The Human Genome Project is one of the most impressive exploration achievements in human history. And yet it did not involve travel to distant territories. Instead it was an inward quest to map out all of the genes of the human species. The project began on October 1, 1990 and was completed in April 2003. One of its biggest surprises was that the human genome contains only 20,000 to 25,000 genes in its entirety, an astonishingly smaller number than researchers had expected to find (1). In the ensuing search for the missing pieces of genetic material that simply had to exist to account for all the intricacies of human function, a new task emerged. This was the investigation of the human microbiome, the collective genome of all the microbes that live in and on the human body. In 2007, the National Institutes of Health (NIH) launched the Human Microbiome Project, opening another vast treasure chest of previously unknown truths about the complex ties between human beings and the microscopic organisms with which we coexist. Since then, intense scrutiny of the human microbiome has unearthed a succession of revelations for human health. The first was the discovery that there are likely more than 8 million unique microbial genes making up the microbiomes of humans, suggesting that the genetic contribution stemming from the microbiome is many hundreds of times greater than the genetic contribution of the human genome itself. In the ensuing years we have learned that the microbiome of the gut plays fundamentally essential roles in digestion, nutrition, immune regulation, and metabolism. One of the more important contributions of the microbiome to human beings may be its powerful effects on the metabolism of glucose and, specifically, on the disease known as type-2 diabetes (2).
What is type-2 diabetes?
Type-2 diabetes is a chronic disease whose incidence is steadily increasing worldwide. Development of type-2 diabetes is a continuous process, beginning with prediabetes, when blood glucose levels are higher than normal but not high enough to be considered diabetes, and continuing with gradually rising blood sugar levels due to increasing insulin resistance and decreasing insulin production by the pancreas (3). Type-2 diabetes is a disease of glucose metabolism that inflicts widespread damage in many areas of the body, compromising both life span and health span. Any new knowledge that can be gathered to bring us closer to understanding the ways that this disease attacks the human body, and how we in turn react to its course, could set us on the path towards new therapies to add to our present woefully inadequate arsenal of diabetes medications. Sadly, despite treatment, type-2 diabetes is still poorly controlled in the majority of patients (4).
NOTE: Insulin resistance is the inability of body cells to communicate with the hormone insulin, leaving glucose particles, the preferred fuel for the human body, unable to enter cells. Glucose then accumulates in the bloodstream resulting in ever-increasing blood sugar levels. Higher fat levels in the blood, either from a high fat diet or obesity, is the root cause of insulin resistance because the fat interferes with the communication between insulin and cells.
Insulin sensitivity is the other side of the same coin. It describes how sensitive the body is to the effects of insulin. When insulin sensitivity increases, smaller amounts of insulin are needed for glucose to enter the cells (5,6,7).
What factors exert an influence on the development of type-2 diabetes?
Human genetics appear to contribute very little to the development of type-2 diabetes. On the other hand, socioeconomic and environmental factors seem to have much more influence. Recent evidence has illustrated a close link between metabolic diseases (including obesity, diabetes and cardiovascular disease) and alterations of the gut microbiome content and activity, suggesting that the gut microbiota may be an important environmental factor in these challenging health conditions. Results of a European trial from 2013 showed that the composition and function of the gut microbiome alters in participants as their body’s ability to deal with glucose transforms from normal, through impaired (insulin resistance and prediabetes) to severely impaired (type-2 diabetes). The microbiome deviations observed were so consistent that researchers were able to develop a mathematical model that could predict the onset of type-2 diabetes with high accuracy by defining the microbe mix making up a particular gut microbiome and incorporating abnormalities in its function (8).
Research illustrating links between the gut microbiome and type-2 diabetes
A 2018 Danish study showed that the populations of certain species of gut microbes were altered in individuals with prediabetes compared to those with normal glucose regulation. Specifically, there was decreased abundance of several bacteria types capable of producing the health-promoting short-chain fatty acid, butyrate. This suggests that gut microbial modifications may be a signature of diabetes that could be used to identify individuals most likely to develop type-2 diabetes (3).
In July 2020, an investigation in Sweden looked into the microbiomes inhabiting the intestinal tract of people with prediabetes and type-2 diabetes. This study also noted that overall gut microbiota characteristics shift as glycemic status changes. In individuals with prediabetes (impaired glucose tolerance along with high blood sugar levels) or full-blown type-2 diabetes, the gut microbiome composition showed significant irregularities; if elevated fasting blood glucose was the only symptom present, no fluctuations in gut microbiome features were detected. In addition, the population of healthful, butyrate-producing microbes in the gut progressively decreased as the severity of illness progressed from prediabetes to overt diabetes. Analysis of the results revealed that insulin resistance is strongly associated with variations in the gut microbiome. Researchers proposed that gut microbiota may represent an important modifiable factor to consider in the prevention and treatment of type-2 diabetes (9).
