Can poor gut health lead to type 2 diabetes?

Introduction

Type 2 diabetes has reached the reputation of a global pandemic causing significant public health burden. The International Diabetes Foundation has recently estimated that the global prevalence of type 2 diabetes in adults to be 536 million. These numbers are projected to rise to 783 million by 2045. Once known as a disorder that was exclusively seen in adults, the revelation that increasing number of children and adolescents are affected calls for intensive intervention strategies.

Brief overview of Type 2 diabetes

<a href="https://www.freepik.com/free-vector/realistic-pancreas-anatomy-medical-composition-with-editable-text-captions-pointing-colored-parts-internal-organs-vector-illustration_28795248.htm#query=pancreas&position=0&from_view=search&track=sph">Image by macrovector</a> on Freepik

Type 2 diabetes is one of the most common metabolic disorders encountered worldwide. The word metabolism refers to a series of chemical reactions taking place in a living organism that is needed to sustain life. Basically, in a metabolic process, the food we consume is converted into energy that is used to maintain vital body functions such as respiration and circulation. Metabolic disorders occur when there is disruption to the above processes. Type 2 diabetes is one such disorder in which there is persistent increase in the blood sugar levels above the normal range. The reason behind this is inadequate production of insulin or the presence of insulin resistance or a combination of both.

So, what is insulin? It is a hormone produced by special cells called beta cells present in the pancreas, an organ located behind the stomach. It plays a vital role in maintaining the normal blood glucose levels. When there is rise in the blood sugar levels, for example after a meal, insulin is released from the pancreas. It helps to relocate the glucose from the blood into the liver, muscle and adipose (fat) tissues. Once the blood sugar reaches normal levels, another hormone called glucagon released by the alpha cells of the pancreas takes over to prevent a sharp fall in the blood sugar levels. Hence a coordinated action of these two hormones is essential to keep the blood glucose levels within a normal range.

Insulin resistance, which is considered as the hall mark of type 2 diabetes, is a state wherein there is reduction in the biological action of insulin. As a result of this, the glucose that is normally driven into the liver, muscle and fat tissue is affected leading to increase in the blood glucose levels. In the initial stages there is compensatory increase in the insulin production to sustain a normal blood glucose level. In the due course, the production of insulin reduces leading to a consistent raise in the blood glucose and eventually type 2 diabetes.

The development of type 2 diabetes involves the interplay between a number of factors including genetic, metabolic and environmental factors. So, taking into consideration that the risk related to genetics, ethnicity and family history cannot be changed, several studies support the fact that the development of diabetes can be prevented or delayed by addressing the risk factors such as overweight/obesity, unhealthy diet and low physical activity.

Analysis of the individual risk factors has brought into light about the various parameters related to the development of type 2 diabetes. On a global note, variations in the ethnicity and geographical distribution have been observed with type 2 diabetes. Generally, people from Black African, African Caribbean and South Asian (India, Pakistan, Bangladesh) descent are at increased risk for developing type 2 diabetes from a young age compared to the White population. Though there are no clear-cut reasons to explain this occurrence, life-style and genetic factors have been put forward.

One of the most defined risks for the development of type 2 diabetes is the presence of obesity. In terms of body mass index (BMI), a value above 30 is taken as obesity whereas above 25 as overweight. BMI is calculated by using the formula weight in kilograms divided by height square. The normal value is between 18-25. The presence of metabolic abnormalities especially insulin resistance further escalates the diabetes risk.

Scientific evidence from various studies have supported that increasing the physical activity levels significantly reduces the diabetes risk. Regular physical exercise has been shown to improve the blood flow to the muscle thus encouraging the transfer of glucose from the blood to be stored in the muscle. Also, another important outcome from exercise is the reduction in the abdominal fat. Increased abdominal fat is a huge risk factor for the development of insulin resistance.

Though there are variations in the outcomes from a number of studies analysing the effect of diet on the development of type 2 diabetes, it has been proposed that high intake of simple carbohydrates, refined sugars and fats are linked to diabetes risk. While the role of high consumption of red meat, sweets, fried foods and white rice has been put forth, recent evidence points to the link between the consumption of high-fructose corn syrup and chemicals present in the soft drinks to the development of obesity, insulin resistance and type 2 diabetes.

In addition to the above, recent studies have explored the role of gut microbes not only in the development but also as a potential strategy in the prevention and treatment of type 2 diabetes.

What’s in the gut?

<a href="https://www.freepik.com/free-vector/tiny-doctors-examining-gut-flora-flat-vector-illustration-therapists-checking-digestive-system-gastrointestinal-tract-bowel-friendly-microorganisms-bacteria-nutrition-health-concept_24644943.htm#query=gut%20bacteria&position=7&from_view=search&track=ais">Image by pch. vector</a> on Freepik

The human intestinal tract harbours one of the largest collection of microbes that maintain a harmonious relationship with the host. The trillions of microbes that are present in the gut microbial ecosystem include bacteria, fungus, archaea and viruses. However, the bacterial colonies dominate the picture and it is estimated that more than 1000 species of bacteria colonise the gut. In fact, it is said that the bacterial colonies outnumber the genes present in the cells. It is interesting to note that these bacteria continuously evolve throughout the life span of an individual adjusting to the changes that occur in the human body. However, at any stage of life, the type of colonies depends upon the age, nutritional status, lifestyle, genetics and hormones.

Despite the presence of innumerable bacterial colonies, only five bacterial phyla make up the majority of the count. These include Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia. Among these Firmicutes and Bacteroidetes constitute 90% of the population. Some of the types of bacteria that come under the above-mentioned phyla include Lactobacillus, Clostridium, Roseburia, Ruminococcus, Veillonella, Faecalibacterium, Bacteroides, Prevotella, Bifidobacterium and Akkermansia muciniphila. Though these names sound as tongue-twisters, it is interesting to note their uniqueness in offering innumerable health benefits. Despite the Clostridium species having the identity as a friendly bacterium, some of the bacteria belonging to this species are considered to be harmful.

Though the contribution of intestinal health to the overall well being was known since the time of Hippocrates, the scientific research conducted in the last few decades has expanded the horizon about the key role played by the microbes in the normal functioning of the organs and organ systems in the body. The complex carbohydrates that are derived from dietary sources such as vegetables, fruits, legumes, whole grains form the main source of nourishment to the gut bacteria. A type of complex carbohydrate called as non-digestible complex carbohydrates which form a major source of dietary fiber, encourages the growth of healthy bacterial colonies in the intestine. As the name indicates, these do not undergo digestion but rather reach the large intestine intact where they are fermented by the bacteria to produce metabolites (compounds produced from metabolism). One such metabolite is called short chain fatty acids (SCFA) which include acetate, propionate and butyrate. Apart from being an important source of nourishment to the cells of the large intestine, they possess anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic and heart protecting effects.

