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The microbiome constitutes the diverse ecosystems of bacteria, fungi, and viruses that live in and on our bodies. The region of the body most densely populated by microbes is the colon, which is home to over 100 trillion bacteria. Thus, there are over three times more bacteria in the colon than human cells in the entire body. However, these bacteria are not mere bystanders; they engage in extensive metabolic exchange with host cells and, in doing so, can directly alter their gene expression and cellular functions. Emerging research increasingly points to the significant roles of the gut microbiome in the etiology and progression of various diseases including both type 1 and type 2 diabetes.
Although both forms of diabetes manifest as an inability to effectively clear glucose from the circulation, their mechanisms of onset and progression differ.
Type 1 Diabetes: autoimmune-mediated attack on the insulin producing cells of the pancreas, leading to insulin insufficiency
Type 2 Diabetes: begins with insulin resistance in the skeletal muscle, which then progresses to insulin resistance in the liver; over time, the insulin-producing cells of the pancreas begin to die resulting in insulin insufficiency
Here, we will focus on type 2 diabetes, as the research in this area is more robust given its high prevalence in Western society.
Previously, the primary risk factors for the development of type 2 diabetes included:
Now, changes to the diversity of the gut microbiome and modulation of the levels of key species of bacteria therein are recognized as characteristic of patients with diabetes [1].
Within the more than 40 observational studies conducted in humans to assess the relationship between type 2 diabetes and the microbiome, a few genera popped out as being the most significantly altered in patients with type 2 diabetes relative to healthy controls [3]. Specifically, the following bacteria showed a negative association with type 2 diabetes, meaning that populations of these bacteria were diminished in the diabetic patients [3]:
Conversely, another set of bacteria showed a positive association with type 2 diabetes or, in other words, elevated levels were observed in diabetic patients [3]:
Among all of the bacteria assessed, Bacteroides and Bifidobacterium were the most commonly reported beneficial microbes among all of the studies [3]. Bifidobacterium appear to be the strongest correlate to protection against type 2 diabetes and, in animal studies, administration of a Bifidobacteria-based probiotic was shown to improve glucose tolerance [4, 5, 6].
With regards to Bacteroides, studies have also shown that levels of key species including B. intestinalis and B. vulgatus were depleted in diabetic patients [7], and the administration of Bacteroides-based probiotics was also able to improve glucose tolerance and insulin sensitivity in a mouse model of diabetes [8].
There are four primary mechanisms by which researchers believe certain bacteria may exert protective or causal effects in type 2 diabetes [3]:
1) Modulation of the inflammatory response
Type 2 diabetes is closely associated with increased levels of pro-inflammatory factors. When gut barrier integrity is compromised, lipopolysaccharide (LPS) —an endotoxin expressed by some microbes in the gut like E. coli—can leech into the bloodstream where it triggers systemic low-grade inflammation. Additionally, Fusobacterium nucleatum and Ruminococcus gnavus can stimulate the production of multiple inflammatory factors and contribute to the pathophysiology of other diseases of inflammation like colon cancer and inflammatory bowel disease (IBD) [3].
Conversely, several species of Lactobacillus have been shown to decrease levels of IL-8, C-reactive protein, IL-1β, and MCP-1, which are all factors indicative of an inflammatory response [3]. Meanwhile, studies suggest that Lactobacillus, Bacteroides, and Akkermansia are all able to decrease levels of the pro-inflammatory factor TNF-α [3]. Additionally, the short chain fatty acid (SCFA) butyrate—produced by bacteria including Roseburia and Faecalibacterium—is known to exert anti-inflammatory effects by modulating immune cell function [3].
2) Changes to Gut Permeability
Individuals with type 2 diabetes have higher levels of intestinal permeability compared to healthy controls. As a result, bacterial endotoxin can enter the circulation and create metabolic endotoxemia, which is a major cause of inflammation. Research in animal models suggests that B. vulgatus and B. doreican enhance the expression of the genes in colon cells that make up the tight junctions between cells. In doing so, gut permeability was reduced, leading to amelioration of endotoxemia in these models [9]. Akkermansia muciniphila has also been shown to enhance tight junctions and overall gut integrity. Meanwhile, butyrate can reduce gut permeability by altering colon cell gene expression. Thus, the butyrate-producing species indirectly support gut barrier integrity via this crucial SCFA.
3) Impact on Glucose Metabolism
The gut microbiome influences glucose metabolism and insulin sensitivity in the major metabolic organs: skeletal muscle, liver, and adipose tissue. Bacteria can affect glucose metabolism in multiple ways including:
Specifically, B. lactis has been shown to improve the ability of the glucose transporter GLUT4 to translocate (i.e. insert itself) into the cell membrane in response to insulin signaling; in other words, B. lactis improves insulin sensitivity [10]. L. gasseri BNR17 also appears to exert a similar beneficial effect on GLUT4 translocation [11]. Meanwhile, A. muciniphila and L. plantarum have the ability to inhibit the expression of an enzyme in the liver called Fmo3 and, as a result, helps to prevent hyperglycemia (i.e. elevated blood glucose levels) and hyperlipidemia (e.g. elevated blood lipids). L. casei has shown efficacy in reducing insulin resistance by increasing the expression of genes involved in glucose metabolism and insulin signaling [3], while another species of Lactobacillus, L. rhamnosus, has been shown to improve insulin sensitivity by boosting levels of the hormone adiponectin in fat tissue [12].
