If Hippocrates the father of modern medicine is to be believed, “All disease begins in the gut”. The gastrointestinal tract with its microbiota is a complex, open, and integrated ecosystem. It is widely accepted that healthy gut microbiota is essential for optimal health. Imbalance in the gut flora could lead to one being vulnerable to a large spectrum of infectious and non-communicable diseases, including diabetes and obesity. There is an urgent need to develop efficient strategies to prevent and treat metabolic disorders such as diabetes and obesity. In this article, we will look at the implications of gut microbiota in diabesity and review ways of achieving optimal metabolic conditions.

What is Gut Microbiota and Gut Microbiome?

The gut microbiota is a collective term for the microbial community in the gut, whereas the gut microbiome is defined as the full collection of genes in the gut microbiota. The intestinal microbiota is known to be associated with metabolic syndrome and related comorbidities. Associated diseases including obesity, T2D, and fatty liver disease (NAFLD/NASH) all seem to be linked to altered microbial composition; however, causality has not been proven yet. This points to the potential causal and personalized role of the human gut microbiota in obesity and T2D is highly prioritized.

The gut microbiome contains an immense diversity of microorganisms, varying from bacteria as well as viruses, fungi, phages, protozoa, and archaea all colonizing our adult bodies. There is a proposed view that our microbiota is a microbial (endocrine) organ living symbiotically inside our gut. This has led to a new perspective suggesting multiple lineages capable of communicating with each other and shaping host immune-metabolism in several ways. Some of the capabilities of these “organ” are:

The degradation of otherwise indigestible components of our diet
harvesting of energy and nutrients
shaping of the host immune system
maintaining the integrity of the gut mucosal barrier
xenobiotic metabolism

In this way, gut microbiota complement our biology in ways that are mutually beneficial.

The current research data regarding the precision/personalized nutrition suggest that dietary interventions, including administration of pre-, pro-, and syn-biotics, as well as antibiotic treatment should be individually tailored to prevent chronic diseases based on the genetic background, food and beverage consumption, nutrient intake, microbiome, metabolome, and other omic profiles.

The gut and diet….

Diet is essential in the composition and the function of the gut microbiota. Microbiota alters rapidly when exposed to great and fast changes in diet. Short-term dietary changes such as switching between plant- and meat-based diets, or adding more than 30 grams of fiber per day to the diet, or following a diet with different fat/fiber content can change the human gut microbiota in function and composition significantly in 48 hours.

Fiber-enriched diets have been shown to improve insulin resistance in lean and in obese subjects with diabetes. However, only long-term dietary habits are effective in shaping the composition of the gut microbiota as short-term dietary interventions failed to change the major features and classification of the microbiota.

What is the impact of Gut Microbiome in Insulin Resistance and Type 2 Diabetes?

When there is low diversity in the gut microbiome, there is a higher prevalence of obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and low-grade inflammation. Furthermore, low bacterial diversity was characterized by pro-inflammatory properties, suggested by the reduction in butyrate-producing bacteria and the increase in mucin-degrading bacteria. These characteristics potentially impair the gut integrity causing low-grade inflammation through endotoxemia. This low-grade inflammation of visceral adipose tissue may provide a link between obesity and insulin resistance.

Ethnic differences between human populations may also affect microbiota composition. Karlsson et al. compared data of T2D-associated metagenomes between Chinese and Swedish subjects with T2D, which indicated that different intestinal bacterial species were involved in similar metabolic functions. The authors were also able to distinguish subjects with T2D from healthy subjects, with a predictive power exceeding that of body mass index (BMI).

What is the effect of Gut Microbiota in Lipid Metabolism?

In recent decades, it has become clear that many metabolic, inflammatory, and innate immune mechanisms are also coordinated by (dietary-derived) lipids. The nutritional importance of dietary lipids is unequivocal.

Lipid accumulation in conjunction with low-grade inflammation is a pathophysiological hallmark of atherosclerosis. There is emerging evidence that the pathophysiology of atherosclerosis is related to interpersonal gut microbiome differences. Atherosclerosis seems to be related to TMAO, which is a new marker associated with increased risk of atherosclerosis and coronary artery disease.

