How Hyperglycemia Drives Gut Barrier Dysfunction and Dysbiosis

Obesity, diabetes, and metabolic syndrome have long been associated with gut barrier dysfunction and an altered gut microbiota composition. Now, a new study suggests that hyperglycemia itself might be to blame. Read on to learn what the researchers found and what implications this has for restoring gut health.

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Obesity, diabetes, and metabolic syndrome have reached epidemic proportions. In the United States today, someone dies from diabetes-related causes every 10 seconds. Recent reports suggest that one-third of all U.S. adults will have diabetes by 2050 if current trends continue (1).

Blood glucose must be tightly controlled for an organism to maintain physiological homeostasis. Chronically high blood glucose levels, as in obesity, diabetes, and associated metabolic disorders, can result in a number of health problems, including kidney disease, neuropathy, and cardiovascular disease.

A recently published study suggests that high blood sugar can also directly impair gut barrier function, alter the gut microbiota, and increase susceptibility to gut infection (2). In this article, I’ll break down the methods and results of the study and discuss the implications of this research. As always, if you get caught up in the details, I’ll provide a succinct takeaway section at the end.

Leptin Deficiency and Excess Body Fat Are Not the Culprit

Obesity has long been associated with increased gut permeability and translocation of bacterial products into circulation, but why exactly this happens has remained a mystery (3). Christoph Thaiss and his colleagues at the Weizmann Institute of Science in Israel set out to answer the question once and for all.

The researchers first hypothesized that it was a deficiency in the satiety hormone leptina that drove intestinal barrier dysfunction. After all, mice with genetic leptin deficiency or leptin receptor defects, two common animal models of obesity, exhibit impaired gut barrier function, increased susceptibility to gut infection, and elevated microbial products in circulation. Yet specific deletion of the leptin receptor in intestinal epithelial cells did not produce the same barrier dysfunction or infection susceptibility (2).

 A recently published study suggests that high blood sugar can also directly impair gut barrier function, alter the gut microbiota, and increase susceptibility to gut infection. Learn about the results of the study, and discuss the implications of this research.

Next, they thought, perhaps excess fat itself is driving the effect on barrier function. Previous studies had shown that feeding mice a “high-fat diet” caused weight gain and resulted in increased gut permeability and microbial translocation. Yet, when Thaiss et al. restricted the food access of leptin-resistant mice to induce weight loss, they saw no improvements in gut barrier function, suggesting that excess body fat itself was not responsible for the effects on the gut.

So, if it wasn’t leptin and it wasn’t excess body fat, what was it? Notably, obesity is often accompanied by glucose intolerance and hyperglycemia. Indeed, both the leptin deficiency model and the “high-fat diet” model of obesity are characterized by significantly elevated blood glucose. (A “high-fat diet” in animal studies would be more accurately called “a highly refined, high-polyunsaturated-vegetable-oils-and-high-sugar-diet.”) This led Thaiss and colleagues to ask whether high blood glucose levels could be responsible for the gut-harming effects of obesity.

High Blood Glucose Causes Leaky Gut

To test whether elevated blood glucose levels were involved in regulating gut barrier function, the researchers needed to induce hyperglycemia in the absence of obesity. They did so using a drug called streptozotocin (STZ), which destroys pancreatic beta cells in mice. The resulting phenotype closely mimics type 1 diabetes in humans.

STZ caused dysfunction of the adherens junctions between intestinal epithelial cells. When challenged with the enteric pathogen Citrobacter rodentium, STZ-treated mice also developed more severe infection than control mice. This was accompanied by enhanced bacterial growth, adherence to the gut epithelium, and systemic translocation. Moreover, treatment with insulin to restore normal blood glucose levels ameliorated the effects. Altogether, this suggests that elevated blood glucose itself is sufficient to cause gut permeability.

But does this happen in humans? The researchers were curious too, so they recruited 27 healthy participants to take some measurements. Hemoglobin A1c (HbA1c), an indicator of an individual’s average plasma glucose concentration over the last three months, showed a strong correlation to biomarkers of bacterial translocation. Meanwhile, BMI and other metabolic parameters did not show any significant associations (2).

Blocking Gut Glucose Metabolism Restores Gut Function

The researchers next turned to cell culture to determine what was going on at the molecular level. They found that bathing cultured intestinal epithelial cells in a high-glucose solution induced barrier dysfunction in a dose- and time-dependent manner and resulted in global reprogramming of epithelial gene expression patterns. Over 1,000 genes were differentially expressed in intestinal epithelial cells that had been exposed to excess glucose! This included several genes involved in metabolic pathways that are critical for the maintenance of the intestinal barrier.

Intriguingly, inhibiting glucose metabolism using 2-deoxyglucose (2-DG), which competitively blocks the second step of glycolysis, completely rescued barrier and immune function. It also prevented the global reprogramming of gene expression in STZ-treated mice. Likewise, selective deletion of the glucose transporter GLUT2 in intestinal epithelial cells rendered mice resistant to STZ-induced gut barrier function, C. rodentium susceptibility, and epigenetic reprogramming. This suggests that glucose uptake and metabolism by epithelial cells is necessary for barrier breakdown to occur.

