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Gut microbiome and type 2 diabetes: where we are and where to go?
Accepted Manuscript Gut microbiome and type 2 diabetes: Where we are and where to go?
Sapna Sharma, Prabhanshu Tripathi PII: DOI: Reference:
S0955-2863(18)30307-3 doi:10.1016/j.jnutbio.2018.10.003 JNB 8077
To appear in:
The Journal of Nutritional Biochemistry
Received date: Revised date: Accepted date:
1 April 2018 17 September 2018 3 October 2018
Please cite this article as: Sapna Sharma, Prabhanshu Tripathi , Gut microbiome and type 2 diabetes: Where we are and where to go?. Jnb (2018), doi:10.1016/j.jnutbio.2018.10.003
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ACCEPTED MANUSCRIPT Gut microbiome and type 2 diabetes: where we are and where to go?
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Authors: Sapna Sharma1, Prabhanshu Tripathi2*
Affiliations: 1Gene Regulation Laboratory,
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School of Biotechnology, Jawaharlal Nehru University,
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New Delhi, 110067, India
Centre for Human Microbial Ecology, Translational Health Science, and Technological
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Institute, NCR Biotech Science Cluster, 3rd Milestone Gurgaon-Faridabad Expressway,
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Faridabad, Haryana 121001, India
*Corresponding Author
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Prabhanshu Tripathi, PhD
Ramalingaswami Fellow (Scientist D), CHME Division, Translational Health Science and Technological Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad–Gurgaon Expressway Faridabad, Haryana 121001 Email: [email protected] Phone- +91-129-2876474
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ACCEPTED MANUSCRIPT Abstract Type 2 diabetes mellitus (T2D) is a highly prevalent metabolic disorder characterized by an imbalance in blood glucose level, altered lipid profile and high blood pressure. Genetic constituents, high fat and high-energy dietary habits and a sedentary lifestyle are three major
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factors that contribute to high risk of T2D. Several studies have reported gut microbiome
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dysbiosis as a factor in rapid progression of insulin resistance in T2D that accounts about 90% of
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all diabetes cases worldwide. The gut microbiome dysbiosis may reshape intestinal barrier functions and host metabolic and signaling pathways, which are directly or indirectly related to
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the insulin resistance in T2D. Thousands of the metabolites derived from microbes interact with
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the epithelial, hepatic and cardiac cell receptors that modulate host physiology. Xenobiotics including dietary components, antibiotics and non-steroidal anti-inflammatory drugs (NSAIDS)
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strongly affect the gut microbial composition and can promote dysbiosis. Any change in the gut
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microbiota can shift the host metabolism towards increased energy harvest during diabetes and obesity. However, the exact mechanisms behind the dynamics of gut microbes and their impact
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on host metabolism at the molecular level are yet to be deciphered. We reviewed the published
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literature for better understanding of the dynamics of gut microbiota, factors that potentially induce gut microbiome dysbiosis and their relation to the progression of T2D. Special emphasis
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was also given to understand the gut microbiome induced breaching of intestinal barriers and/or tight junctions and their relation to insulin resistance.
Keywords: Diabetes mellitus, gut microbiome, dysbiosis, T2D, SCFAs, tight junctions, gut permeability, intestinal integrity.
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ACCEPTED MANUSCRIPT Introduction Metabolic disorders are a group of health disorders that include type 2 diabetes mellitus (T2D), cardiovascular disease (CVD) and other such disorders that are diagnosed by monitoring defined biochemical, clinical and metabolic factors. Metabolic disorders can also be defined by a
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combination of obesity with hypertension, elevated fasting hyperglycemia, triglycerides, low-
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density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol in
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plasma [1].
A continuous increase in the prevalence of obesity (BMI ≥ 30kg/m2) and related
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metabolic diseases are a big challenge in developed countries [2]. A recent report estimated that
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about 42% of the US adult population will be obese by 2020 [3]. Prevalence of obesity and related metabolic diseases are also a major public health burden in developing countries [4].
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Obesity leads to various life threatening non-communicable diseases, including CVD and T2D,
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which are major contributing factors towards premature deaths worldwide [5]. In the developing countries T2D alone contributes ~80% premature mortality due to metabolic disorders [6].
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World Health Organization (WHO) has projected that T2D could be one of the top ten potent
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reasons of death worldwide by 2030 [7]. Globally, 347 million people are affected by DM and in more than 36 million cases, the syndrome is undiagnosed [8, 9]. In the past 3-4 decades, due to
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changes in lifestyles, diet patterns, less physical activities and exposure to adverse environmental factors the prevalence of diabetes has dramatically increased [10]. India, the second most populous country in the world with a huge burden of malnutrition and poor quality of life is also facing obesity and other health related problems [11]. The size of the Indian population and fast growing economy may provide a reasonable platform for studying the impact of obesity on metabolic diseases such as CVD and T2D [12, 13]. In the past, traditional Indian culture and dietary habits limited the influence of western/modern lifestyle 3
ACCEPTED MANUSCRIPT limiting the incidences of metabolic diseases like obesity and diabetes that are considered to be associated with such lifestyle [14]. However, the changes in the socioeconomic status of urban life have now become the leading cause of lifestyle-related diseases in India [15]. Such alterations in lifestyle include changes in dietary habits, sedentary life and improper medications.
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Previously, obesity and its related metabolic diseases have been correlated with heredity,
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lifestyle and certain environmental factors.
