The Cogence Clinical Pearls Series

Hyperglycemia Drives Barrier Dysfunction,
Risk of Infection, and Systemic Inflammation

What the research says…

In this Clinical Pearl, we look at a paper from Science in which the authors show that hyperglycemia, rather than obesity, is responsible for increased paracellular intestinal permeability. In 27 humans, average plasma glucose (extent of hyperglycemia) correlated with intestinal permeability more strongly than body mass index. In mice, the authors also showed that increased intestinal permeability leads to translocation of microbial products into the systemic circulation, with an increase in microbial ligands being detected at several sites. The effect of this combination of increased intestinal permeability and increased systemic burden of microbial products is an upregulated inflammatory process. Interestingly, the authors found that mice without hyperglycemia who had genetic deficiencies of leptin production or of the leptin receptor did not have increased systemic pathogen burden, suggesting that obesity was not sufficient to drive intestinal permeability in the absence of glycemic dysregulation. This is important, because from a clinical point of view, it means that during the process of working with a patient who is losing weight from a high starting point, it’s possible to repair the intestinal lining and address permeability issues successfully by establishing glycemic control, even in a patient who still has substantial excess adipose tissue.

Application…

There are several insights available from this paper. Several factors need to be considered:

• Patients with elevated hemoglobin A1c need to be suspected of having increased intestinal permeability.
• Patients with low 1,5-ag (glycomark) levels likewise need to be suspected of increased intestinal permeability. 1,5-ag is often low in patients with normal HA1c.
• Research suggests that glutamine levels are determined by extent of systemic inflammation, rather than by dietary intake. Patients with low glutamine intake don’t develop increased intestinal permeability unless they are also inflamed. In this case, the presence of increased permeability, driving increased systemic burden of inflammation, will tend to drive down glutamine levels, making the permeability worse.

From a therapeutic application point of view, it would be useful to consider the following factors:

• Improving glycemic regulation, in particular involving drastic reduction of direct sugars and simple carbohydrates,
• Addressing the systemic pathogen burden,
• Addressing systemic inflammatory process,
• Supplementing glutamine.

The key point overall is that patients with excessive consumption of glucose will be very likely to have permeability issues that are driving systemic inflammation. The hyperglycemia, permeability, systemic pathogen burden, and systemic inflammation all need to be addressed. Leaving out the hyperglycemia is likely to diminish the effectiveness of the rest of the work.

The research…

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.

Thaiss CA1, Levy M1, Elinav E, et al. Science. 2018 Mar 23;359(6382):1376-1383.

(Color and bold added.)

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.

The above paper is also discussed in:

Mucosal immunology: Glucose not good for the gut.

Nat Rev Immunol. 2018 May;18(5):291.

Minton K.