Other key intestinal regulators of lipid and cholesterol metabolism are bile acids, which are involved in facilitating intestinal absorption and transport of diet-derived nutrients, vitamins, and lipids. Whereas bile production takes place in the liver (and is facilitated by products derived from lipid catabolism), 95% of all bile acids will be reabsorbed in the terminal ileum and subsequently re-absorbed by the liver, constituting the so-called enterohepatic circulation.

The intestinal microbiota is responsible for converting primary bile salt to secondary bile salts via bile acid de-hydroxylation. Although short courses of oral antibiotics affect intestinal microbiota composition and bile acid metabolism in humans, we found differential effects on glucose metabolism.

What effect does the Gut Microbiome have on Appetite?

Obesity is defined as an imbalance between energy intake (usually food intake) and energy expenditure. The brain is a key regulator in detecting alterations in energy balance and induces behavioral and metabolic responses to correct these alterations. The hypothalamus plays an important role in regulation of both food intake as well as energy homeostasis, receiving hormonal and (vagal) neuronal information from the periphery.

Changing the gut microbiome composition with prebiotics has also been shown to affect portal vein levels of other hormones including GLP-1, which in turn affected food intake, followed by a decrease in body weight and fat mass.

What are the Microbial Signatures in T2DM and Obesity?

Dysbiosis, which is the disruption of normal microbiota, has been described to be involved in a large spectrum of diseases, including diabetes, obesity, and insulin resistance, through disturbing the energy balance. It has therefore been suggested that the modulation of microbiota, either directly (by antimicrobials, diet, prebiotics and/or probiotics, stool transplant, microbial-derived signaling molecules or metabolites) or indirectly (e.g., immunotherapy) may contribute to the therapeutic management of these pathologies.

What is the Influence of Diet on Gut Microbiota in Diabetes and Obesity?

Diet is one of the major lifestyle factors involved in the genesis, prevention and control of diabetes, obesity and other cardiometabolic diseases, being also strongly linked to changes in microbiota. Many reports have shown that the genetic susceptibility to obesity may have interacted with an obesogenic environment (e.g., a major shift in dietary patterns influencing the gut microbiota, a sedentary lifestyle and physical inactivity) in determining the obesity epidemic. To date, there are many popular diets including Mediterranean, gluten-free, vegan, Western, omnivore, vegetarian. To date, most of these diets have been clearly linked to different microbiome profiles.

Following the industrial revolution, countries in the West underwent a nutritional transition from the traditional diet to a diet rich in heavily processed foods, fats, sugars, proteins, plus different additives, while remaining low in micronutrients and dietary fibers (also referred to as Western diet). These diets were deficient of dietary fibers, which are essential for gut health due to their role in stimulation of the growth and/or activity of certain beneficial microorganisms.

Conversely, people in traditional societies, with a fiber intake of almost 50–120 g/day harbor a much more diverse gut microbiota, which indicates good health. SCFAs are found in lower amounts in individuals consuming a Western diet. Western diet was correlated with a decrease in the total bacterial load and in beneficial commensals. On the other hand, subjects consuming vegan and vegetarian diets which are rich in fermentable plant-based foods were reported to have a microbiota characterized by a lower abundance of Bacteroides sp. and Bifidobacterium sp.

The Mediterranean diet (vegetables, moderate consumption of poultry, olive oil, cereals, legumes, winenuts, fish and a low amount of red meat, dairy products, and refined sugars) provides beneficial effects through the elevated content in mono-unsaturated and poly-unsaturated fatty acids, as well as high levels of antioxidants, fibers and vegetable protein content. The gut microbiota in individuals receiving Mediterranean diet is characterized by a high colonization by Lactobacillus sp., Bifidobacterium sp., and Prevotella sp., and low levels of Clostridium sp, species which are associated with weight loss, improvement of the lipid profile and decreased inflammation.

Dietary proteins have also been reported to be involved in shaping the microbiota. Individuals consuming a diet rich in beef had high levels of Bacteroides sp. and Clostridia and were low in Bifidobacterium adolescentis unlike individuals eating a meatless diet. Several studies have recently shown that diets including vegetarian whey/pea protein, and animal protein (meats, eggs, and cheese) are linked with microbial diversity. Consumption of animal-based protein was positively associated to a richness in bile-tolerant anaerobes, including Alistipes sp., Bilophila sp., and Bacteroides sp.

