Gut Dysbiosis in Diabetes

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Diabetes has become a global health epidemic, affecting more than 400 million people worldwide (1). The adoption of a Western lifestyle, consumption of processed foods, lack of physical activity, and urbanization have all contributed to the rise in diabetes, but recent research also reveals a strong correlation between diminished gut health and the onset of diabetes.

A myriad of lifestyle factors can lead to dysfunction in the gut microbiome of the human gastrointestinal tract, but intestinal hyperpermeability, or leaky gut, may be the most detrimental for overall health. In fact, researchers suggest that leaky gut may be the underlying pathogenesis of several chronic conditions, including diabetes and obesity (2).

The intestinal lining is tightly stitched together by tight junctions and coated in a thick layer of mucus to keep unwanted toxins and pathogens out of the bloodstream, where they could trigger an inflammatory immune response.

However, studies have found that high-fat diets, chronic hyperglycemia, stress, and other factors can cause these tight junctions to malfunction and the mucosal barrier to deteriorate, creating gaps in the intestinal lining that can allow inflammatory toxins and pathogens into circulation (3).

Researchers have discovered that lipopolysaccharide, or LPS, is a key endotoxin that triggers the low-grade inflammation that breeds many chronic diseases, including diabetes. LPS is a component of the cell membrane of gram-negative bacteria that naturally inhabit the gut microbiome. And while LPS is generally harmless inside the intestinal lumen, it is known to initiate a cascade of inflammatory events when released into the bloodstream.

Hypothalamic Dysfunction

In the hypothalamus, this inflammatory cascade can lead to leptin and insulin resistance by blocking the PI3K pathway responsible for appetite suppression. Studies performed on rats have shown that high-fat diets delivered to subjects for 4 weeks increased circulating levels of LPS, which increased fasting glucose, insulin, and total weight gain (4).

This has led researchers to conclude that chronic exposure to LPS can actually induce diabetes (4). In a human study from the Journal of Molecular and Cellular Biochemistry, researchers discovered that LPS activity is significantly higher in type II diabetic patients than healthy individuals with normal glucose levels (5).

Furthermore,  LPS exposure appeared to increase fasting glucose, 2-hr postprandial glucose, HbA1c, triglycerides, and inflammatory biomarkers TNF-α and IL-6.  These findings support the notion that leaky gut may be the initial insult that ultimately leads to insulin resistance and diabetes.

Most interestingly, LPS has also been shown to severely impact the hypothalamus prior to diagnosis, suggesting that diabetes might actually be a disease that originates in the brain. A recent study published in the International Journal of Molecular Sciences found that LPS-induced inflammation of the hypothalamus could trigger leptin and insulin resistance irrespective of body weight changes through the expression of the JNK cascade (6).

Pancreatic Dysfunction

In addition to hypothalamic dysfunction, LPS has also been shown to cause pancreatic dysfunction. The inflammatory cascade triggered by LPS involves the expression of cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) that not only induce inflammation but also destroy the beta cells of the pancreas (6-7).

The beta cells of pancreatic islets are responsible for insulin secretion, which makes their destruction an important step in the pathogenesis of diabetes. Studies performed in human subjects have shown that both TNF-α and IL-1β, in combination or separately, can destroy these insulin-secreting beta cells (7).

IL-1β, for example, causes an excessive production of nitric oxide (NO) in beta cells, which interferes with electron transport, inhibits mitochondrial ATP synthesis, and induces the expression of pro-inflammatory genes (7).

TNF-α, on the other hand, induces apoptosis in insulin-secreting beta cells through the inhibition of caspase activation (7). In either case, these inflammatory cytokines lead to dysfunction of pancreatic beta cells resulting in reduced insulin secretion and increased insulin resistance.

Butyrate and Insulin

Short-chain fatty acids (SCFAs), like butyrate, are normally responsible for regulating the expression of inflammatory cytokines in the intestines. Butyrate can regulate the production of TNF-α by reducing the activity of histone deacetylase (HDAC), an enzyme that promotes the expression of TNF-α in the gut (8). In this way, butyrate has a strong anti-inflammatory effect in the intestines.

