How diabetes is linked to gut bacteria

The majority of cells within our bodies are not human-nor is the majority of our DNA. We are hosts to 10¹⁴ bacterial cells (50 percent to 90 percent of all cells) that make up as much as 95 percent of our total DNA.¹ Most of these organisms live within the gastrointestinal (GI) tract but also within the genitourinary tract, on our skin, and on the ocular surface-forming what is collectively known as the “microbiome.”

Given this abundance of nonhuman species living on and within our bodies, it is not surprising that there is a link between specific bacteria to systemic and ocular disease-including diabetes and diabetes-related eye disease.

What studies tell us

A reduction in gut bacterial diversity precedes the onset of clinical diabetes.² Reduction of intestinal species that produce short-chain fatty acids (SCFAs), especially butyrate but also propionate and acetate, appears to be particularly important. These SCFAs improve insulin sensitivity by stimulating peroxisome-proliferator agonist gamma receptors³ (PPARg), analogous to the PPARg diabetes medication, pioglitazone (Actos, Takeda).

Previously from Dr. Chous: Using OCT with your diabetes patients

Butyrate enhances production of the intestinal hormone, glucagon-like peptide-1⁴ (GLP-1), which increases insulin production, decreases glucagon secretion, and inhibits appetite. The mechanism is analogous to GLP-1 analog drugs like exenatide (Byetta, Amylin) and liraglutide (Victoza, Novo Nordisk).

Butyrate also enhances intestinal barrier function, preventing translocation of bacteria and lipopolysaccharides derived from the cell walls of Gram-negative organisms (endotoxemia) that leads to so-called “leaky gut syndrome.” Leaky gut syndrome has been linked to autoimmunity in type 1 diabetes and inflammatory cytokine production in type 2 diabetes (T2DM).^5,6

Related: How diabetes affects contact lens wear

Introduction of butyrate-producing bacteria via probiotic supplementation has been shown to improve insulin sensitivity and reduce inflammation in humans with type 2 diabetes.⁷

Perhaps more convincingly, transplanting fecal material from healthy adults with markedly higher numbers of butyrate-producing bacteria to obese patients with T2DM and lower numbers of such bacteria resulted in nearly 80 percent better insulin sensitivity in one small study.⁸

Recent meta-analysis of 11 studies with more than 600 subjects shows that multi-species probiotic supplementation modestly but significantly improves insulin resistance, excess insulin production, fasting blood sugars, and mean blood glucose (HbA1c) in humans with T2DM.⁹

SFCAs play important role

Maintenance of butyrate-producing species has also been demonstrated with increased dietary fiber intake and use of prebiotic supplements containing the poorly digested fructose polymer, inulin, and related oligosaccharides that provide a food source for these beneficial bacteria.¹⁰

Interestingly, the widely prescribed diabetes medication, metformin (Glucophage, Bristol-Myers Squibb) as well as dietary fasting regimens have been shown to increase numbers of butyrate-producing bacterial species like Roseburia and Akermansia mucinophila.¹¹

SCFAs-especially butyrate-inhibit a variety of inflammatory proteins linked to diabetic retinopathy (DR), including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), tumor necrosis factor alpha (TNF-alpha) and high-sensitivity C-reactive protein (hsCRP),¹² suggesting that we might be able to lower the risk of eye disease by increasing numbers of butyrate-producing intestinal bacteria.

Related: What’s new for diabetes management and prevention

The best way to avoid DR is by preventing diabetes in the first place. Table 1 lists a few strategies aimed at manipulating the microbiome to reduce the risk of developing both diabetes and DR.

Reducing Staph bacteria key

In addition to fostering beneficial bacteria within the GI tract, another potential strategy may be to reduce Staph bacteria residing on the skin and perhaps even the conjunctiva.

One recent study showed that an exotoxin produced by S. aureus, toxic shock syndrome toxin 1 (TSST-1), causes insulin resistance and T2DM in an animal model. This raised the possibility of reducing Staphylococcal species via topical antiseptics in obese and/or hyperglycemic patients that often demonstrate hypercolonization of S. aureus.¹⁵

Related: Worldwide diabetes epidemic approaches half a billion

This could have potential impact on eye disease because T2DM patients have higher numbers of Gram-positive conjunctival bacteria, especially in those with proliferative retinopathy.¹⁶ Activation of T lymphocytes in the GI tract has been shown to cause autoimmune uveitis in lab animals, a phenomenon that is diminished by oral antibiotics.¹⁷ Autoimmunity has also been implicated in pericyte death in early diabetic retinopathy,¹⁸ suggesting that selective destruction of gut bacteria by antibiotics might also interfere with the pathogenesis of DR.

Our modern diet is characterized by excessive consumption of calories, highly refined carbohydrates, food additives-including antibiotics and pesticides, little plant food, and dietary fiber. These factors contribute to a sub-optimal microbiome that appears to play a role in auto-immunity, inflammation, glucose dysmetabolism, and diabetes. 

References

1. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, Elinav E. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014 Oct 9;514(7521):181-6.

2. Remely M, Hippe B, Geretschlaeger I, Stegmayer S, Hoefinger I, Haslberger A. Increased gut microbiota diversity and abundance of Faecalibacterium prausnitzii and Akkermansia after fasting: a pilot study. Wien Klin Wochenschr. 2015 May;127(9-10):394-8.

3. Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell. 2016 Jan 28;164(3):337-40.

4. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012 Sept 26;490,55-60.

5. Wang HB, Wang PY, Wang X, Wan YL, Liu YC. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci. 2012 Dec;57(12):3126-35.

6. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009 Jul;58(7):1509-17.

7. de Kort S, Keszthelyi D, Masclee AA. Leaky gut and diabetes mellitus: what is the link? Obes Rev. 2011 Jun;12(6):449-58.

8. Li X, Atkinson MA. The role for gut permeability in the pathogenesis of type 1 diabetes--a solid or leaky concept? Pediatr Diabetes. 2015 Nov;16(7):485-92.

9. Asemi Z, Zare Z, Shakeri H, Sabihi SS, Esmaillzadeh A. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab. 2013;63(1-2):1-9.

10. Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7.

11. Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: a meta-analysis of randomised placebo-controlled trials. Br J Nutr. 2016 Apr 14;115(7):1167-77.

12. Slavin J. Fiber and prebiotics: mechanisms and health benefits. Nutrients. 2013 Apr 22;5(4):1417-35.

13.  Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014 Oct;80(19):5935-43.

14. Tang J, Kern TS. Inflammation in diabetic retinopathy. Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site. Immunity. 2015 Aug 18;43(2):343-53.

18. Nayak RC, Agardh CD, Kwok MG, Stjernquist H, Farthing-Nayak PJ, Agardh E. Circulating anti-pericyte autoantibodies are present in Type 2 diabetic patients and are associated with non-proliferative retinopathy. Diabetologia. 2003 Apr;46(4):511-3.

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