What are the Future Perspective on the Gut Microbiome?

Accumulating evidence suggests that gut microbiota plays a significant role in the initiation and progression of MS. The gut microbiota was proven to modulate plasma glucose, appetite, serum lipids and pro-inflammation. In addition, prebiotics or probiotics, which are widely used to manipulate the microbiota, can reduce low-grade intestinal inflammation and improve gut barrier integrity to reduce plasma glucose and serum lipid levels, induce weight loss and decrease insulin resistance. Based on these current achievements, the gut microbiota may be a potential therapeutic target for MS. However, clinical trials addressing the efficacy and efficiency of current or potential treatments on therapeutic applications in metabolic syndrome are needed.

Also, Individuals who are obese are likely to have an imbalance in gut microbiota composition. This possibility is a thrilling avenue for further research and possible novel treatment targets. However, because most studies have been undertaken in animals, direct translation of the findings to human is limited.

Prebiotics or other newly identified beneficial bacterial strains are potential interventions that will be used for treatment in the near future, and it will be important to evaluate their efficacy. Similarly, interventional studies with metabolites of microbiota will be performed (including SCFA butyrate supplementation) to evaluate if this compound has similar effects on food intake, energy expenditure, and improved metabolic features in humans.

The modifiable effects of the human gut microbiota on the development of metabolic syndrome make its handling a promising therapeutic approach. Analyzing and mapping individual microbial composition on a metagenomic level provides insight into specific targets for treatment and contributes to personalized therapeutic interventions.

References

Frontiers in Nutrition: Gut Microbiota, Host Organism, and Diet Trialogue in Diabetes and Obesity. Retrieved from https://www.frontiersin.org/articles/10.3389/fnut.2019.00021/full

NCBI (2018): The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013535/

NCBI (2017): Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655955/

Given that obesity and associated disorder type II diabetes mellitus have reached epidemic proportions worldwide, the development of efficient prevention and therapeutic interventions is a global public health interest. There is now a large body of evidence suggesting that the micro-organisms colonizing the human gut, known as gut microbiota, play a central role in human physiology and metabolism. Understanding how gut microbiota affects and regulates key metabolic functions such as glucose regulation and insulin resistance is an important health issue. We will highlight how prebiotic/probiotic interventions affect these bacterial processes and are now considered as promising approaches to treat obese and diabetic patients.

1. The gut microbiota of an obese person…

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. Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease.

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. 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.

2. Obesity, Diabetes, and Dysbiosis

The preservation a normal and healthy gut microbiota plays a critical role in maintaining good health. 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 is related to lower microbial diversity and greater depletion. In early obesity, microbiota studies report that an increase of body weight is associated with a microbiota shift.

Although T2DM is generally considered as an attribute to obesity, some studies have correlated glycemic control impairment and insulin resistance to specific gut microbiota composition. Furthermore, antidiabetic drugs liraglutide and metformin have been recently shown to significantly lower body weight and improve glucose metabolism while considerably modifying the composition of gut microbiota.

Liraglutide decreased obesity-related microbial phenotypes and increased lean-related phenotypes while metformin modifies the intestinal microbiota composition by inducing the growth of several bacteria.

There is proof that gut microbiota is involved in the beneficial glucose-lowering effects of antidiabetic agents and that it is a promising therapeutic target in T2DM and the glycemic control impairment context.

3. How can Gut Microbiota be moderated?

Through several mechanisms, gut bacteria influence the chronic low grade inflammation that culminates in insulin resistance and the increase in fat deposits and body weight gain, characteristic of obese individuals.

With the acknowledgement of these obesity and inflammation induction mechanisms, several strategies to block or attenuate them are being developed and tested, in order to benefit obese and type 2 diabetic patients. We will look at these mechanisms and the effect they have:

3.1. Antibiotic Therapy

The use of broad spectrum antibiotic therapy greatly modifies the gut microbiota profile although the prevalence of surviving bacteria and the benefits for the host have not been determined, as the concept of a “healthy” gut microbiota is still under investigation.