The link between the gut and type 2 diabetes

Dysbiosis or imbalance in the gut microbial ecosystem has been linked to a number of diseases like metabolic disorders (diabetes), cardiovascular disorders (heart attack, angina, heart failure), cerebrovascular disease (stroke, transient ischaemic attack), autoimmune diseases (rheumatoid arthritis, multiple sclerosis – a disabling condition affecting the brain and spinal cord, type 1 diabetes – destruction of insulin producing beta cells leading to high blood sugar levels), inflammatory bowel disease ( Chron’s disease and ulcerative colitis – inflammatory conditions involving the digestive tract or large intestine ), psychotic disorders (disorders affecting the mental well-being wherein the person is not connected to the reality) and cancer.

Before proceeding to the gut microbial changes in type 2 diabetes, it is worth getting an idea about the gut barrier as this is the potential area where the problem starts. One of the most important protective systems in the intestine is called gut barrier. Basically, this barrier system is composed of a mucus layer, which is a slimy layer lining the intestines both on outside as well as inside. A single layer of special cells called epithelial cells that are tightly packed are located beneath the mucus layer. This barrier system not only acts as a first line of defence, but also senses the presence of substances such as food particles, bacteria etc inside the intestine. It selectively allows the important nutrients to pass through them while restricting the entry of bacteria and other harmful substances.

Now coming back to the gut microbial changes pertaining to diabetes, it is a well-known fact that the gut microbial ecosystem is dominated by two phyla namely Bacteroidetes and Firmicutes. Alterations in the ratio between these two phyla have been observed in individuals with type 2 diabetes. Any disturbances in the ratio have the potential to affect the intestinal barrier function. The consequence of this is the development of a leaky gut wherein the bacteria and its products escape into the body leading to the development of the inflammatory changes possibly linked to diabetes.

The recent lines of evidence from many scientific studies have observed that there is a decrease in the population of butyrate producing bacteria in individuals with type 2 diabetes. The majority of the butyrate producing bacteria belong to the Firmicutes phylum. Some of the bacteria include Ruminococcus, Clostridium, Eubacterium, Coprococcus, Faecalibacterium and Roseburia. Reports have put forth a significant reduction in the population of Firmicutes and Clostridium in individuals with type 2 diabetes.

As already mentioned, butyrate or butyric acid is one of the short chain fatty acids produced by the gut bacteria. It is considered as one of the major sources of nourishment for the cells of the colon (large intestine). In addition to this, butyrate strengthens the gut barrier, reduces inflammation and strengthens the gut as well as the overall immunity. Also, the acidic environment created in the intestine by these bacteria not only maintains a healthy gut bacterial balance, but also keeps the harmful bacteria at bay. Hence the butyrate producing bacteria are regarded as probiotics.

The reductions in the butyrate producing bacteria with concomitant increase in the population of harmful bacteria in individuals with type 2 diabetes further compromises the gut barrier and promotes inflammation. Some of the harmful bacteria that have been found in increased numbers are those belonging to the Clostridium species and E. coli. Apart from reduced numbers of butyrate producing bacteria, lower count of Akkermansia muciniphila has been observed.

Though these findings have provided insights into the link between gut bacteria and type 2 diabetes, factors such as the stage of diabetes, presence of complications, diabetic medications, dietary changes such as a low glycemic index diet or a diet rich in complex carbohydrates and presence of obesity should be taken into consideration. While comparing the gut bacterial alterations especially with non-diabetic individuals, it should be noted that most of the above-mentioned factors seen in diabetic individuals are not present in those without diabetes. However, it should be noted that modifying the gut bacteria could be a potential treatment target for type 2 diabetes in the future.

Gut bacteria in diabetes related scenario

<a href="https://www.freepik.com/free-vector/diabetes-infographic-composition-with-prevention-tips-symptoms-treatment-complications-blood-sugar-meter-monitor-flat-set_6869545.htm#page=2&query=diabetes&position=1&from_view=search&track=sph">Image by macrovector</a> on Freepik

Prediabetes

This is a condition wherein the blood glucose values are above the normal range but not high enough to be classified as diabetes. The cut-off blood sugar values for the diagnosis of prediabetes are a fasting blood glucose between 100-125 mg/dl after a 12 hour fast also called as impaired fasting glucose (IFG) and a 2-hour blood glucose level of 140-199 mg/dl also called as impaired glucose tolerance (IGT). Individuals with prediabetes may not have any signs or symptoms of diabetes despite a higher-than-normal blood sugar value. This makes the majority of the individuals unaware of the fact that they are living with above normal blood sugar values. The presence of prediabetes is a not only a risk factor for the development of type 2 diabetes, but also for heart disease and stroke. Since the conversion rate of prediabetes to diabetes can be as high as 70%, lifestyle modifications are recommended as an early intervention strategy.

Analysis of the gut microbes in individuals with prediabetes and newly diagnosed type 2 diabetes have revealed changes in the composition. Studies have observed reductions in the populations of Clostridium, Akkermansia muciniphila and butyrate producing bacteria. Increase in the number of harmful bacteria such as E. coli and Streptococcus were also noted.

Comparative analysis of individuals with normal glucose tolerance (NGT which means those having a normal blood glucose level), impaired glucose tolerance (IGT) alone, Combination of impaired fasting glucose and glucose tolerance and impaired fasting glucose (IFG) alone have revealed significant imbalances in the gut microbial composition with the exception of IFG group. Taking into consideration that IGT and IFG are two different types of insulin resistance wherein the defect in IGT lies in the muscle and that of IFG in the liver, it becomes evident that gut bacterial alterations does have a role in the development of peripheral (muscle) insulin resistance.

Prediabetes is now regarded as a condition that can be reversed by increasing awareness and bringing about changes in the life style such as diet and exercise. Evidence from studies also strongly support the effectiveness of life style modifications compared to medications in reversing prediabetes. With more evidence accumulating on the role of gut microbes in the development of prediabetes, the question is if modification of the gut microbes can reverse prediabetes.

Recent studies have explored the beneficial effects of probiotics in individuals with prediabetes. Probiotics are defined as the foods or supplements that contain live microbes such as yeast and bacteria that are beneficial for health. Administration of probiotics has been shown to balance the intestinal microbial composition as well as the blood glucose levels. Studies have observed increase in the population of beneficial bacteria such as the butyric acid producing bacteria and enhanced production of glucagon like peptide-1, an intestinal hormone that stimulates the secretion of insulin. This effect was attributed to the increases in Lactobacillus and Bifidobacterium. Though these findings provide insights regarding the benefits of probiotics in individuals with prediabetes, more long-term studies analysing its safety, stability and efficiency are warranted.

Diabetic complications

Uncontrolled diabetes is associated with macrovascular (involving large blood vessels) and microvascular (involving small blood vessels) complications. The macrovascular complications include coronary heart disease (involving the blood vessels of the heart), stroke (involving blood vessels of the brain) and peripheral arterial disease (commonly involving the blood vessels of lower limbs). These complications are attributed to the building up of atherosclerotic plaques. The microvascular complications include diabetic kidney disease, eye disease and peripheral neuropathy (involving the nerves outside the brain and spinal cord).

