Regulating Blood Glucose via the Gut Microbiome

Our bodies’ internal mechanisms maintain the balance between health and disease. Gut microbiota can help prevent and control blood sugar metabolism disorders by targeting multiple pathways in the intestine, liver, and pancreas. These pathways can tip the balance in favor of improved gut health, glycemic control, lipid profile, insulin resistance, and reduced inflammation.

There are about 10–100 trillion microbial cells in the human body, most of which are in the gut. Different gut microbiota can have disease-promoting or protective properties: Some microbiota-derived metabolites serve as vitamins or energy sources and have anti-inflammatory, antioxidant, pain relief, and gut barrier functions, while others, such as cytotoxins, genotoxins, and immunotoxins, are harmful.

In diseased states, there are changes in the mucosal, physical, and chemical barriers that separate the gut microbiome from the host. Such alterations can affect the relationship between the microbiome and blood sugar. For example, people with diabetes have dysbiosis, where the gut bacteria comprise more gram-negative bacteria and less beneficial bifidobacteria compared to healthy individuals. The dysbiosis increases lipopolysaccharides levels and gut permeability, resulting in mucosal inflammation, endotoxemia, systemic inflammation, insulin resistance, and poor glycemic control. These physiological changes increase the risk of metabolic syndrome, a condition characterized by a set of risk factors, including obesity, hyperglycemia, dyslipidemia, hypertension, and hyperuricemia, which increases the risk of cardiovascular and cerebrovascular disease.

In particular, established positive and negative relationships exist between different gut bacteria and type 2 diabetes (T2D). Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia, and Roseburia are all bacteria negatively associated with T2D, whereas Ruminococcus, Fusobacterium, and Blautia are positively associated with T2D.

Manipulating the gut microbiome to influence blood glucose

Prebiotics

Various dietary compounds with bioactive components can influence the composition of gut microbiota and the production of gut metabolites, even inhibiting the production of dangerous compounds, such as lipopolysaccharides, also known as endotoxins, which are involved in the development of diabetes.

Beneficial gut bacteria consume prebiotics, which are substances from certain carbs (mostly fiber) that humans can't digest. Beta-glucan, a prebiotic, is a natural polysaccharide found in plant and fungal cell walls, oats and wheat, in baker's yeast, and some microorganisms. Beta-glucan stimulates the growth and activity of natural intestinal microbiota while inhibiting pathogen growth. Hence, in addition to antioxidant and immunostimulatory and anti-tumor effects, ingesting beta-glucan can help reduce cholesterol and blood glucose.

In a 2019 study, children with type 1 diabetes who received a three-month dose of prebiotics (oligofructose-enriched inulin) had higher levels of beneficial gut bifidobacteria, improved intestinal permeability, and an increase in C-peptide, when compared to children who received the placebo. Because C-peptide is produced by the pancreas in equal amounts to insulin, it is used as a measure of insulin levels. Thus, the higher C-peptide levels in those who received prebiotics show that this type of treatment can help improve blood glucose levels. 

Probiotics

Probiotics are live bacteria found in certain foods or supplements that can help promote the ideal balance between harmful and beneficial bacteria.   

A complex interplay of factors beyond diet and exercise lead to obesity. High-fat diets lead to poor microbiome health and, in turn, dysbiosis. Obesity management in clinical practice includes manipulating the gut microbiota via dietary changes, supplements containing prebiotics and probiotics, and even fecal microbiota transplants from healthy individuals. In a recent study, obese individuals who received a two-week dose of Bifidobacterium had an increase in beneficial gut bacteria and a decrease in pathogenic and opportunistic gut bacteria, resulting in lowered total blood sugar. Likewise, in a 2020 study published in Scientific Reports, obese individuals who received a six-month dose of Lab4P probiotic had notable decreases in weight and improvements in lipid profiles, quality of life, and incidence of upper respiratory tract infections.

Similarly, animals who received different Lactobacillus and Bifidobacterium had decreased weight gain and decreased fat tissue mass in specific locations compared to controls. These bacteria also had antiatherogenic and anti-inflammatory effects.

Nevertheless, probiotics act via microbe-associated molecular patterns whose chemical structure varies among strains, which may explain part of their strain specificity. Furthermore, changes in individual metabolic, genetic, and lifestyle factors also influence the gut ecosystem. For example, among identical twins, researchers have found a large interindividual variability in responses of blood triglyceride, glucose, and insulin levels following identical meals.

Using the microbiome as a predictive tool

Researchers are in the process of validating which microbes and microbial genes/pathways directly impact host physiological processes in order to preempt, and potentially prevent, the development of T2D.

In T2D, there is usually a long prediabetic state characterized by changes in different metabolic parameters. In routine clinical practice, regular monitoring of glycated hemoglobin levels (HBA1c) and insulin are used in the prediabetic state to assess the likelihood of developing T2D. In one study, researchers found that adding metabolomics and sequencing data of the gut microbiome from stool samples from 608 men with T2D to the usual HBA1c and insulin data used in a predictive model, increased the model’s accuracy in predicting the development of T2D in the short term (1.5 years) and the long term (4 years). 

In the prediabetic state, clinicians can develop personalized diets based on known associations between microbiome composition and clinical markers. A recent cross-sectional study of 3,400 people published in Nature Communications found that 40 different clinical markers were negatively associated with microbial diversity, including weight, blood pressure, HBA1c, and body mass index (BMI), while those positively associated with microbial diversity included height, exercise, and eating raw salads and cruciferous vegetables. These results demonstrate the potential of using dietary interventions to influence the microbiome and improve health.

Improving understanding and control of the gut microbiome

In both healthy and diseased states, prebiotics and interventions to alter the relationship between microbiota and glycemic control offer a potential therapeutic option for metabolic interventions to improve health and prevent chronic non-communicable diseases and cancer. Manipulating gut microbiota can prevent and treat obesity in the long term with minimal side effects.

However, it can be difficult to achieve a particular health outcome using probiotics due to strain-specific responses to diet and interactions with the host’s genetic background. Further research into how glucose metabolism promotes different mutualistic, commensal, and parasitic relationships within the gut microbiome is needed as a way to support glucose control in diabetes, as well as to help manage enteric bacterial infections, which are more likely to occur in people with diabetes. Thus, before prebiotics and probiotics can be used to control glucose metabolism, more research is needed to investigate the mechanisms underlying the microbiome's hormonal, immunomodulatory, and metabolic effects.