The main mechanism suggested by antibiotic administration is a reduction in circulating LPS levels, which lessens inflammation and improves the insulin resistance induced by obesity in the liver, muscle, and adipose tissue. Improved intestinal function has also been noted as a benefit of the administration of antibiotics.

However, even with this striking metabolic improvement in antibiotic therapy experiments, it seems that translating this strategy to humans is not the best option, as there are complex issues such as antibiotic resistance in chronic administration panels and evidence that indicates a relationship between chronic low-dose antibiotic therapy and body weight gain.

3.2. Probiotics

Probiotics are live microorganisms that can be consumed through fermented foods or supplements. More and more studies show that the balance or imbalance of bacteria in your digestive system is linked to overall health and disease. Probiotics promote a healthy balance of gut bacteria and have been linked to a wide range of health benefits.

As obesity is a key cause of diabetes, probiotics can help with weight loss through a number of different mechanisms. An example is that some probiotics prevent the absorption of dietary fat in the intestine.The fat is then excreted through feces rather than stored in the body. Probiotics may also help you feel fuller for longer, burn more calories and store less fat. This is partly caused by increasing levels of certain hormones, such as GLP-1.

Probiotics may also help with weight loss directly. In one study, dieting women who took Lactobacillus rhamnosus for 3 months lost 50% more weight than women who didn’t take a probiotic. Another study of 210 people found that taking even low doses of Lactobacillus gasseri for 12 weeks resulted in an 8.5%.

It is however important to note that not all probiotics aid in weight loss. Some studies have found certain probiotics, such as Lactobacillus acidophilus, can even lead to weight gain.

3.3. Prebiotics

Prebiotics are classified as the non-digestible food ingredients that probiotics can feed off. They are used in the gut to increase populations of healthy bacteria, aid digestion and enhance the production of valuable vitamins. Galactooligosaccharides (GOS) are the most advanced form of prebiotics which belong to a group of particular nutrient fibers that feed and encourage the growth of good bacteria in the gut.

The major source of prebiotics is dietary fibre. They occur naturally in fruits and vegetables, but you can also take them in the form of nutritional supplements.

3.4. Bariatric Surgery

Bariatric surgery is an important method in the treatment of obesity. It is quite effective in achieving and protecting weight loss. This effectiveness of obesity treatment after bariatric surgery is not only related to food consumption. The altered microbiota after bariatric surgery has an impact on its effectiveness. Malabsorption status after bariatric surgery, changes in the metabolism of bile acids, changes in gastric pH, and changes in the metabolism of hormones lead to gut microbiota changes. Changes in microbiota also affect energy homeostasis. Because of these reasons, body weight loss is achieved after bariatric surgery.

4. What role will gut microbiota play in the treatment of T2DM in the future?

It is becoming increasingly clear that gut microbiota has profound impact on general health and well-being. Notably, it is now well-established that imbalanced gut microbiota is linked to host glycemic control impairment and T2DM development. Although the precise role of gut microbiota remains incompletely understood, further investigation is likely to be very helpful in the treatment and control of obesity, and resultant Type 2 Diabetes.

Current treatments of this complex chronic disease are far from being ideal since in a majority of patients, T2DM remains poorly controlled in the long run. Using pre/probiotics to control blood glucose has been considered for a long time, and the discovery of the key roles of gut bacteria in T2DM has boosted research efforts in this field.

A better understanding of how gut microbiota impacts general health will help in outlining new treatment strategies. These strategies will help in identifying probiotic strains with antidiabetic activities, or nutritional interventions that can increase helpful microbiota in the gut.

References:

1. Hindawi (2013): Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance. Retrieved from https://www.hindawi.com/journals/mi/2013/986734/2. Frontiers in Endrocrinology (2019): Impact of Gut Microbiota on Host Glycemic Control. Retrieved from https://www.frontiersin.org/articles/10.3389/fendo.2019.00029/full

3. NCBI (2019): The effects of bariatric surgery on gut microbiota in patients with obesity: a review of the literature. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343052/

4. Bimuno(2018) : Prebiotics. Retrieved from https://www.bimuno.com/prebiotics

5. Healthline (2016): 8 Health Benefits of Probiotics. Retrieved from https://www.healthline.com/nutrition/8-health-benefits-of-probiotics