Gut Microbiota Potential in Type 2 Diabetes

Abstract

Appropriate metabolic regulation is vital for health. Multiple factors play important roles in maintaining the metabolic system in different physiological conditions. These factors range from intestinal metabolism of food and absorption of nutrients, pancreatic hormones and their interplay under feeding and fasting, hepatic regulation of macronutrient formation and metabolism storage of macronutrients in skeletal muscles. Intestinal metabolism of ingested food and subsequent nutrient absorption depends on the symbiotic microbial community residing in the gut. The specific ratio of different microbial phyla in the gut has proved to be extremely important for the beneficial role of the gut microbiome. The importance of gut microbiome in the regulation of metabolism has been highlighted with reports of the abnormal ratio of gut microbial community resulting in different metabolic disturbances ranging from obesity to the development of diabetes mellitus. The physiological impact of insulin on the metabolic regulation of macronutrients has recently been shown to be augmented by the secondary metabolites produced by anaerobic fermentation. The current chapter aims to highlight recent findings in the regulation of extraintestinal metabolism by gut microbiome with a specific emphasis on the physiology and pathophysiology of the pancreas in health and disease.

1. Introduction

Insulin is predominantly the most important endogenous protein responsible for the physiological regulation of metabolism [1]. Exogenous insulin is the only substantial treatment option for patients suffering from insulin deficiency since the initial discovery of insulin by Sir Frederick G Banting and its purification by James B. Collip in 1921 [2, 3]. The pancreatic gland is responsible for the regulated secretion of insulin to maintain glucose homeostasis under different physiological conditions [4, 5]. Islets of Langerhans present in the pancreas contain cells that secret specific hormones which help in maintaining glucose levels during feeding and fasting [5, 6, 7, 8, 9]. Islets of Langerhans are defined as closed areas containing multiple cell types with enormous vascular and nervous innervation [5]. Islets of Langerhans are designated as the endocrine portion of the pancreas. The exocrine part of the pancreas surrounds islets of Langerhans. Different cell types present in the islets secrete different types of hormones. Islets contain four different types of endocrine cells: alpha (α) cells (glucagon), beta (β) cells (insulin), delta (δ) cells (somatostatin) and PP cells (pancreatic polypeptide) [5]. Alpha cells are responsible for the secretion of glucagon hormone to enhance blood glucose levels under fasting conditions while β cells are responsible for insulin secretion which initiates postprandial glucose metabolism and thus controls the rising blood glucose levels [10, 11]. Apart from glucose metabolism, insulin is also involved in lipid and protein metabolism [12, 13, 14]. Blood glucose level acts as the main trigger for the release of insulin from β cells, a phenomenon known as glucose-stimulated insulin secretion (GSIS) [15, 16, 17]. Glucose at normal physiological levels not only induces insulin gene transcription by recruiting transcription factors (PDX-1, MafA and NeuroD) but also improves the insulin mRNA stability thus acting as a major physiologic regulator of insulin [18, 19, 20]. Glucose enters the β cells via glucose-specific channels present on the cell membrane commonly known as glucose transporters (GLUT) [4, 17]. Numerous types of glucose transporters are present in different tissue of the body [21]. But specifically, GLUT2 is most abundant and functional in the pancreas (β cells) and liver (hepatocytes) whereas GLUT4 is present on skeletal and cardiac muscles and adipocytes [21, 22].

