MIAMI – Hyperglycemia increases intestinal permeability, which facilitates enteric infections and systemic inflammation, reported Christoph Thaiss, PhD.
Dr. Christoph Thaiss
The findings upend the old idea that intestinal barrier dysfunction leads to diabetes, Dr. Thaiss said during a plenary session at the annual Gut Microbiota for Health World Summit. Multiple mouse models link hyperglycemia to intestinal barrier dysfunction, and hemoglobin A1C (HbA1c) levels in humans “highly correlate with the influx of microbial molecules into the intestinal epithelium.”
Researchers often struggle to decide if apparent causes are really confounders or even downstream results (reverse causation). In the metabolic syndrome, patients are known to have increased intestinal permeability – so-called leaky gut – and microbes crossing the gastrointestinal epithelium have been found to cause both gut mucosal infections and chronic systemic inflammation. But because these mechanisms were poorly understood, some experts posited that intestinal barrier dysfunction induced pancreatic beta cell inflammation, insulin resistance, and diabetes.
To take a deeper dive, Dr. Thaiss and his associates at the University of Pennsylvania, Philadelphia started with a mouse model of morbid obesity. The mice had multiple systemic sites with microbial pattern recognition ligands, signifying microbial influx from the gut. They also had genetic signatures indicating a marked disruption of junctions between epithelial cells, compared with healthy controls.
The obese mice also were much more susceptible to enteric infections with Citrobacter rodentium (a Salmonella analog), but obesity itself did not drive this risk, Dr. Thaiss explained. In fact, two different murine models of nonobese type 1 diabetes mellitus showed “leaky” intestinal epithelial adherence junctions, heightened susceptibility to C. rodentium infection, and showed systemic pathogen spread. Ribosomal DNA sequencing showed that these hyperglycemic (diabetic) mice had shifts in their gut microbiomes; however, translocating the altered microbiota to normal mice did not make them more susceptible to enteric infections or systemic inflammation.
Based on these findings, the researchers hypothesized that hyperglycemia itself drove susceptibility to enteric infections. They confirmed this by administering insulin to the mice with type 1 diabetes, which restored intestinal epithelial adherence junctions and stopped the systemic spread of pathogens. In vitro, exposing intestinal epithelial cells to glucose-induced barrier dysfunctions that increased over time and with higher glucose concentrations. RNA sequencing demonstrated that hyperglycemia markedly changed expression of genes that encode proteins that regulate intestinal barrier function. Moreover, hyperglycemic mice lacking the bidirectional glucose transporter GLUT2 showed no intestinal barrier dysfunction and were not susceptible to C. rodentium infection and systemic spread.
Finally, the investigators studied more than 30 clinical measures and microbial products in the systemic circulation of 27 healthy human volunteers. “Of all the variables we measured, HbA1c showed the strongest correlation with the influx of microbial molecules,” said Dr. Thaiss. Serum HbA1c correlated highly (P = .008) with levels of toll-like receptor 4, an indicator of systemic pathogens, but not with body mass index (P = .76).
The findings in humans confirm those in mice and indicate that hyperglycemia is a direct cause of intestinal barrier dysfunction and susceptibility to enteric infection, Dr. Thaiss said, adding that the systemic influx of microbial products might explain the wide range of otherwise unrelated inflammatory conditions seen in patients with metabolic syndrome. Future studies of therapies for enteric infection and systemic inflammation might focus on glucose as a modifier of intestinal barrier function.
These findings, reported at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, were also published in Science.
The work was supported by a Boehringer Ingelheim Funds PhD fellowship, the Leona M. and Harry B. Helmsley Charitable Trust, the Adelis Foundation, the Gurwin Family Fund for Scientific Research, the Crown Endowment Fund for Immunological Research, and others. Dr. Thaiss and his coinvestigators reported having no conflicts of interest.
SOURCE: Thaiss CA et al. Science. 2018;359(6382):1376-83.