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.

Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

“…We used DBA/2J mice because HFD is ineffective in C3H/HeJ mice (Figure S5F-I). HFD has been previously suggested to cause leaky gut in C57BI/6 mice and render mice more susceptible to CR extraintestinal dissemination (Thaiss et al, 2018) but does not in DBA/2J mice (Figure S6A-D). We confirmed that CR establishes a lethal infection and that dietary iron protects from a lethal CR challenge, induces IR, reduces intestinal glucose absorption and increases glucose availability in the lumen of the intestine during infection in DBA2/J mice (Figure 6G-J and S6E-J).…”

Leaky gut: mechanisms, measurement and clinical implications in humans

“…However, there is evidence that there may be altered expression of cellular transport mechanisms that may ultimately lead to intercellular barrier dysfunction and systemic inflammation. An excellent example of the potential impact of increased transcellular permeability without apoptosis or intestinal ulceration is provided by the demonstration, in mouse models of obesity and diabetes, that hyperglycaemia drives intestinal barrier permeability through glucose transporter 2-dependent transcriptional reprogramming of IECs and alteration of tight and adherence junction integrity 39. These findings were demonstrated by reduced ZO-1 expression and increased fluorescein isothiocyanate (FITC)-dextran in serum after oral administration, indicating increased intestinal permeability, as well as an increased short-circuit current measured across the epithelial layer in Ussing chambers.…”

Faecalibacterium prausnitzii‐derived microbial anti‐inflammatory molecule regulates intestinal integrity in diabetes mellitus mice via modulating tight junction protein expression

“…Previous studies have shown that DM patients and animal models suffer impaired intestinal barrier structure and function . Malfunction of the intestinal barrier promotes the absorption of pathogens and toxins from the lumen, which induces intestinal inflammation and hyperglycemia deterioration . These pathological alterations worsen DM prognosis.…”