Though the above-mentioned conventional complications still pose a significant public health challenge, overall, the rates of their occurrence are showing a downward trend due to the advancements in medical care. However, concerns have been expressed in the light of emerging complications related to diabetes such as cancer, liver disease, infections, affective disorders (mood disorders) and dementia. But more evidence based analytical studies are needed with these emerging complications in relation to diabetes.

Diabetic nephropathy (kidney disease)

It is said that the gut bacteria play a role in the normal functioning of the kidneys. The metabolites produced by them protect the kidneys against damage, infections and injuries. Evidence from the recent studies have supported the fact that imbalances in the gut microbial ecosystem could lead to the development of diabetic kidney disease. The end stage renal (kidney) failure as a consequence of diabetic kidney disease has been linked to the exacerbation of gut microbial imbalance. Observations from the studies conducted on individuals with chronic kidney disease have revealed reductions in the population of beneficial bacteria such as Lactobacillus, Bifidobacterium, Ruminococcus, Roseburia, Faecalibacterium. Increase in the number of harmful bacteria especially Bacterioidaceae and Clostridiaceae in chronic kidney disease has been linked to widespread inflammation.

A selected number of studies have explored the role of probiotics and synbiotics (combination of prebiotics and probiotics that are beneficial to health) in individuals with chronic kidney disease. It was observed that the administration of Lactobacillus, Bifidobacterium and Streptococcus thermophilus brought about reductions in the blood levels of urea, nitrogen and uric acid. Similar results were also observed in individuals on dialysis wherein significant reductions in the concentration of harmful chemicals in the blood was noted. These results have provided insights into the beneficial role of probiotics and synbiotics application in individuals with diabetic kidney disease.

Diabetic retinopathy (eye disease)

The link between the gut microbes and eye health has been explored in recent studies. It has been revealed that the short chain fatty acids produced by the gut bacteria ensure normal functioning of the eyes. Also, the butyrate has been said to have a role in protecting the eyes against inflammation. Though a possible link between gut bacteria and retinal health has been proposed, the evidence behind this is sparse.

Uncontrolled diabetes is a risk for the development of diabetic eye disease. The complications related to the diabetic eye include cataracts, glaucoma (increased internal eye pressure leading to blindness) and retinopathy (a condition caused by damage to the blood vessels of the retina, a light-sensitive tissue at the back of the eyeball). Similar to the gut microbial ecosystem, the external (outer side) of the eyes also harbor bacterial colonies wherein most of the population is represented by Proteobacteria, Actinobacteria and Firmicutes. Imbalances seen in the gut microbiota in diabetes is said to affect the microbial balance in the eyes leading to diabetic complications and this has been supported by studies. Though variations have been reported with the type of bacterial colonies affected, overall reductions in the anti-inflammatory bacteria such as Bifidobacterium, Faecalibacterium, Roseburia, Clostridium, Lachnospira was observed.

Also, alterations in the beneficial fungal colonies called Mucoromycota have been reported in individuals with diabetic retinopathy. In addition to this, increased levels of a bacterial metabolite called trimethylamine-N-oxide (TMAO) has been linked to the development of diabetic retinopathy. The levels of TMAO are increased on consumption of foods such as red meat (beef, pork, lamb, ham, processed meat) and full fat dairy products (cream cheese, butter).

The effect of modifications in the gut microbiota by the administration of probiotics in individuals with diabetic retinopathy has been so far experimented in animal studies only. Though the results have been encouraging in terms of improvement in eye health, human studies are warranted to appreciate the full benefits of probiotics in the presence of diabetic retinopathy. Recently conducted animal studies have provided insights about the protective effect of intermittent fasting against the development of diabetic retinopathy by increasing the population of Firmicutes.

Diabetic neuropathy

Diabetic neuropathy in its simplest form is defined as the nerve damage caused by diabetes. This is considered as one of the most frequent complications of diabetes. It is seen in about 50% of the individuals living with diabetes and stands out as the most common cause for hospitalizations compared to the other diabetic complications. Apart from causing considerable economic burden, it affects the overall well-being and the quality of life due to the resulting pain and disability. The nerve damage could involve the peripheral nerves (also called peripheral neuropathy affecting the feet and legs), autonomic nerves (also called autonomic neuropathy involving the nerves that supply the internal organs), single nerve (also called focal neuropathy) and proximal nerves (also called proximal neuropathy affecting the nerves of the hip, buttock or thigh).

Studies have shown increased disruption of the gut microbial balance in the presence of diabetic neuropathy compared to the presence of type 2 diabetes alone. Apart from the imbalances seen with the proportion of Firmicutes and Bacteroidetes, increase in the number of bacteria like E. coli, Escherichia-Shigella (these bacteria cause gut inflammation), Megasphaera, Lachnoclostridium are seen. These alterations in the bacterial colonies are presumed to be related to the severity of insulin resistance. It has been found that the increased levels of the bacteria Megasphaera are related to the degree of insulin resistance in individuals with diabetic neuropathy.

The intensity of the pain encountered in diabetic neuropathy is also presumed to be related to the degree of gut microbial imbalance. The increase in the population of the harmful bacteria is said to affect the intestinal barrier resulting in the escape of the bacterial products into the blood stream. One such harmful product is called Lipopolysaccharide (LPS), which is said to directly affect the nerve cells causing inflammation resulting in severe pain.

It is a well-known fact that the gut microbiota influences the functioning of the nervous system. Hence bringing about a gut microbial balance could potentially prevent the development or improve the symptoms associated with neuropathy. However, the role of probiotics as supplements in diabetic neuropathy needs further investigation.

Cerebrovascular disease

The term cerebrovascular disease refers to a group of disorders that occur as a result of interruption in the blood flow to the brain. Stroke is one such disorder wherein the blood flow is affected either due to blockage (ischaemic stroke) or rupture (hemorrhagic stroke) of the blood vessels supplying the brain. Also called as the cerebrovascular accident, it stands as the second major cause of death worldwide. It is also one of the important causes of disability affecting the quality of life in addition to increasing the financial burden.

Apart from the risk factors such as high blood pressure, increased cholesterol, obesity, smoking and high alcohol consumption, diabetes is also considered as a significant risk factor for stroke. Though it is said that poor diabetic control can enhance the risk of stroke, it is hard to ascertain the exact cause in most cases. Based on the presence of gut-brain axis, a two-way communication between the brain and the gut, recent studies have explored the association between gut microbial dysbiosis and stroke.

It has been estimated that about half of the individuals have gastrointestinal disturbances after a stroke which includes constipation, dysphagia (difficulty in swallowing), stool incontinence (inability to voluntarily control the passing of stools) and gastrointestinal bleeding. These disturbances could further exaggerate the gut microbial imbalance. Also, studies have put forth that the alterations in the behaviour, neuroinflammation (meaning inflammation of the brain and spinal cord) and the severity of the consequences in a stroke is related to imbalances in the gut microbial ecosystem.