A High-Sugar Diet May Have the Same Effect

It’s not just diabetics and those with insulin resistance who need to be wary though. It’s likely that a high-glucose diet could likely have the same effect, even in those who are metabolically healthy:

While our study focused on the impact of systemic glucose levels on the intestinal barrier, similar effects might be caused by a high-glucose diet, which may affect intestinal epithelial cells in a similar manner, potentially resulting in diet-induced alterations of barrier function. (2)

Mechanistically, this makes perfect sense. The two-way glucose transporter GLUT2 normally resides on the basement membrane of the epithelial cell and mediates transport between the epithelium and circulation. However, a high glucose concentration in the small intestine also triggers the insertion of GLUT2 into the brush border membrane, enhancing glucose influx from the intestinal lumen into the cell (4). More glucose uptake and metabolism likely means greater risk of epigenetic reprogramming and leaky gut.

High Blood Glucose Causes Gut Dysbiosis

The study didn’t stop there, though. Hyperglycemia was also associated with an altered gut microbiota. 16S rRNA gene sequencing revealed a significant shift in the gut microbiota of hyperglycemic mice. While taxonomic information was not provided, the authors reported that the alterations in the microbiota were corrected by insulin treatment and the restoration of normal blood glucose levels.

Interestingly, the changes in the microbiota did not seem to play a critical role in hyperglycemia-driven barrier dysfunction, as transplanting fecal material from STZ-treated donors into sterilely raised germ-free mice did not induce bacterial translocation or increase susceptibility to C. rodentium infection. Nevertheless, I look forward to future studies investigating the role of high blood sugar in gut dysbiosis.

Could Hyperglycemia Impair All Mucosal Barriers?

This study also opens questions for the impact of blood sugar regulation on other mucosal barriers, such as the oral cavity, lungs, and skin. The authors write:

The impact of hyperglycemia on epithelial barrier function might be relevant beyond the gastrointestinal tract and affect other mucosal surfaces, such as the respiratory tract, as was indicated by a recent study of close to 70,000 diabetes patients highlighting a positive correlation between HbA1c values and a variety of mucosal community and hospital acquired infections.” (2)

Glucose uptake from circulation occurs in a wide range of mucosal tissues, so it’s possible that the same mechanisms are at play at all mucosal barriers.

Which Comes First, the Leaky Gut or the Hyperglycemia?

But wait, doesn’t leaky gut itself also contribute to inflammation, which can cause insulin resistance and metabolic syndrome? Absolutely. In 2007, a seminal paper by Cani et al. showed that continuous infusion of the microbial toxin LPS was sufficient to cause hyperglycemia, insulin resistance, and weight gain (5).

So, which comes first, the chicken or the egg? The honest answer is that we still don’t know. It’s possible that a gut infection, exposure to environmental toxins, or immunogenic foods could initiate the first breach of the gut barrier, allowing for bacterial translocation and LPS-induced hyperglycemia. However, chronically high carbohydrate intake and a predisposition to high blood sugar could also initiate the first barrier breach, which would then allow bacterial translocation to cause further metabolic damage.

Regardless of which comes first, it’s abundantly clear that we need to treat the gut and metabolic health simultaneously in order to break this vicious cycle. If we focus solely on trying to heal the gut while allowing blood sugar to run up to 200 mg/dL, we’re going to be constantly fighting against glucose-driven mechanisms that are trying to break the barrier down. Similarly, any strategy to improve blood glucose control and insulin sensitivity should include a comprehensive gut analysis and seek to remove dietary and other environmental irritants of the gut barrier.

What Does This Mean in Practice?

Hopefully you stuck with me through all of the details. The data I’ve discussed here offers a key missing piece to our understanding of how to improve and maintain gut health. Here’s a summary of the key takeaways and how you might integrate these findings into your practice:

1. Blood sugar regulation is critical for restoring and maintaining gut barrier integrity. Achieving normal blood glucose levels with insulin therapy appeared to ameliorate all of the harmful effects on the gut, at least in mice. If this holds true in humans, type 1 diabetics should not be shy about using insulin to tightly regulate blood glucose levels, particularly when trying to heal a gut issue. Additionally, both type 1 and type 2 diabetics would likely benefit from a low-carb, low-glycemic-load diet, which has been reported to improve blood sugar control (6).
2. Blood sugar regulation should be considered when treating gut infections. While the exact mechanism remains unknown, this study suggests that hyperglycemia downregulates host defenses and increases the adherence of pathogens to the gut epithelium. Improving glycemic control may therefore be a key part of supporting the gut immune system during and after treatment for gut infections.
3. Dietary glucose may be just as bad as high blood glucose for gut health. Although this study focused on high circulating blood glucose, it’s likely that high dietary glucose can also cause gut permeability and susceptibility to infection 
4. Dietary fat may have been wrongly blamed for gut permeability. Countless animal studies have suggested that feeding mice a “high-fat diet” results in increased gut permeability, yet the high-fat diet used in these studies is also loaded with sugars and refined carbohydrates that—no surprise—result in chronically elevated blood sugar. I’d love to see a study that assesses the effects of a whole-food based, low-carb, high-fat diet on gut permeability.