A team of researchers affiliated with multiple institutions in China has found that the makeup of the gut microbiome can be a determiner for the efficacy of exercise with prediabetics.
In their paper published in the journal Cell Metabolism, the group describes their study of prediabetic volunteers and exercise and what they found.
In the medical community, type 2 diabetes is considered to be preventable in most people – all it takes is a change in diet and an increase in exercise.
But things may not be as simple as that as the researchers with this new effort discovered – they found that exercise does not always lead to reductions in glucose metabolism.
The study by the team involved asking 29 male prediabetic volunteers to undergo glucose metabolism and gut microbe testing.
Then the group was divided into two – 20 volunteers were asked to undergo an exercise regimen for three months while the other 19 were asked to maintain their normal eating and exercise habits.
At the end of the three-month period, all of the volunteers once again underwent glucose and gut microbe metabolic testing.
The researchers report that only 70 percent of the volunteers who carried out the exercise regimen saw improvements in glucose metabolism and changes in sensitivity to insulin. None of those in the sedentary group saw any improvement.
The researchers also report that they found differences in the gut microbiomes between those who followed the exercise regimen – those who had reductions in glucose metabolism were also generating more short-chain fatty acids.
They were also doing a better job breaking down branched chain amino acids.
The researchers also transplanted fecal samples from the volunteers into obese test mice.
They found that those mice that received such samples from the volunteers who saw improvements in glucose metabolism developed better insulin resistance – none of the other mice saw any improvements.
The researchers suggest their experiment gives evidence of the gut microbiome playing a role in glucose metabolism and degree of sensitivity to insulin.
This, they further suggest, indicates fecal transplants may be a viable option for people who do not gain glucose metabolism benefits from exercise.
Obesity is a chronic, complex, and multifactorial disease representing the fifth leading cause of death in the world and accounting for almost 3.4 million deaths each year (1).
In adults, obesity is characterized by an excessive fat accumulation and is defined conventionally as a body mass index equal or higher than 30 kg/m2. Epidemiological studies indicate that more than 2.1 billion people are currently overweight or obese worldwide. If current trends continue, estimations show that 38% of the world’s adult population will be overweight and another 20% will be obese by the year 2030 (1, 2).
Obese state is associated with multiple severe comorbidities and complications (3). In the same way as obesity, the prevalence of diabetes has increased tremendously around the world and is becoming a leading cause of death in many countries.
The International Diabetes Federation (IDF) Diabetes Atlas, 8th Edition, 2017 highlights some alarming statistics: some 425 million people worldwide, or 8.8% of adults 20–79 years, are estimated to have diabetes. If these trends continue, the number of people 20–79 years with diabetes worldwide will reach 629 million by 2045 (4). Type 2 diabetes mellitus (T2DM) accounts for more than 90% of the cases. Approximately 5.0 million deaths worldwide were attributable to diabetes in 2017, which is equivalent to one death every 8 s (4).
Diabetes results in exceptional healthcare costs; it is estimated that more than 700 billion US dollars are spent yearly by people with diabetes, which corresponds to one for every eight dollars spent on healthcare (5, 6). Although diabetes mainly occurs in people aged over 40 years old, it is also becoming increasingly prevalent in younger age groups (7).
T2DM is diagnosed by the presence of elevated blood glucose levels (hyperglycemia), which is the hallmark of the disease. Hyperglycemia is due to concomitant insulin resistance and insufficient insulin secretion due to beta-cell function impairment over time, resulting in failure to control blood glucose levels.
Even if the precise mechanisms by which obesity leads to insulin resistance affecting skeletal muscle and liver, but also adipose tissue and brain, are not fully understood, epidemiological studies have established that T2DM is the result of complex gene-environment interactions. Excess caloric intake and reduced energy expenditure are important predictors of obesity and T2DM.
Recent experimental and clinical evidence suggests that another key endogenous factor may be considered as a critical host metabolism regulator: the gut microbiota. Although still debated, it is estimated that up to 100 trillion micro-organisms reside throughout our body and that the collective gene set of our gut microbes is about 150 times larger than our own human genome (8, 9).
Microbiota is now recognized as a real functional “organ” due to its immense impact on human health and has become the subject of intensive research over recent years. The vast majority of microbes reside in the intestinal tract, where they influence host physiology by playing fundamentally important roles in digestion, nutrition, immune regulation, and metabolism. Gut microbiota composition and activity can fluctuate over time and depend on different factors including genetics, sex, age, health status, and drug/antibiotic consumption (10).
Over the last decade, a large number of publications have reported a prominent role of microbiota in metabolic diseases. Notably, accumulated evidence suggests an association between a dysregulated gut microbiome and obesity, glycemic control impairment, and therefore T2DM pathophysiology (11, 12).
Obesity, Diabetes, and Dysbiosis
The preservation a normal and healthy gut microbiota plays a critical role in maintaining good health. Bacteroidetes and Firmicutes, including species of the Ruminococcus, Lactobacillus, and Clostridium genera, constitute over 90% of the known phylogenetic categories and dominate the healthy intestinal microbiota (13).