Evidence from animal and human studies have supported that imbalances in the gut microbiota may be a sole risk factor for stroke. Though variations in the gut microbial dysbiotic pattern has been observed in studies relating to stroke, overall reductions in the butyrate producing bacteria have been noted in individuals with stroke. Also, an increase in the population of opportunistic pathogenic bacteria (which means a bacterium which is friendly turns out to be a harmful one especially when one’s immunity is low) that belong to Enterobacteria, Veillonella, Lactobacillus and Bifidobacterium groups have been observed. The presence of atherosclerotic plaques in the blood vessels as well as excessive TMAO production have been linked to gut microbial imbalance thus providing a possible association between gut microbial disruptions, cardiovascular and cerebrovascular diseases.

The role of probiotics as supplements in stroke has been so far investigated only in animal studies. Though the results have been promising in terms of risk reduction and injuries related to stroke, human studies in a clinical set up are warranted in order to ascertain the role of probiotics in the prevention and treatment of stroke.

Coronary heart disease

Coronary heart disease is a condition of the heart that occurs as a result of interruption to the blood supply due to the build up of atherosclerotic plaques in the coronary arteries (blood vessels that supply the heart). These plaques are primarily made up of fats and their gradual accumulation triggers an inflammatory reaction affecting the blood supply to the heart.

The coronary heart disease presents in the form of stable ischaemic heart disease or acute coronary syndrome. In the first one, there is imbalance between the oxygen demand and supply to the heart and presents as angina. Here the patients experience chest pain or tightness on exertion which is relieved by rest. In acute coronary syndrome, the blood supply to the heart is blocked and presents as heart attacks. An individual having a heart attack presents with chest pain felt under the sternum. This is usually accompanied by other symptoms such as breathing difficulty, left arm and jaw pain, nausea, light-headedness and weakness. A quick evaluation and timely treatment can be life saving as the death rates from heart attacks are high.

On a global note, coronary heart disease is one of the leading causes of death and disability. In addition to the known risk factors such as age, gender, family history, genetics, obesity, smoking, increased blood cholesterol and unhealthy eating, the presence of diabetes escalates the risk to a much higher level for the development of coronary heart disease.

Evidence from the recent studies support the link between imbalances in the gut microbiota and coronary artery disease. It is a well-known fact that the gut microbes play an important role in regulating the blood cholesterol levels. Any disturbances in the gut microbial balance have been shown to affect the cholesterol metabolism leading to increase in the cholesterol levels, a known risk factor for the coronary heart disease.

Comparative analysis of the gut microbial pattern between heathy individuals and those with coronary heart disease have revealed reduced population of the butyrate producing bacteria and increase in the numbers of Collinsella (a type of bacteria which is said to grow abundantly with a low dietary fibre intake. It has been linked to type 2 diabetes and alterations in the cholesterol metabolism), Escherichia, Shigella and Enterococcus. The TMAO produced by the gut bacteria also strongly correlates with coronary heart disease.

The effectiveness of probiotics in individuals with diabetes and coronary heart disease has been investigated in recent studies. The intake of probiotic supplement containing Lactobacillus and Bifidobacterium was found to bring about reductions in the LDL (bad) cholesterol levels, increase in the HDL (good) cholesterol levels, reduced inflammation and improved blood glucose control. Hence probiotics have been regarded as a favourable strategy in the management of coronary artery disease in individuals with diabetes associated with gut microbial imbalance.

Peripheral vascular disease

Peripheral vascular disease includes peripheral arterial and venous disease. The Peripheral arterial disease refers to the condition that occurs as a result of reduction in the blood flow to the extremities, most commonly the lower limbs. Most often this condition is quoted as ‘poor circulation’. One of the most common causes for the reduced blood flow is the build-up of the atherosclerotic plaques causing narrowing of the blood vessels. The reduced blood flow is often felt as pain in the thigh and calf on exertion. The combination of peripheral arterial disease, neuropathy and poorly controlled diabetes worsens the symptoms resulting in critical limb ischemia, wherein the blood flow is severely affected and gangrene (death of the tissues due to poor blood flow).

Diabetic foot is one of the most distressing complications wherein damage to the blood vessels and nerves of the feet leads to loss of sensation and development of ulcers. Also, the considerably reduced pain sensation further increases the risk for injuries and ulcers. These ulcers are difficult to heal due to poor circulation and get complicated by the development of inflammation and gangrene eventually increasing the risk for amputation.

Uncontrolled diabetes can also affect the veins increasing the risk of varicose veins, leg pain and swelling and blood clot formation.

Animal studies exploring the effect of probiotics on peripheral vascular diseases have produced encouraging results. The administration of kefir (fermented milk drink) was found to enhance the wound healing process and this was attributed to the effects lactic acid producing bacteria present in kefir. Human studies investigating the effectiveness of probiotic supplements in individuals with diabetic foot have revealed that administration for 12 weeks produced significant improvement in ulcer healing with respect to reductions in the length, breadth and depth of the diabetic foot ulcer. Also, improvements in the blood glucose levels were observed on administration of probiotics containing Lactobacillus and Bifidobacterium bacteria.

Studies conducted on the potential of other bacteria in improving the diabetic parameters has shown encouraging results. An improvement in the insulin sensitivity, blood cholesterol levels and inflammation were observed with supplementation of Akkermansia muciniphila for three months. Along with this bacteria, recent studies have recognised the probiotic potential of bacteria other than Lactobacillus and Bifidobacterium. These include Akkermansia muciniphila, Ruminococcus, Faecalibacterium and Roseburia which have been labelled as the next generation probiotics. These studies have provided insights not only on the role of specific bacteria in improving the metabolic health, but also to develop novel food and pharmacological supplements that protect against metabolic diseases.

Diabetic medications

A good control of the blood sugar is an essential prerequisite in the management of diabetes in order to prevent long term complications. This can be achieved by a combination of diet, exercise and diabetic medications. There are different classes of anti-diabetic medications and their selection depends upon many factors such as the age of the patient, duration of diabetes, presence of complications, affordability etc. However, recent studies have revealed the existence of a link between the anti-diabetic drugs and the gut microbes. Evidence points to the presence of a two-way communication between the gut microbiota and anti-diabetic drugs, wherein it is said that these medications do bring about alterations in the gut microbial ecosystem. The gut bacteria in turn enhances the efficiency and safety of the medication.

Metformin

Metformin is one of the frequently used medications in the management of type 2 diabetes. Though this drug has been around for more than six decades, a complete in-depth understanding about its mechanism of action is not fully known. However, a number of studies investigating the same have revealed that this drug acts on three areas namely, the liver, muscles and intestine. Metformin has been shown to stabilize the blood glucose levels by reducing the glucose production in the liver, also called gluconeogenesis. In addition to this, studies have revealed that metformin helps in relocating the glucose present in the blood into the muscle.

A number of studies have supported the significance of metformin action on the intestine over the liver. The intestine has been regarded as the point where the action of metformin begins. It has been demonstrated that metformin slows the rate of absorption of glucose from the small intestine thereby enhancing the presence of glucose in the more distant part of the intestine. This action increases the production of Glucagon-like-peptide-1 (GLP-1), a hormone that increases the secretion of insulin thereby balancing the blood glucose levels.

