Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

被引：811

作者：

Thaiss, Christoph A. ^{[1
]}

Levy, Maayan ^{[1
]}

Grosheva, Inna ^{[2
]}

Zheng, Danping ^{[1
]}

Soffer, Eliran ^{[1
]}

Blacher, Eran ^{[1
]}

Braverman, Sofia ^{[1
]}

Tengeler, Anouk C. ^{[1
]}

Barak, Oren ^{[1
,3
,4
,5
]}

Elazar, Maya ^{[1
]}

Ben-Zeev, Rotem ^{[1
]}

Lehavi-Regev, Dana ^{[1
]}

Katz, Meirav N. ^{[1
]}

Pevsner-Fischer, Meirav ^{[1
]}

Gertler, Arieh ^{[6
]}

Halpern, Zamir ^{[7
,8
,9
]}

Harmelin, Alon ^{[10
]}

Aamar, Suhail ^{[11
]}

Serradas, Patricia ^{[12
]}

Grosfeld, Alexandra ^{[12
]}

Shapiro, Hagit ^{[1
]}

Geiger, Benjamin ^{[2
]}

Elinav, Eran ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel

[2] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[3] Kaplan Med Ctr, Dept Obstet & Gynecol, Rehovot, Israel

[4] Hebrew Univ Jerusalem, Rehovot, Israel

[5] Hadassah Med Sch, Rehovot, Israel

[6] Hebrew Univ Jerusalem, Robert H Smith Fac Agr Food & Environm, Rehovot, Israel

[7] Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Tel Aviv, Israel

[8] Tel Aviv Sourasky Med Ctr, Res Ctr Digest Tract & Liver Dis, Tel Aviv, Israel

[9] Tel Aviv Sourasky Med Ctr, Digest Ctr, Tel Aviv, Israel

[10] Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel

[11] Hadassah Hebrew Univ Hosp, Dept Med, Jerusalem, Israel

[12] Sorbonne Univ, UPD Univ Paris 05, Sorbonne Cites, INSERM,Ctr Rech Cordeliers,CNRS,IHU ICAN, Paris, France

来源：

SCIENCE | 2018年 / 359卷 / 6382期

基金：

以色列科学基金会; 欧洲研究理事会;

关键词：

INFLAMMATION; OBESITY; LEPTIN; GLYCOSYLATION; HOMEOSTASIS; PROMOTES; FUCOSYLATION; DISEASE; IMPACT; MODEL;

D O I：

10.1126/science.aar3318

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：1376 / +

页数：8

共 46 条

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Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching [J].