In a healthy gut, butyrate comes from butyrate-producing bacteria, like Bifidobacteria and Faecalibacterium prausnitzii. When these bacteria die, from antibiotics or high fat diets, the availability of butyrate in the gut is limited. Not surprisingly, patients with type II diabetes appear to have much lower concentrations of butyrate-producing bacteria like Roseburia intestinalis and F. prausnitzii (9).

Furthermore, studies have shown that supplementation with butyrate can prevent and treat diet-induced insulin resistance (10). Interestingly, this is the mechanism of action behind drugs like metformin, which is commonly used to promote insulin sensitivity. However, metformin also causes many unwanted side effects like muscle pain, weakness, nausea, vomiting, chills, constipation, and upper respiratory infections.

For this reason, increasing populations of butyrate-producing bacteria in the gut, like F. prausnitzii, could be a more effective solution for insulin resistance.

Conclusion

Although F. prausnitzii is impossible to take as a supplement, due to its anaerobic nature, patients can increase their populations of this protective bacteria with Bacillus spores and selective prebiotics.

Bacillus spores have been shown to increase F. prausnitzii populations in the gut by 40%, and Precision Prebiotics like fructooligosaccharides (FOS) have been shown to increase F. prausnitzii by 100% in as little as 4 weeks (11).

Another clinical trial published in the World Journal of Gastrointestinal Pathophysiology found that Bacillus spores in a multi-spore commercial probiotic could reduce serum LPS, IL-1β, and TNF-α levels in as little as 30 days (12).

Due to these encouraging findings, the American Diabetes Association continues to study the connection between LPS and diabetes, suggesting that diabetes has outgrown its classification of being a purely metabolic disorder. Like heart disease, more and more research continues to suggest that diabetes starts with inflammation.

 

References

1. “Diabetes.” World Health Organization website. URL: http://www.who.int/news-room/fact-sheets/detail/diabetes.

2. Jayashree B, Bibin YS, Prabhu D, et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Molecular and Cellular Biochemistry. 2013;388(1-2):203-210. doi:10.1007/s11010-013-1911-4

3. Arrieta MC. Alterations in intestinal permeability. Gut. 2006;55(10): 1512-1520. doi:10.1136/gut.2005.085373

4. Cani PD, Amar J, Iglesias MA, et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. 2007;56(7):1761-1772. doi:10.2337/db06-1491

5. Montandon SA, Jornayvaz FR. Effects of Antidiabetic Drugs on Gut Microbiota Composition. Genes. 2017;8(10): 250. doi:10.3390/genes8100250

6. Rorato R, Borges BD, Uchoa ET, et al. LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes. International Journal of Molecular Sciences. 2017;18(7): 1431. doi:10.3390/ijms18071431

7. Wang C, Guan Y and Yang J. Cytokines in the Progression of Pancreatic β-Cell Dysfunction. International Journal of Endocrinology. 2010;1-10. doi:10.1155/2010/515136

8. Vinolo MAR, Rodrigues HG, Nachbar RT, and Curi R. Regulation of Inflammation by Short Chain Fatty Acids. Nutrients. 2011; 3(10): 858–876.

9. Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut. 2014;63(9):1513-21.

10. Gao Z, Yin J, Zhang J, et al. Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes. 2009;58(7): 1509-1517. doi:10.2337/db08-1637

11. Blatchford P, Stoklosinski H, Eady S, et al. Consumption of kiwifruit capsules increases Faecalibacterium prausnitzii abundance in functionally constipated individuals: a randomised controlled human trial. J Nutr Sci. 2017; 6: e52.

12. McFarlin BK, Henning AL, Carbajal KM. Oral spore-based probiotic supplementation was associated with reduced incidence of post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers. World J Gastrointest Pathophysiol. 2017 Aug 15; 8(3): 117–126.

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