2. Insulin and macronutrient metabolism

Insulin is the primary hormone responsible for initiating carbohydrate metabolism through phosphorylation of glucose and subsequent formation of glucose-6-phosphate inside the cells [23, 24]. Insulin activates the hexokinase enzymes in non-hepatic tissues and glucokinase (GCK) in β cells and hepatocytes to initiate glucose phosphorylation [25, 26, 27, 28]. The insulin hormone acts by binding to the cell surface insulin receptors which are vastly distributed in different tissues of the body [29]. The binding of insulin to its receptors activates adaptor proteins known as insulin receptor substrates (e.g. IRS1, IRS2) [30]. IRS protein converts the tyrosine phosphorylation signal into the lipid kinase by activating phosphoinositide2-kinase enzyme (PI3K). Activated PI3K further recruits ATP molecules which activates AKT (serine and threonine kinase) [31]. The Discovery of insulin’s primary role in activating AKT proved a landmark in explaining the conversion of tyrosine phosphorylation into serine/threonine phosphorylation signal. AKT activation also explains the insulin induced regulation of key steps in insulin signaling including (a) glucose uptake by glucose transporter (GLUT4), (b) glycogen synthesis by glycogen synthase kinase 3 (GSK3) inhibition, (c) synthesis of protein and fats via activation of the mechanistic target of rapamycin (mTOR), (d) gene expression regulation at the transcriptional levels by forkhead family box O (FOXO) transcription factor proteins. Insulin enhances GLUT4 activity in muscle and adipose tissue thus increasing the rate of glucose transport, glycolysis and subsequent glycogen synthesis in these tissues [32]. Insulin also prevents hepatic glucose synthesis by inhibiting hepatic glycogenolysis and gluconeogenesis [33, 34, 35].

Apart from glucose metabolism, insulin influences lipid and protein metabolism through multiple means. Insulin lowers the plasma fatty acid levels by decreasing adipocyte lipolysis and enhancing the hepatic formation of very low density lipoprotein (VLDL) [36, 37, 38, 39, 40, 41]. Insulin increases the protein synthesis in skeletal muscles and the liver by enhancing the amino acid transport inside the cells and reducing protein degradation and urea formation [13, 42, 43, 44, 45, 46, 47]. These metabolic effects of insulin on carbohydrates, lipids and proteins highlight the importance of insulin signaling in maintaining a nutritional consistency at the cellular level and ensuring a balanced physiological interplay between multiple tissues under diverse physiological conditions.

3. Glucose homeostasis: insulin-glucagon interplay

Alpha and β cells work together to maintain glucose homeostasis under feeding and fasting conditions through the periodic release of insulin and glucagon respectively [4, 25, 48]. Feeding results in increased plasma glucose levels. Rising plasma glucose levels demand immediate systemic activation of glucose metabolism by insulin. A delayed or deficient activation of glucose metabolism will result in abnormally high plasma and cellular glucose levels, a medical condition known as hyperglycemia. Glucose at higher-than-normal concentrations induces glucotoxic effects inside the cells. Rising postprandial glucose levels will trigger β cells to synthesize and secrete insulin. The postprandial rise in insulin levels activates glucokinase and hexokinase activity resulting in glucose phosphorylation in hepatocytes and muscle cells. Conversion of glucose into glucose-6-phosphate will result in the decline of plasma glucose levels over time. Physiologically because of GSIS the postprandial rise in the insulin secretion from β cells declines over time as the blood glucose level decline [15]. Thus, the rising plasma glucose levels provide positive feedback to enhance insulin secretion and the declining plasma glucose levels act as a negative feedback loop to lower insulin levels. Insulin negatively impacts glucagon secretion [49, 50, 51, 52]. Plasma glucose levels decline under fasting conditions. As glucose is the primary cellular source to generate ATP, a minimum threshold of plasma glucose levels must be maintained to avoid hypoglycemia.

Hypoglycemia is a serious medical condition characterized by very low plasma glucose levels. Fasting induced a decline in plasma glucose levels and subsequent diminished insulin levels initiate glucagon synthesis and secretion from alpha cells. To avoid hypoglycemia during fasting, glucagon enhances plasma glucose levels by activating hepatic gluconeogenesis/glucogenolysis thus forming glucose molecules from non-carbohydrate sources [10, 53, 54, 55, 56, 57]. Glucagon secretion from alpha cells and insulin secretion from β cells are also regulated by incretin hormones secreted from the intestines [58]. Incretin hormones are gut peptides secreted from the L and K cells of the small intestine and include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [59, 60]. GIP and GLP-1 functional receptors are present on both alpha and β cells. In normal physiological conditions, the GIP induces glucagon secretion from alpha cells during fasting or hypoglycemic state whereas GLP-1 induces insulin secretion from β cells and inhibits glucagon secretion from alpha cells [59, 61].