To a lesser extent, species belonging to other phyla such as Actinobacteria, Verrucomicrobia, and Fusobacteria are also present. Alterations of both composition and function of the microbiota, termed dysbiosis, are common features of several pathologies including metabolic diseases such as obesity and T2DM.
A number of preclinical and clinical studies have attempted to describe the differences between gut microbiota in obese compared to lean individuals and have reported that obesity condition is related to lower microbial diversity and taxon depletion (14, 15).
Early obesity-microbiota studies report that an increase of body weight is associated with a microbiota shift identified by a change in the Bacteroidetes/Firmicutes ratio with a larger proportion of Firmicutes and a decline in Bacteroidetes populations.
An increased ratio of Firmicutes to Bacteroidetes has also been described in a model of mice genetically predisposed to obesity (ob/ob), with a 50% reduction in the abundance of Bacteroidetes, and a proportional increase in Firmicutes compared to their lean siblings (16).
Importantly, controversial data have been reported in more recent studies. Schwiertz et al. observed opposite results and determined lower ratios of Firmicutes to Bacteroidetes in overweight human adults compared to lean controls (17). Also, in other studies, authors found no proof of the association between the proportion of Bacteroidetes and Firmicutes and human obesity (18, 19).
Some of the variability of results reported between studies might be due to differences in laboratory protocols, study design or different methodology used over time. Moreover, it is noteworthy to mention that the measure of the Bacteroidetes/Firmicutes ratio is a rough method to characterize the microbiota. More standardized and accurate procedures are needed to compare studies from different laboratories as well as a more taxonomically detailed description than phylum level changes (20).
Dysbiosis has been linked to important metabolic consequences and profound deregulations: a higher expression of microbial genes that encode enzymes related to carbohydrate metabolism and a tendency to an overgrowth of bacteria more efficient at extracting energy from food, inducing excessive fat accumulation (21).
Although T2DM is generally considered as an attribute to obesity, recent metagenomics approaches have helped define the specific composition of fecal microbiota in T2DM patients. Interestingly, some studies have correlated glycemic control impairment and insulin resistance to specific gut microbiota composition.
In 2012, deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals showed that patients with T2DM were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria, and an increase in various opportunistic pathogens (22). Later, Karlsson et al. used shotgun sequencing to characterize the fecal metagenome of 145 European women with normal, impaired or diabetic glucose control (20).
Authors highlighted compositional and functional modifications in the metagenomes of T2DM patients, and proposed a mathematical model based on metagenomics signatures that identified T2DM with high accuracy. However, they concluded that metagenomics predictive tools for T2DM should be specific for the age and geographical location of the populations studied (20).
Very recently, prediabetes state (defined as fasting plasma glucose of 6.1–7.0 mmol/l) has also been associated with aberrant gut microbiota profiles (23).
This case-control study including 134 Danish adults with prediabetes and 134 healthy individuals with normal glycemic control showed that the abundance of five bacterial genera and 36 operational taxonomic units (OTUs) were altered in individuals with prediabetes compared to those with normal glucose regulation. Notably, mucin-degrading bacterium Akkermansia muciniphila was found at lower abundance in microbiota of individuals with prediabetes (23). These findings suggest that gut microbial alterations may represent a disease signature and a potential tool to distinguish individuals presenting a precursor state of T2DM.
Collectively, these data clearly suggest that the composition/function of gut microbiota may contribute to host glycemic regulation and insulin sensitivity. Furthermore, antidiabetic drugs liraglutide and metformin have been recently shown to significantly lower body weight and improve glucose metabolism while modifying considerably the composition of gut microbiota (24, 25).
Notably, liraglutide decreased obesity-related microbial phenotypes and increased lean-related phenotypes (24). In a comparable approach, several preclinical and clinical studies highlighted that metformin modifies the intestinal microbiota composition by inducing the growth of several bacteria, such as Akkermansia muciniphila (26, 27). Moreover, fecal transfer to germ-free mice improved glucose homeostasis in recipients of samples from patients who received metformin (28).
These last data suggest that gut microbiota is involved in the beneficial glucose-lowering effects of antidiabetic agents and confirm that gut microbiota is a promising therapeutic target in T2DM and the glycemic control impairment context.
Importantly, since these antidiabetic drugs have a major impact on gut microbiota composition, they might partly explain inconsistent and conflicting results observed among studies investigating gut microbiota composition in obese and T2DM patients. This further highlights the necessity to design and compare standardized studies and to take into account the consumption of these drugs before establishing any causal relationships.
The main proposed molecular mechanisms by which the gut microbiota modulates and interferes with host glycemic control are discussed below and include: modulation of incretin secretion, short chain fatty acid production, bile acid transformation, and regulation of adipose tissue inflammation and function (summarized in Figure 1).
More information: Yan Liu et al. Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2019.11.001
Journal information:Cell Metabolism