These studies and other similar ones looking into the relationship between microbiomes and diabetes all point to a strong link between glucose metabolism status and gut microbiome quality. A question remains though. What came first in these situations? Are the microbiome changes the cause of metabolic problems or the result of the microbiome responding to disease?
Fecal transplant studies shed some light on this conundrum. A fecal transplant involves placing the stool of a healthy person into the colon of someone who is not healthy. Investigations contributing to the Human Microbiome Project found that a fecal transplant from a lean donor placed into someone with metabolic syndrome (a constellation of symptoms including three or more of the following – increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels (20)) results in higher insulin sensitivity in the recipient six weeks later. Additionally, levels of butyrate-producing intestinal bacteria (“beneficial” microbes) also rose. Alas, these health improvements are temporary and, by nine weeks after the fecal transplant, they had disappeared and the microbiomes of all the participants had returned to their original states (10,11).
A randomized study from 2018 added more information. Researchers began by identifying a group of bacteria that could create acetate and butyrate, short-chain fatty acids (SCFAs) that confer a myriad of health-giving effects on the human body. Their trials showed that the production of these fatty acids is intensified if higher quantities of fermentable carbohydrates (fiber) are made available to these bacteria. When the study subjects consumed extra fiber, the population of beneficial bacteria increased in both abundance and diversity and levels of hemoglobin A1c, a marker of blood sugar control, improved as well. Moreover, the formation of detrimental metabolites by other gut microbes was diminished. The conclusion of this study stated that chronic diseases such as type-2 diabetes may be a consequence of the loss of, or deficiency of, an advantageous function such as SCFA production from carbohydrate fermentation in the gut ecosystem (12).
February 2020 brought another interesting study on health-giving metabolites produced by bacteria living in the intestines. Researchers at McGill University in Montreal, Kyoto University in Japan and INSERM/University of Paris collaborated to uncover which gut bacterial metabolites might help those with either type-1 or type-2 diabetes. They discovered a metabolite called 4-cresol that appears to be a marker of lower risk of diabetes. Though 4-cresol is toxic in higher doses, this animal study revealed that low doses of 4-cresol increased proliferation of pancreatic beta cells, the cells that secrete insulin, and improved glycemic control while reducing obesity. 4-cresol is produced by a number of gut bacterial species. Both the presence of these species and concentrations of 4-cresol in the blood have been found to be lower in diabetics than in non-diabetics. The scientists performing this study found these results encouraging. There is currently a lack of therapies that stimulate pancreatic beta cell proliferation and improve beta cell function enough to restore insulin secretion. Researchers intend to further investigate 4-cresol and other bacterial metabolites that may be directly associated with the development of specific diseases and/or helpful in their therapy (13).
It appears that a strong case can be made that changes in the gut microbiome might indeed be the instigators of variations in glucose metabolism and not simply a reaction to a disease state.
Mechanisms for the health-promoting effects of the gut microbiome on glucose control
Studies of fecal transplants and beneficial bacterial metabolites illustrate a possible direct causative effect of a healthy microbiome on improved host glucose metabolism and insulin sensitivity. Research is beginning to uncover possible mechanisms for these favourable effects. Here are some of them;
Incretin Hormone Regulation:
Incretin hormones (mainly glucagon-like peptide-1 (GLP-1)) stimulate insulin secretion from beta cells of the pancreas in response to nutrient intake. Incretin secretion is markedly impaired in individuals with obesity and just prior to the onset of type-2 diabetes. In fact, low GLP-1 secretion may be a warning of impending diabetes. Some gut bacteria directly regulate incretin secretion through the metabolic compounds they produce. Higher blood GLP-1 levels have been linked to the fermentation of fiber by microbes living in the colon and also to improved glucose tolerance and insulin response. (4).
Short-chain Fatty Acid (SCFA) Production:
SCFAs, mainly butyrate, propionate and acetate, are produced in the colon through fermentation of fiber by certain species of gut bacteria. SCFAs are the preferred energy source for the cells lining the intestine and contribute to many biological pathways including glucose control and decreased insulin resistance. SCFAs also stimulate the secretion of gut hormones such as GLP-1. Deficiency in SCFAs has been directly associated with the development of obesity, insulin resistance and diabetes (4).