4. Diabetes mellitus

Diabetes mellitus is primarily a metabolic dysfunction resulting in a significant reduction in the cellular ability to metabolize glucose because of either the lack of insulin or insulin inactivity (insulin resistance) [62, 63]. Diabetes mellitus is expected to affect 700 million worldwide by 2040 [64]. The compromised ability of the cells to metabolize glucose results in increased cellular and plasma levels of glucose, a condition known as hyperglycemia. Hyperglycemia induces tissue damage mainly through the increased influx of glucose through the polyol pathway and increased formation of advanced glycation end products (AGEs) and subsequent increased expression of AGE receptors and their ligand [65, 66]. Overproduction of reactive oxygen species (ROS) due to hyperglycemia through mitochondria acts as the main trigger for the activation of the polyol pathway, formation of AGEs and increase in AGE receptor expression [67].

Diabetes mellitus has been categorized in two primary forms: Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM). T1DM has been characterized by a mutation in the insulin gene or immune cell-mediated destruction of β cell resulting in either the synthesis of abnormal insulin protein that fails to activate insulin receptors or a complete lack of endogenous insulin secretion [63]. T1DM patients are usually diagnosed early in their life. The only possible medical treatment referred to these patients is the multiple daily doses of synthetic insulin. T2DM on the other hand is much more complicated and requires a thorough diagnostic approach [62, 68, 69, 70]. T2DM is considered one of the most common metabolic disorders globally. Major risk factors for T2DM include a sedentary lifestyle, lack of exercise, excessive use of a high-carb and high-fat diet, overweight and obesity [71]. Poor lifestyle and dietary habits have been attributed to the global incidence of type 2 diabetes in the last 2 decades. Obesity, visceral fat deposition and increased body mass index (BMI) play a central role in the pathophysiology of type 2 diabetic patients [62]. Quality, quantity and type of food have been debated to be the primary cause of this global incident. A healthy diet with the appropriate amount of nutrients and fiber and a certain level of physical activity has been advised globally to counter the incidence of T2DM in young adults.

The development of T2DM is mainly caused by the significant decline in insulin secretion from β cells or the inability of insulin-responsive tissues (muscles, fat and liver) to respond to insulin, mainly because of defective insulin signaling resulting in hyperinsulinemia and subsequent insulin resistance [72, 73, 74, 75]. Failure of the insulin hormone to activate insulin receptors at the cellular level has been attributed to be the major cause of hyperinsulinemia and insulin resistance [76, 77]. Insulin binding to insulin receptors at the plasma membrane activates a signaling cascade that initiates glucose metabolism inside the cells. Insulin-bound insulin receptors or activated insulin receptors go through internalization at the plasma membrane, a phenomenon known as insulin receptor endocytosis [1, 78]. Following the activation, the endocytosis of the insulin receptor is the primary physiological mechanism through which the duration and intensity of insulin signaling are controlled. Hyperinsulinemia accelerates insulin receptor endocytosis and affects the presence of adequate functional insulin receptors at the plasma membrane resulting in insulin resistance [79]. Apart from accelerated insulin receptor endocytosis, insulin-stimulated insulin receptor kinase activity is also decreased in diabetic patients [80]. Compromised insulin signaling fails to activate glucose metabolic enzymes like glucokinase and hexokinase resulting in hyperglycemia. High plasma glucose levels initiate glucose-stimulated insulin secretory (GSIS) response from β cells resulting in the rise of plasma insulin levels. The rising insulin levels should be normalized over time because of the renal insulin clearance mechanism. But compromised renal insulin clearance rate in diabetic subjects results in abnormally high plasma levels of insulin (hyperinsulinemia) [81, 82].

Hyperinsulinemia and hyperglycemia in theory cannot trigger alpha cells to secrete glucagon. But it has been observed that T2DM patients with insulin resistance, hyperinsulinemia and hyperglycemia also have abnormally high plasma levels of glucagon [83]. Hinting toward the disturbance in the alpha and β cell interplay through the inability of the insulin to block glucagon gene transcription [84]. T2DM is also characterized by a decrease in GLP-1 secretion from L cells of the small intestine [85, 86]. Indicating a pathophysiological role of the gut in the development and progression of type 2 diabetes [87, 88]. GLP-1 receptor agonists which induce an increase in insulin secretion from β cells and inhibit glucagon secretion are the major treatment option for T2DM patients to combat hyperglycemic conditions [89, 90, 91].

