Research Article

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

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Science  23 Mar 2018:
Vol. 359, Issue 6382, pp. 1376-1383
DOI: 10.1126/science.aar3318

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  • RE: Measurement of bacterial products in serum and tissues

    Dear Katryn,

    Thank you for this comment. The TLR reporter cell lines used in our study (Invivogen HEK-Blue) may indeed be activated by a broad range of NF-kB inducers. In each experiment, we therefore used the parental reporter cell lines and normalized the signals obtained from tissue extracts to this control. The fact that we observed elevated signals across all TLR reporter lines makes the intestinal microbiome the most likely source of these ligands. Nonetheless, microbial TLR ligands cannot be distinguished from endogenous ones in this assay, and the low-grade inflammatory state associated with obesity and hyperglycemia may contribute to elevated levels of endogenous TLR ligands in this scenario. We therefore corroborated the observed defects in the intestinal barrier by several independent methods that we believe are required to fully assess barrier function in vivo, including analyses of tight and adherence junction complexes, FITC dextran-based permeability assays, Ussing chamber recordings, enteric infections, and 16S rDNA qPCRs.

    Best regards,
    Christoph Thaiss and Eran Elinav

    Competing Interests: None declared.
  • RE: Measurement of bacterial products in serum and tissues
    • Katryn J Stacey, NHMRC Senior Research Fellow, The University of Queensland

    The results presented in this paper are important for our understanding of diabetes-associated pathology and show that hyperglycemia rather than obesity per se compromises the gut epithelial barrier. The paper made extensive use Toll-like receptor (TLR)-driven NF-kB reporter assays in HEK293 cell lines to assess levels of bacterial products penetrating into tissues and serum. However, these commercially available cells (Invivogen) respond not only to their respective TLR ligands, but also to the inflammatory cytokine TNF-alpha (see for example results for response of TLR4 reporter cells to TNF-alpha, and to any other factors activating NF-kB within HEK293 cells. Modest induction of TNF-alpha from monocytes in vitro by high glucose has been reported (1). Demonstration that tissue extracts contain TLR-specific signals would require assessment of the level of background signal seen with the parental NF-kB reporter line lacking TLR expression. It would help if the authors can clarify whether this was done, as it is not detailed in the methods. However, even with that control, some signal may derive from endogenous TLR ligands (2). Hence this is not an unambiguous measure of pathogen products and the responses measured could result from other stress or inflammatory signals. Otherwise, this paper represents a comprehensive and important examination of me...

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    Competing Interests: None declared.
  • RE: Glucose control and gut microbiota alter gut defense

    Diabetes has been considered to be associated with gastrointestinal dysfunctions. As shown in the latest article by Thaiss et al., hyperglycemia was the risk factor linked to the attenuation of enteric barrier functions with inflammatory responses and infection (1). Nevertheless, the beneficial effects of suitable glucose control and gut microbiota on gut immunity are worthwhile to investigate.
    How to control glucose homeostasis has a critical influence on the regulation of metabolic immunity. Hyperglycemia induces oxidative stress accompanied by inflammatory cytokines to destroy gut immunity (epithelial cell function and barrier integrity), which leads to gastrointestinal disorders and increases the prevalence of infection. Based on the insights from Dr. Chung, the impairment of gut homeostasis was related to abnormal metabolic markers (trimethylamine/trimethylamine N-oxide, uremic toxins, bacterial lipopolysaccharides, etc.), and the modification of gut microbiota alleviates diabetes via the modulation of multiple metabolic functions, including glucose and lipid metabolism (2, 3). Moreover, the recent report has shown that higher fructose consumption initiated inflammatory responses toward gut mucosal integrity and promoted bacterial infection due to advanced glycation end products (AGEs) accumulation and gut microbial dysbiosis (4).
    In addition, metabolic hormones, related receptors and glucose transporters are involved in the regulation of gut glucose metab...

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    Competing Interests: None declared.

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