From the digestive standpoint, A. muciniphila and certain species of Lactobacilli produce molecules that act as alpha glucosidase inhibitors, thereby preventing the digestion of starches and other complex carbohydrates and reducing post-meal elevations in blood glucose levels.
4) Alterations in fatty acid oxidation and energy expenditure
By increasing energy expenditure, rates of fatty acid oxidation will increase accordingly to provide metabolic heat and energy needed to sustain the body. A. muciniphila, Bacteroides acidifaciens, and Lactobacillus gasseri, as well as the short chain fatty acids (i.e. acetate, propionate, and butyrate) produced by various bacteria have been implicated in promoting fatty acid oxidation within adipose tissue.
It is well-established that gut microbiome composition is highly dependent upon nutritional inputs, with major shifts in microbial communities occurring in as little as 24 hours [2]. The primary source of energy for the bacteria within the gut is carbohydrates, which include:
Dietary fiber intake is inversely related to type 2 diabetes incidence, meaning that higher dietary fiber consumption is associated with decreased risk of diabetes. The consumption of fibers and other indigestible carbohydrate molecules feed beneficial microbes within the gut including Bifidobacteria and Akkermansia.
Bifidobacteria break down substrates like resistant starches and polyphenols to form the metabolites lactate and acetate. Lactate is an organic acid, while acetate is one of the SCFAs. Both lactate and acetate subsequently feed other commensals in the gut including the butyrogenic (i.e. butyrate-producing) bacteria. In this way, bolstering Bifidobacteria populations via the consumption of indigestible carbohydrates can provide direct benefits through the production of acetate, as well as indirect benefits via boosting butyrate production.
Akkermansia, which live in the mucus lining of the gut, also consume polyphenols from brightly colored fruits and vegetables. Specifically, the pigment molecules present in red apple peels and cranberries are particularly effective at supporting levels of this important microbe. The primary food source for Akkermansia is the mucus layer itself. Indeed, Akkermansia feast on the carbohydrate decorations present on mucus protein. Doing so stimulates the mucus-producing cells within the gut to create more mucus. Thus, perhaps counterintuitively, consumption of mucus by Akkermansia results in fortification of the mucus layer, enhanced gut barrier integrity, and decreased gut permeability.
In addition to providing a food source for commensal microbes in the gut, fibers also delay gastric emptying. Specifically, soluble fibers increase the viscosity of gastric contents, reducing rates of digestion, which not only increases satiety but prevents large spikes in blood glucose levels.
Type 2 diabetes is a strikingly prevalent metabolic disease characterized by a combination of chronic low-grade inflammation, insulin resistance, and insulin insufficiency. The gut microbiome is now emerging as a major contributor to the onset and progression of this illness. There are four primary mechanisms by which researchers believe the microbiome can exert protective effects against the development of type 2 diabetes:
There are key microbes believed to confer these benefits including contributions by Akkermansia muciniphila, Faecalibacterium, Rosburia, and species of Bifidobacteria, Lactobacilli, and Bacteroides.
Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions. Follow Dr. Cowan on Instagram: @dralexisjazmyn
References
[1] Gowd V, Xie L, Zheng X, Chen W. Dietary fibers as emerging nutritional factors against diabetes: focus on the involvement of gut microbiota. Crit Rev Biotechnol. 2019 Jun;39(4):524-540. doi: 10.1080/07388551.2019.1576025. Epub 2019 Feb 27. PMID: 30810398.
[2] Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, Abrouk M, Farahnik B, Nakamura M, Zhu TH, Bhutani T, Liao W. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017 Apr 8;15(1):73. doi: 10.1186/s12967-017-1175-y. PMID: 28388917; PMCID: PMC5385025.
[3] Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, Shulzhenko N. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020 Jan;51:102590. doi: 10.1016/j.ebiom.2019.11.051. Epub 2020 Jan 3. PMID: 31901868; PMCID: PMC6948163.
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[6] Kikuchi K., Ben Othman M., Sakamoto K., Sterilized bifidobacteria suppressed fat accumulation and blood glucose level. Biochem Biophys Res Commun. 2018; 501: 1041-1047
[7] Wu X. et al. Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr Microbiol. 2010; 61: 69-78
[8] Yang J.Y. et al. Gut commensal bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol. 2017; 10: 104-116
[9] Yoshida N et al. Bacteroides vulgatus and bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation. 2018; 138: 2486-2498
[10] Kim S.H. et al. The anti-diabetic activity of bifidobacterium lactis HY8101 in vitro and in vivo. J Appl Microbiol. 2014; 117: 834-845
[11] Kang JH et al. Anti-obesity effect of lactobacillus gasseri BNR17 in high-sucrose diet-induced obese mice. PLoS ONE. 2013; 8: e54617
[12] Singh S. et al. Lactobacillus rhamnosus NCDC17 ameliorates type-2 diabetes by improving gut function, oxidative stress and inflammation in high-fat-diet fed and streptozotocintreated rats. Benef Microbes. 2017; 8: 243-255
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