5. Gut microbiota profile in Type 2 diabetes mellitus

The gut microbiome was first defined scientifically in 2001 as “an ecological community of commensal, symbiotic and pathogenic microorganisms that collectively share our body space” [92]. Approximately 100 trillion microbes are found in the human gastrointestinal tract (GIT) and strongly influence the health status of individuals either directly or indirectly [93, 94, 95, 96, 97]. The primary reason for the pathophysiological effect of the gut microbiome on human physiology has been attributed to the disruption of the stable communities of gut microbes through medication, diet and lifestyle. A normal, healthy gut microbiome profile is termed eubiosis and abnormal gut microbiome composition is called dysbiosis [98, 99, 100, 101, 102, 103, 104, 105, 106]. Eubiosis typically refers to an ideal bacterial population comprising 95% of Bacteroidetes and 5% Firmicutes producing abundant microbial metabolites like short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs) and impacting lipid metabolism. SCFAs like butyrate, acetate and propionate are produced by the anaerobic fermentation of non-digestible carbohydrates (dietary fiber) and promote gut integrity and protect gut epithelial lining by forming tight junctions and preventing gut permeability [107]. These microbial secondary metabolites act as central components in microbe to host signaling pathways activation. Much of the specific microbiota involved in the production of these important secondary metabolites are reduced in T2DM patients.

Substantial data from human studies support the possibility that dysbiosis triggers obesity, inflammation, insulin resistance and T2DM [108, 109, 110, 111]. Association of dysbiosis is also attributed to the pathogenesis of intestinal tissue. Intestinal disorders attributed to dysbiosis include inflammatory bowel disease, irritable bowel syndrome (IBD) and coeliac disease [102, 111, 112]. Whereas metabolic syndrome, obesity, and cardiovascular complications are attributed as extra-intestinal effects of dysbiosis. Dysbiosis has also been attributed not only to the initiation of the T2DM in humans (a condition known as prediabetes) but also during the progression and subsequent secondary complications of T2DM with several lines of evidence suggesting that manipulation of the gut microbiome helps to minimize or alleviate the T2DM conditions [98, 113, 114, 115, 116, 117, 118, 119, 120, 121].

The role of gut microbiota in health and disease and specifically the pathogenesis of T2DM has been experimentally investigated mainly by using rodent models as a limited amount of experimental data can be generated through human studies. Keeping in mind that the rodents and human physiology are not exactly similar and certain physiological differences exist. The non-human primates seem to be a much more appropriate animal model to study different aspects of primate physiology including the gut microbiome and its interaction with metabolic dysregulation [122, 123, 124, 125, 126, 127]. Nonetheless, the current understanding of the role of the gut microbiome in the context of metabolic syndrome or pathogenesis of diabetes mellitus has primarily originated from the data on rodent and human studies [94, 97, 116, 128, 129, 130, 131, 132, 133]. Interestingly efforts have been made in the past to characterize the gut microbiome in normal and diabetic individuals as well as some therapeutic approaches have been adopted [95, 98, 113, 116, 117, 120, 121, 134].

The attempts to characterize the normal human gut microbiome revealed four primary phyla which are responsible for the physiological role of gut in metabolic modulation [128, 132, 133, 135, 136, 137, 138, 139, 140, 141]. These four specific phyla/families of microbes present in the gut include Bacteroidetes (Bacteroidota), Firmicutes (Bacillota), Proteobacteria (Pseudomonadota) and actinobacteria (Actinomycetota) [95, 142]. The specific proportion for each of these phyla in normal physiological and homeostatic conditions indicates that the largest group of microbes is the Firmicutes which make up to 64% of the total gut microbiota. Followed by the Bacteroidetes, which make up the second-largest group, contributing up to 23% of the total gut microbiota. Proteobacteria and actinobacteria contribute the rest with 8% and 3% respectively. These specific percentage contributions of each phylum are extremely important physiologically. Increased prevalence of pro-inflammatory conditions such as obesity, T2DM, arthritis and even cancer have been attributed to the disruption of these specific percentage contributions of each phylum [132, 143]. Human and animal data have highlighted the unique compositional changes in the microbiota profiles at the phylum level in T2DM conditions [113, 128]. T2DM patients exhibit increased membrane transport of sugars, BCAA transportation, methane metabolism and sulfate reduction [128]. These patients also have reduced butyrate biosynthesis and cofactors/vitamins metabolism.