Studies have brought into light the gut microbial changes brought about by metformin in individuals with type 2 diabetes. A deeper investigation of the gut microbes at the genome level has revealed increased production of short chain fatty acids particularly butyrate and propionate brought about by metformin. These two fatty acids are beneficial in terms of strengthening the intestinal barrier as well as balancing the blood glucose levels.

Another significant finding with metformin is an increase in the population of the bacterium Akkermansia muciniphila. This bacterium needs a special mention due to its unique qualities. Being present in the slimy mucus layer of the intestine, it survives on mucin, a special protein present in the mucus. Some of the health benefits related to this bacterium include maintaining a healthy mucus layer, protecting the gut against inflammation, obesity as well as type 2 diabetes. Studies have demonstrated the capacity of this bacterium to reverse the metabolic disorders. But all said and done, about 30% of the individuals taking metformin report side effects such as nausea, vomiting, diarrhoea, bloating and lactic acidosis (a life-threatening condition that occurs as a result of the build-up of lactic acid in the blood).

Alpha-glucosidase inhibitors

These constitute a group of drugs that are used in the treatment of type 2 diabetes either alone or in combination with other diabetic medications. These are useful in individuals who are intolerant to other diabetic medication and are high risk candidates for the occurrence of hypoglycaemia (low blood sugar) and lactic acidosis. They act by preventing the absorption of carbohydrates from the small intestine thereby bringing about reductions in the post-prandial (post meal) blood glucose levels. The drugs that fall under this group includes acarbose, voglibose and miglitol.

Recent studies have put forth the possible influence of alpha-glucosidase inhibitors on the gut microbes. Emerging evidence from various studies have revealed increase in the population of beneficial bacteria such as Lactobacillus and Bifidobacterium. These bacteria stand out for their health benefits and probiotic effects. Also, studies have revealed that administration of voglibose for 12 weeks brought about a balance in the Firmicutes and Bacteroidetes ratio resulting in a balanced blood glucose and lipid levels. In addition to these effects, acarbose has been said to increase the butyric acid production and this effect is possibly attributed to the increased fermentation of the non-digestible carbohydrates in the large intestine brought about by this drug.

Glucagon like peptide-1 (GLP-1) agonists

Glucagon like peptide-1 is a hormone that is produced in the intestine in response to food. It belongs to the family of hormones called incretins. GLP-1 enhances the secretion of insulin by the pancreas and also suppresses the release of glucagon. It also augments the feeling of fullness related to meal times. In addition to this, it brings down the appetite and also delays the emptying of the stomach. Reduced amounts of this hormone increase the chances of developing obesity or worsens obesity if already present. It is also more likely that an individual may eat more during meals or frequently snack as the point of satiety (feeling of fullness or satisfaction following a meal) is affected. Evidence from many studies have put forth that the gut microbes regulate satiety and blood glucose levels by increasing the production of GLP-1.

GLP-1 agonists or incretin mimetics or GLP-1 analogues are a group of newer anti-diabetic medications used for the treatment of type 2 diabetes and in certain instances obesity. Some of the drugs that belong to this class include exenatide, liraglutide, semaglutide, albiglutide etc. These drugs mimic the action of GLP-1 thus balancing the blood sugar levels. The observations from the recent studies point to the alterations in the gut microbiota brought about by these drugs.

It is a well-known fact that type 2 diabetes and obesity are associated with alterations in the Bacteroidetes and Firmicutes ratio. Reports from the animal studies have revealed the ability of the drug liraglutide to balance the ratio of these bacteria and bring about reductions in the blood glucose levels as well as the weight. In addition to this, increase in the population of short chain producing bacteria such as Bacteroides, Lachnospiraceae and probiotic bacteria such as Bifidobacterium have been observed with the drug liraglutide. These findings have provided insights about the potential of the GLP-1 agonists to balance the gut microbial ecosystem.

DPP4 inhibitors

Dipeptidyl peptidase 4 or DPP4 is an enzyme that suppresses the action of the hormone glucagon like peptide-1. DPP4 inhibitors are a group of anti-diabetic medications that prevent the action of the enzyme DPP4 thereby increasing the availability of glucagon like peptide-1 which increases the insulin production and balances the blood glucose levels. Some of the drugs that belong to this group include sitagliptin, saxagliptin, linagliptin, vildagliptin.

Some studies have put forth the DPP4 like activity exhibited by the gut microbes. References have been made to bacteria like Prevotella, Lactobacillus, Lactococcus and Streptococcus having DPP4 like activity. However, more confirmation is awaited regarding the significance of DPP4 derived from the gut microbes. Evidence from the experimental studies conducted on the effects of sitagliptin and vildagliptin have revealed their potential to balance the Firmicutes and Bacteroides ratio in addition to increasing the population of short chain producing bacteria as well as Lactobacillus. These findings have revealed the potential of DPP4 inhibitors to modify the gut microbiota to bring about improvements in the blood glucose levels in individuals with type 2 diabetes.

SGLT2 inhibitors

Sodium-glucose cotransporter-2 inhibitors or SGLT2 inhibitors are a group of anti-diabetic drugs that bring about reductions in the blood glucose levels by preventing the reabsorption of glucose in the kidneys and increasing their excretion through urine. Basically, sodium-glucose cotransporters are a type of protein that are present in the kidney tubules. It is a well-known fact that kidneys play an important role in removing the waste and extra fluids from the body. Each kidney is made up of millions of filtering units called nephrons. Each nephron consists of a cup shaped structure called glomerulus and a tubule. While the glomerulus filters the substances from the blood, the tubule relocates the essential substances into the blood while removing the unwanted ones through urine.

The sodium-glucose cotransporter receptors are of two types. While the SGLT-1 which is responsible for the reabsorption of less than10% of the filtered glucose, SGLT-2 is accountable for more than 90% reabsorption of filtered glucose. Hence inhibiting SGLT-2 is one of the treatment targets in type 2 diabetes. Some of the approved medications that belong to this group are canagliflozin, dapagliflozin and empagliflozin.

The evidence behind the influence of the SGLT-2 inhibitors on the gut bacteria is conflicting. While some studies have questioned the modification of gut bacteria by these drugs, evidence from animal studies have pointed to the effectiveness of dapagliflozin in balancing the Firmicutes and Bacteroides ratio in addition to increasing the population of Akkermansia muciniphila. However, more studies are needed to ascertain these effects.

Thiazolidinediones (TZDs)

Thiazolidinediones or glitazones are a group of anti-diabetic drugs that act by enhancing the insulin sensitivity in the muscle, fat tissue and the liver. These effects of TZDs are related to the activation of a special protein present in the cells called peroxisome proliferator-activated receptor gamma or PPARG, which is responsible for enhancing the action of insulin (insulin sensitivity) and balancing the blood glucose levels. Pioglitazone is one of the approved and commonly used medications of this group. Though concerns have been expressed about the risk of bladder cancer with pioglitazone, studies have produced conflicting results. However, this information has been updated and added in the drug label.