A main determinant of the species makeup of a gut microbiota is diet. Higher intake of dietary fiber is associated with greater SCFA production, lower inflammation and a healthy intestinal barrier. Conversely, higher intake of dietary fat is associated with a reduction in SCFA production and an increase in the release of pro-inflammatory molecules which not only raise inflammation levels directly, but also promote inflammation by increasing the permeability of the intestinal membrane, allowing toxic substances to pass from the intestine into the blood stream (14,4).
Bile Acid Metabolism:
The basic functions of bile acids are in the digestion and absorption of lipids and fat-soluble vitamins. More recently it has been realized that gut microbes also play key roles in the synthesis of bile acids and, in turn, bile acids act as signalling molecules that help to regulate gut microbiota with substantial effects on obesity and type-2 diabetes. Furthermore, enzymes produced by microbes in the gut help in the formation of secondary bile acids which are active in efficient glucose metabolism (4).
Adipose tissue regulation:
Adipose (fat) tissues are no longer considered to be simply storage areas for fats. In fact, they are an active organ of the body with critical roles in metabolism. Adipose tissue does store excess fats, but it also regulates the supply of fat as fuel to body tissues. During these processes, inflammation is created. With overeating, the need for continuous storage of surplus fats results in chronic low-grade inflammation in the adipose tissue and facilitates the development of obesity, insulin resistance, high blood glucose levels and type-2 diabetes (4).
A healthy gut microbiome reduces inflammation in a variety of ways. Its production of SCFAs and its promotion of a healthy gut lining that prevents bacteria and toxins from reaching the rest of the body through the bloodstream, directly lower inflammation (4). Additionally, anthocyanins (phytochemicals in the flavonoid family), which are an integral part of the commonly consumed whole foods that also supply fiber, are also metabolized by gut bacteria and selectively stimulate growth of species of beneficial bacteria that have been shown to reduce obesity-associated inflammation. Foods that contain both fermentable fiber and anthocyanins include fruits such as apples, cherries and grapes; and vegetables such as red cabbage, black beans and red onions (15).
It is becoming increasingly clear that the microorganisms living in our guts have a complex and wide-ranging effect on many biological processes necessary for the health of their human host and, in addition, on the development and progression of certain diseases in the host. Indeed, an imbalance in the number and diversity of the species making up the gut microflora is linked to impairment of glycemic control and the development of type-2 diabetes (16).
The precise role of the gut microbiome in glucose metabolism is still not completely understood. However, diet is known to be a strong driver of high diversity in and healthiness of the microbiome. It is also recognized that microbes residing in the gastrointestinal tract depend on the food that their host consumes for their own sustenance. It is anticipated that, as the mechanisms available to the gut microbiome for influencing glucose control in diabetes become better understood, we will ascertain how best to use prebiotic foods (fibers from plant-based foods that act like fertilizers to stimulate the growth of healthy bacteria in the gut) and probiotics (live microorganisms that directly add to the population of healthy microbes in the gut) to aid in the fight against metabolic diseases such as type-2 diabetes (4).
Fecal transplants have shown promise in improving the health of gut microbiomes. However, their positive changes are transient and gradually disappear, with the treated microbiome eventually reverting back to its pre-transplant condition. Surprisingly, despite the influence of food choices on the state of the gut microbiome, the majority of fecal transplant studies published to date have not included any analysis of the diet being eaten by the participants. This area is in urgent need of further study. We know that a healthy diet high in fiber encourages a healthy gut microbiome. Can such a diet also support the long-term colonization of healthful species in the gut supplied through fecal transplantation? (17,18)
While we wait for answers to such queries, there are lessons to be learned in what has been discovered up to now.
By re-establishing and fostering those microbe species in the gut that produce valuable metabolites such as SCFAs, a healthier gut microbiome can be restored. Research has illustrated that adding fiber to a diet results in rapid microbiome alterations, with healthy effects showing up as soon as 24 hours after the fiber has reached the colon (19). Flourishing beneficial bacteria can also out-compete other potentially harmful microorganisms. Diseases like type-2 diabetes, that have already shown their sensitivity to the composition of the gut microbiome, are highly likely to be benefitted in this situation, perhaps even to the point of disease prevention and/or alleviation (12).
It is easy enough to increase the intake of the high fiber foods that supply a variety of fermentable fibers to the lower gut where they encourage healthy gut inhabitants to thrive. To this end, simply eat a variety of the following foods every day.