Although a certain level of discrepancy does exist in terms of phyla composition data between different T2DM patients which has been attributed to the specific geographical location, culture-specific diet and medication use [144]. Numerous independent research groups have reported widely contrasting microbiota findings in the context of phyla composition in T2DM patients [113, 114, 117, 119, 128, 145, 146]. It seems highly unlikely that a single microbe species can play a significant or dominant role in determining the risk of T2DM. The conflicting data from several independent groups also have some interesting similarities. Specifically, it was a common observation among T2DM patients that butyrate-producing microbes were particularly depleted [117, 128]. As human microbiome is comprised mainly of Bacteroidetes and Firmicutes with a specific ratio (B/F > 1) and obesity has been shown to impact this ratio and result in the increased prevalence of Firmicutes to that of Bacteroidetes [109, 147, 148, 149]. Implicating that a disrupted B/F ratio can contribute to obesity in humans. Similarly increased concentration of Bacteroidetes and Proteobacteria with a significant decline in Firmicutes has been reported in T2DM patients [113] T2DM also demonstrates an increase in pathogenic microbial species like Clostridium symbiosum, Clostridium ramosum, and Escherichia coli resulting in systemic inflammation [119, 128].

Insulin resistance has also been attributed to disrupted Bacteroidetes and Firmicutes (B/F) ratio. An altered B/F ratio impacts intestinal permeability and lipopolysaccharide (LPS) from proteobacteria are translocated from inside the gut. LPS translocation activates immune response through interleukin-1 (IL-1), tumor necrosis factor (TNF), Jun N-terminal kinases (JNK) and IkB kinase (IKK). LPS-induced activation of JNK and IKK results in the phosphorylation of insulin receptor substrate (IRS) which fails to activate downstream effector molecules like PI3K and AKT thus rendering the insulin signaling cascade ineffective [150, 151]. IKK also activates the nuclear translocation of nuclear factor kappa B (NF-kB). NF-kB, a transcription factor, induces the expression of several genes involved in inflammatory and apoptotic responses [152, 153, 154, 155]. The inflammatory state also called metabolic endotoxemia is accompanied by insulin resistance and obesity.

6. Regulation of glucose homeostasis by Gut microbiota

Gut microbiota has been shown to impact the pancreas directly. Gut microbiota has been proposed to modulate glucose homeostasis through multiple mechanisms [115, 116, 118, 156, 157]. Experimental data support four specific mechanisms through which the gut microbiome influences glucose homeostasis; (1) the β cell modulating effects of metabolites that are formed due to gut anaerobic microbial fermentation [157, 158, 159], (2) induction of cytokine activity in the islets of Langerhans via inflammatory cascades [160, 161, 162, 163, 164], (3) direct islets signaling affecting insulin and glucagon secretion through incretins modulation [87, 165], (4) alteration in the gut permeability, thus permitting the influx of toxins through intestinal mucosal barrier [166]. Mechanisms 1 and 3 are mainly considered for increased T2DM susceptibility and whereas mechanisms 2 and 4 are particularly implicated in the development of T1DM in early life. As T1DM is characterized by a significant reduction in the number of functional β cells. Cytokine and toxin-induced β cell apoptosis or dedifferentiation are considered major risk factors for T1DM.

