grosheva, Inna

AU - Zheng, Danping

AU - Soffer, Eliran

AU - Blacher, Eran

AU - Braverman, Sofia

AU - Tengeler, Anouk C.

AU - Barak, Oren

AU - Elazar, Maya

AU - Ben-Zeev, Rotem

AU - Lehavi-Regev, Dana

AU - Katz, Meirav N.

AU - Pevsner-Fischer, Meirav

AU - Gertler, Arieh

AU - Halpern, Zamir

AU - Harmelin, Alon

AU - Aamar, Suhail

AU - Serradas, Patricia

AU - Grosfeld, Alexandra

AU - Shapiro, Hagit

AU - Geiger, Benjamin

AU - Elinav, Eran

PY - 2018/3/23

Y1 - 2018/3/23

N2 - 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.

AB - 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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VL - 359

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JO - Science

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IS - 6382

ER -

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Abstract

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