Whole grains, especially oats, barley and bran
Vegetables including legumes (chickpeas, lentils and all types of beans), cruciferous vegetables (broccoli, cauliflower, cabbage, arugula, kale, Brussels sprouts), root vegetables, onions and garlic
Fruits including apples, citrus fruits and bananas, especially bananas that are not quite ripe
Nuts including almonds and pistachios
Seeds such as flaxseed
At the present rate of gut microbiome research, nutrition may soon become recognized as a new and successful approach for manipulating the gut microbiota to manage diseases related to imbalanced gut microbiomes such as type-2 diabetes (18).
3 Allin, K.H., Tremaroli, V., Caesar, R., Jensen, B.A.H., Damgaard, M.T.F., Bahl, M.I., et al. Aberrant intestinal microbiota in individuals with prediabetes. Diabetologia. 2018; 61:810–820.Doi:10.1007/s00125-018-4550-1.
4 Gérard, C., Vidal, H. Impact of Gut Microbiota on Host Glycemic Control. Front. Endocrinol. 30 January 2019. Doi.org/10.3389/fendo.2019.00029.
5 Sears, B., Perry, M. The Role of Fatty Acids in Insulin Resistance. Lipids Health Dis. 2015; 14: 121.
6 Taylor, R. Banting Memorial lecture 2012: Reversing the twin cycles of type 2 diabetes. Diabet Med. 2013 Mar; 30(3):267-75.
7 Martins, A.R., Nachbar, R.T., Gorjao, R., Vinolo, M.A. et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: important of mitochondrial function. Lipids Health Dis. 2012 Feb; 11:30.
8 Karlsson, F.H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C.J., Fagerberg, B., Nielsen, J., Bäckhed, F. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013 Jun 6; 498(7452): 99-103. Doi: 10.1038/nature12198.
9 Wu, J., Tremaroli, V., Schmidt, C., Perkins, R., Bergström, G., Bäckhed, F. The Gut Microbiota in Prediabetes and Diabetes: A Population-Based Cross-Sectional Study. Cell Metabolism. July 10, 2020; Doi.org/10.1016/j.cmet.2020.06.011.
10 Vrieze, A., Van Nood, E., Holleman, F., Salojärvi, J., Kootte, R.S., Bartelsman, J.F., Dallinga-Thie, G.M. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct; 143(4): 913-6.e7. Doi: 10.1053/j.gastro.2012.06.031.
11 Kootte, R.S., Levin, E., Salojärvi, J., Smits, L.P., Hartstra, A.V., Udayappan, S.D., Hermes, G. et al. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell Metab. 2017 Oct 3; 26(4):611-619.e6. Doi:10.1016/j.cmet.2017.09.008.
12 Zhao, L., Zhang, F., Ding, X., Wu, G., Lam, Y.Y., Wang, X., et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 09 Mar 2018; 359(6380): 1151-1156. DOI: 10.1126/science.aao5774.
13 Brial, F., Alzaid, F., Sonomura, K., Matsuda, F., Zalloua, P., Gauguier, D. et al. The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function. Cell Report. February 18, 2020; 30(7): 2306-2320. Doi:https://doi.org/10.1016/j.celrep.2020.01.066.
14 Puddu, A., Sanguineti, R., Montecucco, F., Viviani, G.L. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm. 2014; 2014: 162021. Doi: 10.1155/2014/162021.
15 Jayarathne, S., Stull, A.J., Park, O.-H., Kim, J.H., Thompson, L., Moustaid-Moussa, N. Protective Effects of Anthocyanins in Obesity-Associated Inflammation and Changes in Gut Microbiome. Mol. Nutr. Food Res. 2019: 1900149-1900167.
16 Sharma, S., Tripathi, P. Gut microbiome and type 2 diabetes: where we are and where to go? J Nutr Biochem. 2019 Jan; 63:101-108. doi: 10.1016/j.jnutbio.2018.10.003.
17 Aron-Wisnewsky, J., Clément, K. & Nieuwdorp, M. Fecal Microbiota Transplantation: a Future Therapeutic Option for Obesity/Diabetes? Curr Diab Rep; 19: 51 (2019). Doi.org/10.1007/s11892-019-1180-z.
18 Johnson, A.J., Zheng, J.J., Kang, J.W., Saboe, A., Knights, D., Zivkovic, A.M. A Guide to Diet-Microbiome Study Design. Front. Nutr. 12 June 2020: Doi.org/10.3389/fnut.2020.00079.
19 Makki, K., Deehan, E.C., Walter, J., Bäckhed, F. The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease. Cell Host & Microbe. 2018; 23(6): 705-715.