Abnormal gut microbiome composition alters the intestinal barrier which favors absorption and increased circulating levels of LPS and BCAA. LPS induces low-grade inflammation and insulin resistance while BCAA is associated with an increased risk of T2DM development. An altered intestinal barrier also reduces the absorption of beneficial SCFAs and secondary bile acids. Metabolically SCFAs are mainly produced as an energy source for the gut epithelium. Butyrate is used by colonic epithelial cells for energy, acetate is used as a fatty acid precursor like cholesterol and propionate is a precursor for the process of hepatic gluconeogenesis [167, 168, 169]. Animal data have shown the beneficial impact of acetate supplementation on insulin resistance and glucose tolerance in animals fed with a high-fat diet [170]. Acetate at high intravenous (i.v) dose has also been reported to acutely enhance circulating levels of GLP-1 in humans [171]. Butyrate supplementation has been reported to enhance insulin sensitivity in mice fed with a high-fat diet while obesity and insulin resistance fail to develop over the course of 16 weeks [165].

Functional modulation of β cells through secondary metabolites is highly important in maintaining homeostatic glucose levels. SCFA has been highlighted as an important signaling molecule as the recent findings of the presence of functional SCFA cell surface receptors on different tissues including gut and peripheral tissues [172, 173, 174, 175]. Gut microbial modulation of the host’s metabolism modulated by SCFA production has been demonstrated by the activation of G-protein coupled cell surface receptors (GPCRs) also known as free fatty acid receptors (FFAR). FFAR includes different GPCRs which bind fatty acids of different chain lengths. GPR40 (FFA1), GPR84, and GPR 120 (FFA4) bind with the medium and long-chain fatty acids. Whereas GPR43 (FFA20), GPR41 (FFA3), and GPR109 bind with SCFAs. Propionate and acetate are found to be the most potent agonists of FFA3/GPR41 while butyrate selectively binds with FFA2. FFARs have been shown to be present in different peripheral tissues including the gut, liver, and pancreas. SCFAs like butyrate and propionate along with secondary bile acids indirectly modulate β cells. SCFAs enhance insulin secretion by activating GLP-1 secretion from the intestines [158, 176]. Butyrate and propionate bind and activate G-protein coupled receptors (GPR43, GPR119) present on the enteroendocrine L cells and stimulate the release of GLP-1 in humans [177, 178]. Propionate also has been reported to influence β cell activity directly in humans. Propionate inhibits inflammatory cytokine-induced β cell apoptosis in human islets and enhances GSIS response from β cells independent of increased GLP-1 levels [179]. FFARs have been expressed by β cells and reported to modulate β cell activity in terms of GSIS [174, 180]. Apart from β cell modulation in terms of GSIS response, an interesting observation was made in these studies that high-fat diet-induced insulin resistance in a mouse model has shown to influence FFA2 receptor expression in β cells. Apart from these above-mentioned in vivo studies a recently published in vitro data further extends the notion that acetate, propionate, and butyrate separately enhance insulin secretion along with an increase in the expression levels of insulin genes from rat islets during long-term incubation [181]. Interestingly the authors noted that long-term incubation with butyrate induced a significant downregulation of β cell-specific key transcriptional factors and functional genes involved in the maturity-onset diabetes of the young (MODY). Another interesting finding which was made in this recent study was the significant suppression of the β cell identity genes like GLUT2, GCK, Pdx1, MafA, Nkx-6.1, and NeuroD1 after the long-term incubation with butyrate. The global suppression of the β cell identity gene was surprisingly independent of the deacetylase activity of butyrate indicating a non-DNA acetylation mechanism involved. A significant decrease in the gene expression pattern of GLUT2 and GCK in rat islets after the long-term incubation with butyrate indicates that glucose or GSIS was not involved in the increased mRNA levels of INS1 and secretion of insulin protein. Instead the basal levels of intracellular calcium ions [Ca²⁺]_i was much higher in butyrate-treated islets as compared to the control. The combined effect of acetate, propionate, and butyrate on isolated rat or mouse islets in short- and long-term incubations needs to be examined in future studies. Along with in vivo approaches to fully characterize the impact of microbial metabolites on glucose homeostasis in different physiological conditions.