Reports from the animal studies have revealed the presence of communication between the gut microbes and TZD. These studies have demonstrated that TZD possess anti-bacterial activity wherein there was a reduction in the population of harmful bacteria. In addition to this, it has been observed that the butyrate producing bacteria have the potential to activate the PPARG thus protecting against the colonization of harmful microbes such as Escherichia and Salmonella. In addition to these findings, the potential of selected gut bacteria to activate the PPARG in the absence of butyrate has been suggested. Though more studies are needed, the available evidence has provided insights into the interaction between the TZD and the gut bacteria.

Sulfonylureas

These are a class of anti-diabetic drugs that have been used in the treatment of diabetes for over five decades. They act by stimulating the insulin production by the beta cells of the pancreas. The older and the newer sulfonylureas are called the first and the second-generation sulfonylureas. Some of the second-generation ones include glibenclamide, glipizide, glimepiride and gliclazide. These have largely replaced the first-generation sulfonylureas.

The direct evidence behind the relationship between sulfonylurea and gut bacteria is lacking. However, indirect evidence from studies have revealed the presence of a substance called Hippurate in higher amounts in the urine of individuals treated with sulfonylureas. This is a normal metabolic product that is obtained from the breakdown of plant phenols by the gut bacteria. Also, preliminary reports from recent studies have pointed that glibenclamide and glipizide may interact with the gut microbes. However, a direct proof needs to be established to ascertain the influence of sulfonylureas on gut microbes.

Therapeutic value of gut microbiota in type 2 diabetes

<a href="https://www.freepik.com/free-vector/different-types-bacteria-intestines_2480485.htm#query=gut%20bacteria&position=9&from_view=search&track=ais">Image by brgfx</a> on Freepik

The scientific evidence that has accumulated over the last decade has provided insights about the multifaceted role of gut bacteria in maintaining the overall health and well-being. Dysbiosis or imbalance in the gut microbial ecosystem has been linked to the occurrence and progression of several diseases. Insulin resistance and diabetes also are included in the list of diseases and recent studies have supported the link between gut bacteria and diabetes. Though the role of gut health in relation to diabetes, its complications and treatment needs further research in certain areas, the available evidence has provided significant clarity about the potential role of gut bacteria in the treatment of diabetes. Some of the gut bacterial based treatment methods are

Fecal Microbiota Transplantation (FMT)

Also known as the stool transplant, this method involves the transferring a small sample of faeces (stool) from one person’s intestine to another. The concept behind this is to diversify the gut microbial ecosystem with healthy bacteria in a person with gut bacterial imbalance for health benefits. The use of stool as a remedy against different diseases including diarrhoea dates back to 4th century in China. But it was only in the middle of 20th century FMT was introduced as a medical treatment for a condition called pseudomembranous colitis, a high-grade inflammatory condition of the colon (large intestine) caused by a bacterium called Clostridium difficile. Later on, FMT has been extended as a treatment for other gastrointestinal disorders such as Ulcerative colitis (inflammation of the lining of the large intestine and rectum) and irritable bowel syndrome (troublesome abdominal symptoms in the absence of any abnormality).

The donor selection is done carefully after excluding the presence of any infections or diseases. The stool sample is medically processed by adding water or saline and the same is filtered in order to remove any unwanted stool particles. This is then administered through a colonoscope, endoscope, enema or as an oral capsule. Though the procedure is regarded as safe with minor side effects such as abdominal pain, nausea, fever and diarrhoea, concerns have been expressed regarding the long-term safety. Also, the health regulatory bodies have put forth varied opinions regarding the use of FMT.

The effectiveness of FMT in the treatment of metabolic syndrome (a collection of abnormalities such as increased waist circumference, high blood pressure, increased fasting blood sugar, high triglyceride and low levels of HDL or good cholesterol putting an individual at increased risk for developing heart disease, diabetes, insulin resistance and stroke) has been explored only in the last decade. Studies conducted in individuals with metabolic syndrome who received FMT have revealed reduction in the insulin resistance and HbA1c levels with increase in the population of butyrate producing bacteria. Evidence from animal studies with diabetes have revealed increase in the population of Akkermansia muciniphila with FMT. With more long-term studies and convincing evidence, FMT has the potential to become a choice of treatment for diabetes in future.

Dietary fibre and Prebiotics

The term dietary fibre or roughage refers to the part of the plant that can neither be digested or absorbed by the body. Prebiotics are a type of fibre that promote the growth of beneficial gut bacteria. While it is considered that all prebiotics are fibres, not all fibres have prebiotic properties. In order to be labelled as a prebiotic, a fibre should pass through the digestive tract intact, resisting the digestion by the stomach acids and get fermented by the gut bacteria thus providing health benefits.

Though the importance of dietary fibre has been known since several centuries, it was in the 20th century that scientific evidence provided insights into their health benefits. The protective effects of the dietary fibre against diabetes were proposed about five decades back and has been an area of considerable research. Several studies that explored the relationship between increased dietary fibre intake and prevention of type 2 diabetes, have revealed reduced risk for the development of type 2 diabetes. One study demonstrated that increasing the consumption of whole grains significantly scaled down the diabetes risk. Similarly, studies exploring the role of the dietary fibre in the treatment of diabetes have revealed improvement in various parameters such as insulin sensitivity, blood sugar control, Hba1c, lipid profile and body weight. However, more research is needed to ascertain the mechanisms of dietary fibre behind these effects. Also, their effectiveness on a long-term basis also needs more clarity.

There are some variations in the recommended daily intake of dietary fibre suggested by various organisations. However, the generally suggested value is 25-35g/day for adults. It is also important that these recommendations are met by consuming natural dietary fibres such as vegetables, fruits, whole grains, legumes, nuts and seeds. Some of the ways to reach the target fibre intake are

*As suggested by World Health Organisation (WHO), it is advised to consume at least 400g (five portions) of fruits and vegetables per day.

*In the meal plans amounting to 2000 calories/day, it is advisable to add a variety of fruits, vegetables, whole grains, legumes, nuts and seeds both during the meal and snack times.

*Refined grain products should be replaced with whole grain products.

*Legumes should be looked upon not only as a source of protein, but also as a source of fibre. Half a cup of cooked legume (85g) can give 4.5grams of dietary fibre.

*The addition of one tablespoon of chia or flax seeds to oatmeal will give additional 3-5 grams of fibre.

*Foods that are labelled as containing >3 grams of fibre/100 grams or > 1.5g/100 K calories or provide more than 10% of the recommended daily allowance are considered good sources of fibre. The presence of twice the above value is regarded as ‘high fibre’.

In addition to the above dietary recommendations, other dietary methods should be looked into in order to improve the compliance. The macrobiotic diet is based on the ancient Eastern philosophy of life, namely Yin-Yang theory and five element theory.