7. Prebiotics, probiotics and diet

Prebiotics are food ingredients that are non-digestible but fermentable oligosaccharides. The primary role of prebiotics in food is to stimulate the fermenting activity of gut microbes and eventually trigger the growth of beneficial gut microbes [182, 183, 184, 185]. Probiotics on the other hand are special foods that contain a certain amount of alive non-pathogenic bacteria which help to improve gut health and confer eubiosis [186, 187]. Bifidobacteria, lactobacilli streptococci and E. coli are the main bacterial strains that constitute most of the available probiotics. Prebiotics and probiotics supplementation has been shown to reduce inflammation and obesity in T2D patients [188, 189, 190, 191, 192]. The beneficial effect of prebiotics and probiotics on gut health, in general, is well accepted. However, the expected benefits of pre and probiotics in dysbiotic T2D patients is limited. Advanced stage or elderly diabetic patients fails to respond to pre and probiotic supplementation as compared to young and early-stage T2D patients [190, 193, 194]. An appropriate ratio of different gut microbes is extremely important for proper metabolic physiology. As dysbiosis has been attributed as an important permissive or causative factor in developing T2D. Extensive use of high-fat diets, diets which are also called western diets or fast food, have the ability to modulate gut microbiota. Specifically, the downregulation of beneficial Bifidobacteria (Actinobacteria), which helps to break down food, and nutrient absorption and helps to alleviate constipation and diarrhea by fighting off pathogenic microbes. As Actinobacteria only makes up to 3% of the total gut microbiota, the high fat diet-induced decrease in Bifidobacteria causes an acute pathological impact on metabolism and gut health. A high-fat diet also induces an unwanted increase in the proteobacteria, which usually accounts for a maximum 8%. An increase in the LPS containing proteobacteria causes inflammation and obesity, a condition known as endotoxemia which is accompanied by insulin resistance. Oligofructose-containing prebiotics has been shown to lower LPS containing Proteobacteria by enhancing Bifidobacterial thus modulating endotoxemia and via GLP-1 dependent pathway improves glucose tolerance [195]. Prebiotics, probiotics and fecal microbial transplantation (FMTs) are the main treatment options to enhance gut microbiota. The limited success of these treatment options to restore and maintain the eubiosis over time and the unique microbiology of the gut microbiome has called for a better understanding of gut microbial response and adaptation to different diets and lifestyles. An elegant recent report documenting the in vivo bacterial gene expression profile in the gut in different groups of mice indicates that bacterial gene expression is hugely impacted by the type of food present in the gut [196]. Lifestyles, cultures and specific diets have been shown to modulate the gut microbiome in healthy non-diabetic subjects (Figure 1). These are lifestyle/diet-induced effects that eventually cause metabolic disorders and obesity. Apart from these detrimental outcomes of certain lifestyles, medications especially antibiotics can severely damage the overall population and the specific ratio of the gut microbiome.

Figure 1.

Impact of the use of probiotics and prebiotics on the gut microbiome in terms of its functionality and improving the glycemic control through manipulation of multiple factors like improved incretin secretions, increase in the production of SCFAs, improved bile acid metabolism and the decrease in the LPs induced low grade inflammatory response.

8. Conclusion

Diabetes mellitus has emerged as the major metabolic disorder in the last two decades. A sedentary urban lifestyle, increased consumption of processed and fried foods and diets high in fat and protein have been indicated as the main reason for unhealthy weight gain causing obesity and disrupting the normal physiological pathways responsible for metabolic homeostasis. The role of the gut microbiome in ensuring a healthy metabolic and immune system is paramount. The remarkable research efforts made in the last two decades highlight gut microbial imbalance or dysbiosis as a common finding in diabetic patients. The direct and indirect regulatory influence of the gut microbial activity on the islet’s functionality has been experimentally characterized in rodent models. The experimental findings highlight the importance of a healthy gut microbial community and the use of the appropriate amount of dietary fiber to support fermentation and production of beneficial SCFAs which not only impact the intestinal permeability but also influence β cell activity directly as well as indirectly. The use of pre or probiotics along with a healthy diet comprising enough dietary fiber is a prerequisite for communities and individuals suffering from obesity and diabetes.