According to traditional medicine, health is a perfect balance between the internal and external environments. The internal environment includes hereditary factors, emotions, nervous system, endocrine system and personality. The external environment includes nutrition, climate and geophysical forces (relating to the movement and forces of the earth). Any imbalances between the external and internal factors or internal factors on its own, affects the body’s internal balance (homeostasis) resulting in disease state.

The Yin-Yang theory is based on the concept of the presence of two opposing forces flowing through the body. The combined effect of Yin and Yang is called as the Qi or vital energy. When there is harmony between these two forces the Qi flows well. Any imbalances between these forces affects the flow of Qi or vital energy resulting in disease process. The five-element theory is centered around the elements such as wood, fire, earth, metal, water and their influence on the overall health and well-being.

Now, getting back to the macrobiotic diet, it was developed for the Western culture by a Japanese philosopher Georges Ohsawa and modified by Mario Pianesi. He formulated 5 Ma-Pi diets among which Ma-Pi 2 was specifically created for individuals with metabolic disorders. The components of this diet are 50%-55% whole grain (rice, barley, millet), 35%-40% vegetables (carrots, Savoy cabbage, red radish, cabbage, onions, parsley, chicory), 8%-10% legumes (chickpeas, black beans, lentils), gomashio (roasted ground sesame seeds with unrefined sea salt), fermented products (miso, soy sauce, pickled ume plums), sea weeds and Beicha tea (caffeine free green tea). It is an anti-oxidant diet with prebiotic and probiotic values which is devoid of animal products and added sugar. Apart from its rich nutrient value, its dietary fibre averages to 50-60 grams/day.

Studies conducted on the effectiveness of the Ma-Pi 2 diet in individuals with type 2 diabetes has revealed reductions in the fasting blood glucose, HbA1c, total cholesterol, triglyceride levels, HDL (bad) cholesterol, body weight, blood pressure and insulin resistance. Similarly comparative analysis of Ma-Pi 2 diet with Italian diet recommended for type 2 diabetes also produced similar results. Though concerns have been expressed about the nutritional deficiencies especially vitamin B12, owing to the absence of animal products, studies have produced convincing results when this diet is followed on a short to medium term basis.

In addition to these findings, studies have demonstrated increase in the population of beneficial bacteria with this diet. It was observed that this diet owing to its prebiotic and probiotic effects enhanced the counts of mucin and short chain fatty acid producing bacteria such as Akkermansia muciniphila, Faecalibacterium, Roseburia, Lachnospira and Bacteroides. However, more studies are needed to ascertain the safety and efficiency of the diet on a long-term basis.

The WTP diet is a type of high-fibre dietary formulation which consists of a combination of whole grains, traditional Chinese medicinal foods and prebiotics. Studies conducted on the efficiency of this diet in obese people has revealed modest reductions in the body weight, improvement in insulin sensitivity, reductions in the cholesterol levels, blood pressure and HbA1c. In addition to this, increase in the population of short chain producing bacteria was observed. These studies have provided insights that gut bacterial modifications through diet as the potential targets in the management of diabetes.

Probiotics

Probiotics are defined as the live microorganisms which offer health benefits when given in appropriate amounts. In accordance with the recent scientific research, there are three types of probiotics for diabetes. They are

Common probiotics

The main bacteria present in common probiotics are Lactobacillus and Bifidobacterium. However, other specific bacteria and yeast having probiotic properties such as Saccharomyces, Enterococcus, Streptococcus, Pediococcus, Leuconostoc and Bacillus can as well be a part of common probiotics. Several studies have explored the effectiveness of probiotics in individuals with type 2 diabetes. While the outcomes from some studies are conflicting, others have produced encouraging results in terms of reductions in the fasting blood glucose levels, HbA1c and insulin resistance. Also, reductions in the number of harmful bacteria and increase in the population of short chain producing bacteria have been observed. In addition to these findings, it was also observed that the addition of probiotics along with metformin resulted in increase in the population of beneficial bacteria thus resulting in reductions in the insulin resistance and better blood sugar control. While more long-term studies are awaited, it is worth taking a note of the positive effects of probiotic supplementation in individuals with type 2 diabetes.

Some of the foods having probiotic values are

Dairy products like yogurt, cultured buttermilk, cheese, kefir (fermented milk drink). The addition of probiotic bacteria to butter results in reduced cholesterol and saturated fat content reducing the risk of heart diseases. Also, the development of cream based fermented dairy products have been put forward. It has been demonstrated that the fermentation of cream by the addition of Lactobacillus and Bifidobacterium along with added sunflower oil, soybean oil and hazelnut oil is beneficial to health.

Plant based products containing high levels of cellulose, a type of complex carbohydrate which is a component of cell wall of plants, have been shown to nourish the Lactic acid bacteria in the intestine. Cellulose is present in corn bran, skin of most fruits like apples, bananas, avocado, vegetables such as zucchini, green beans, celery, cabbage, cauliflower etc. Kimchi, a traditional food from Korea is prepared by fermenting Chinese cabbage along with radish, green onion, red pepper powder, ginger, garlic and probiotic bacteria. Sauerkraut, from the region of China is prepared by fermenting shredded cabbage. Other soybean-based products such as miso and tempeh are the sources of prebiotics.

Fruit based products include the addition of probiotic bacteria to the fruit juices, nectars and juice drinks. Some of the fruits that accomplish this purpose include papaya, lemon, orange, grapefruit, cranberry, blackcurrant, apple and pear.

Cereal based products with probiotic value include Yosa (oats), Kisra (sorghum), Ogi (maize, sorghum), Sourdough bread (rye, wheat), Puto (rice), Selroti (rice, wheat), Kulcha, nan, Bhatura (wheat), Chilra (barley, wheat and buckwheat).

Meat based products with probiotic properties have been shown to have beneficial effects in humans. Studies conducted on fermented sausages having probiotic bacteria have revealed changes in the gut colonisation observed after three days. Also, when effects of fermented sausage consumption were compared to the intake of probiotic capsules, it was revealed that fermented sausages produced increased gut bacterial colonisation compared to those seen with probiotic capsules.

Novel probiotics

The bacterium Akkermansia muciniphila has received considerable attention since its isolation about two decades back. They represent 3%-5% of the gut microbial population and reside in the inner slimy layer of the gut also called as mucus layer. Higher counts of this bacterium are seen in healthy individuals whereas lower counts are associated with diabetes, obesity, metabolic and intestinal disorders. Recent lines of evidence have supported the protective role of this bacterium against obesity, type 2 and type 1 diabetes as well as metabolic syndrome (a condition wherein the presence of a group of abnormalities such as high blood pressure, high blood sugar, high cholesterol and increased fat around the waist puts the person under the risk of diabetes, stroke and heart attack).

A growing number of studies have explored the strategies to increase this bacterial count owing to its probiotic properties. In contrast to the common probiotics, the evidence behind the oral supplementation of live Akkermansia muciniphila is sparse. Though animal studies have produced encouraging results, more studies are warranted regarding its long-term use in a clinical set up. However, recent studies have explored the dietary strategies to increase the Akkermansia muciniphila count. Some of these include

Probiotics: Preliminary report from animal studies points to increase in the Akkermansia muciniphila count on oral supplementation with a combination of live Lactobacillus and Bifidobacterium.

Prebiotics: A type of prebiotic called fructooligosaccharides (FOS) has been shown to enhance the growth of Akkermansia muciniplila. FOS is naturally present in onions, garlic, asparagus, banana, chicory, artichoke, tomatoes, wheat, barley, oats, sugar beet etc.

Polyphenols: These are a group of compounds present in plants that are regarded for their health benefits. Some of the polyphenols like cranberry extract, black raspberries, pomegranate ellagitannin, which is nothing but a type of phenolic compound present in pomegranate, epigallocatechin-3-gallate (EGCG, predominantly present in green tea) and grape proanthocyanidin have been investigated for their effects on Akkermansia muciniphila in animal and human studies. However, the results have been inconsistent and this is possibly attributed to the chemical nature of the polyphenols.

Rhubarb extract: Rhubarb is a type of vegetable having bright pink stocks with a distinct sour taste. These stocks have a crisp texture and are often cooked with sugar to be used in pies and desserts. The root extract of the rhubarb has been a part of the traditional medicine since ancient times. In Traditional Chinese Medicine the root extract is used as a remedy for constipation, jaundice, gastrointestinal bleeding and ulcers. In addition to these, rhubarb has been said to possess anti-cancer and liver protecting properties. Recent studies have demonstrated the effectiveness of the rhubarb extract in increasing the Akkermansia muciniphila counts. However, the exact mechanism behind this effect needs to be evaluated. But given the fact that the rhubarb extract is low in fibre and polyphenol content, it is presumed that a compound called anthraquinone might be responsible for increased counts of Akkermansia muciniphila. The beneficial role of purified rhubarb anthraquinones needs further evaluation.

Despite being acknowledged as a novel probiotic, the application of Akkermansia muciniphila in medical and food industries is sparse. Though the current research has provided some insights about its probiotic potential, more in-depth analysis is needed about its safety and efficiency to be used in clinical practice. With more scientific research, Akkermansia muciniphila could open up new horizons in the management of diabetes, obesity and metabolic disorders.

Genetically modified bacteria

The bacterium Lactococcus lactis has been used for many centuries for the fermentation of yogurt, cheese and sauerkraut. Recent studies have put forward the potential of this bacterium to supply oral glucagon like peptide (GLP-1) on genetic modification, for blood sugar control. However, the road to clinical application of this concept is long needing in-depth scientific research.

Exercise

In individuals with type 2 diabetes, exercise is a prerequisite for enhancing insulin sensitivity, balancing the blood glucose levels and controlling inflammation. The general recommendation is to have at least 150 minutes of moderate-intensity exercise per week which should include two days of muscle strengthening exercise. It could be split as 30 minutes of moderate-intensity activity such as brisk walking each day for five days a week or vigorous aerobic exercise such as jogging for 75 minutes per week or a combination of two for 2 or more days a week.

The research into the gut microbes has provided insights into the ways exercise balances the diabetic parameters. Studies have demonstrated that exercise not only diversifies the gut microbial ecosystem, but also enhances the count of Akkermansia muciniphila. Given the fact that the lower counts of this bacterium are related to obesity and type 2 diabetes, the findings can be correlated to increased lean body mass (muscle weight) in athletes. These changes in the gut microbiota play an important role in the way the glucose is utilised. In addition to this, the increased production of short chain fatty acids by the beneficial bacteria contributes to the blood glucose balance.

Summary

*The increasing incidence of type 2 diabetes on a global note has resulted in a significant health burden.

*The development of type 2 diabetes involves the interplay between genetic, environmental and metabolic factors.

*Insulin resistance is considered as the hallmark of type 2 diabetes.

*The role of gut microbes in the development of diabetes have been explored in recent studies.

*The human intestines harbours trillions of microbes that share a friendly relationship with the host.

*The bacterial colonies that dominate the gut microbial ecosystem includes Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia.

*The short chain fatty acids that are produced as a result of fermentation of dietary fibre by the gut bacteria have innumerable health benefits.

*Dysbiosis of the gut microbiota has been linked to a number of diseases including diabetes.

*Alterations in the Firmicutes and Bacteroidetes ratio, reductions in the population of butyrate producing bacteria and Akkermansia muciniphila with increases in harmful bacteria has been observed in diabetes.

*Gut microbial alterations are also encountered in prediabetes, diabetic complications and with diabetic medications.

*In addition to the lifestyle modifications, a growing number of studies have supported the role of probiotic supplements in individuals with prediabetes.

*Uncontrolled diabetes is associated with the development of macrovascular and microvascular complications.

* The severity of the microvascular complications involving the eyes, kidneys and the nerves is directly related to the degree of gut microbial imbalance.

*Though the administration of probiotics in individuals with chronic kidney disease has produced encouraging results, further studies are warranted with diabetic eye and nerve disease.

*The macrovascular complications of diabetes are attributed to the build-up of atherosclerotic plaques and excessive TMAO production by the gut bacteria.

*With the exception of stroke, the evidence behind the role of probiotics in coronary heart disease and peripheral vascular disease is encouraging.

*The existence of a two-way communication between the gut microbes and anti-diabetic medication has been put forward by recent studies.

*The intestines are regarded as the point where in action of metformin begins.

*Apart from increases in the level of GLP-1, enhanced production of short chain fatty acids by the gut bacteria and increased counts of Akkermansia muciniphila brought about by metformin have been said to contribute to its anti-diabetic effects.

*Alpha-glucosidase inhibitors have been shown to increase the population of Lactobacillus Bifidobacterium and butyrate producing bacteria, in addition to balancing the Firmicutes and Bacteroidetes ratio.

*The GLP-1 agonists have been found to bring about reductions in the blood glucose levels as well as the weight by bringing about increase in the population of short chain producing bacteria and probiotic bacteria.

*Though it has been put forth that selected gut bacteria exhibit DPP4 like effects and also have the potential to balance the gut microbes, the evidence behind this is sparse.

*The evidence behind the role of SGLT-2 inhibitors in balancing the gut microbes is controversial and warrants more studies.

*The available evidence points out to the anti-bacterial activity and the potential of TZDs to activate PPARG.

*There is no direct proof to ascertain the relationship between the sulfonylureas and gut microbes.

*Indirect evidence points to the presence of a metabolite called Hippurate in higher amounts in individuals treated with sulfonylureas.

*The gut bacterial based treatment for type 2 diabetes has been increasingly investigated.

*With evidence backing FMT in the management of metabolic syndrome and diabetes, it could potentially become a future option for treatment.

*Though there is convincing evidence regarding the positive effects of dietary fibre on diabetic values and gut microbes, its effectiveness in the long run needs evaluation.

*The promising role of probiotics in the management of diabetes, obesity and metabolic disorders warrants more studies to be applied into clinical practice.

*Exercise contributes to the diversification of the gut microbial ecosystem with increases in the population of Akkermansia muciniphila and other beneficial bacteria.