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Eukaryotes, bacteria and archaea residing in the gut are collectively known as the gut microbiota. Inclusion of gut environment and the inhabiting microbial genome represent the gut
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microbiome in which bacteria are the major constituents in the gut. Several studies identified
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that changes in the quantity and diversity of gut microbiota have significant importance in the progression of many metabolic disorders [16, 17]. Human gut microbiota provide protection to
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the host against pathogens by competing for space and nutrition or by refining and improving
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the immune system. They also play crucial role in maintaining the intestinal integrity/homeostasis of gut epithelial lining and metabolizing the xenobiotics including drugs
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[18-21]. Adjunct therapy with probiotic (live, beneficial commensal bacteria) species like
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Lactobacillus and Bifidobacterium has been in use for a long time [22, 23]. In addition, to probiotics, resistant fibers that promote the growth of beneficial bacteria are consumed as
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functional foods or “prebiotics” [24]. In contrast to beneficial component of gut microbiota, the imbalance or dysbiosis can cause numerous disease conditions or can worsen the severity of diseases like ulcerative colitis, Crohn’s disease, inflammatory bowel disease and colorectal cancer [25-29]. The dysbiosis has also been linked to several antipathy and metabolic diseases like food allergy, obesity and diabetes and non-alcoholic steatohepatitis (NASH) [30-33]. A recent study has
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ACCEPTED MANUSCRIPT shown the relationship between the gut microbial profiles in children and their nutritional status by clustering of potentially pathogenic microbes into a distinct hub in the severely malnourished gut [34]. Due to the intricate association between gut microbiota and health, a comprehensive
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account on species diversity and their functional mechanism(s) needs to be elucidated further
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for diagnostic and therapeutic purposes. In a recent study, it was shown that certain bacterial
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species could significantly improve the symptom scores in T2D mouse models by reversing several metabolic dysfunctions, including the gain in fat mass, metabolic endotoxemia, tissue
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inflammation, and insulin secretion and sensitivity [35]. In this review, we summarize the role
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and mechanisms of gut microbiota in obesity and related metabolic disorders and future
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prospects.
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Diabetes and current approaches for its management In recent years, management of diabetes using symptom-based medicines against
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hyperglycemia or insulin resistance (such as metformin, sitagliptin, and pioglitazone) and
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medicines for diabetes-related complications like adipose inflammation, have drawn considerable attention. Metformin being advantageous in controlling hyperglycemia without
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inducing side effects like hypoglycemia or weight gain or any cardiovascular complication is the first choice for clinicians to treat T2D patients [36]. This drug has been frequently prescribed as an insulin sensitizer for controlling insulin resistance and lowering the fasting insulin level in plasma. Metformin primarily works by blocking respiratory chain complexes mediated by mitochondria resulting in reduced glucose production in liver [37]. Intermittent treatment of T2D cases with metformin were found to have increased serum bile acids and their conjugates, with a
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ACCEPTED MANUSCRIPT decrease in glucagon like protein-1 (GLP-1) [38]. Metformin helps in metabolism and the gut microbiota. Many studies conclude that metformin induces GLP-1 secretion and serum bile acid suppression and correlate well with changes in Bacteroidetes/Firmicutes ratio [39, 40]. Some
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studies have reported very interesting facts about metformin, such as its capacity to induce mucin
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expression similar to Akkermansia muciniphila [40]. Both Akkermansia and metformin
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administration to mice fed on high fat diet are associated with a decrease in IL-1β and IL-6 expression in adipose tissue. These reports provide evidence about the similarity between
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Akkermansia and metformin in improving the metabolic profile by lowering tissue inflammation
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in diet-induced obesity [40]. Apparently, the bacterial population regulates the metabolism
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Gut microbiota and its functions
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during hyperglycemic conditions along with metformin action.
Targeted metagenomics studies have revealed that approximately 90% of the bacterial
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species present in the gut of adults belongs to phyla Bacteroidetes (Gram-negative) and
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Firmicutes (Gram-positive) [41, 42]. Depending on the anatomy, abiotic environment and diversified functions of different parts of the gut, the microbial composition may also broadly
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differ. A healthy adult harbors 500-1000 bacterial species at a time and there can be 1012-1014 colony forming units (CFU) in the whole gut with a mass weight of about 1-2 kg [43]. The colon alone contains approximately 109-1012 CFU/ml followed by 101-103 CFU/ml in jejunum and 104108 CFU/ml in the ileum [44]. Transfer of microbiota takes place in utero or during birth and achieves stability at around 2 years of age. In addition to host genetics and environmental factors early exposure to microbes
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ACCEPTED MANUSCRIPT during birth play an important role in regulating the composition of gut microbiota. Exposure to (i) vaginal microbiome during normal delivery, (ii) skin microbiota during cesarean sections, exclusive breast-feeding or formula feeding and (iii) antibiotics in neonatal and early childhood also play a significant role in shaping the stable gut microbiome. The gut microbiota both
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directly and indirectly facilitates various vital functions of the human host, including digestion of
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complex dietary foods, harvesting energy from indigestible carbohydrates, vitamin synthesis and
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development of immune cells. Various metabolites like short-chain fatty acids (SCFAs)
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involved in the maintenance of human health [45].
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generated by the colonic microbiota from resistant starch modulate various signaling pathways
Gut microbiota and carbohydrate metabolism
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The regular diet of a healthy individual contains a large fraction of carbohydrates that
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include monosaccharides, disaccharides, as well as complex polysaccharides. Common sugars like cane sugar and fruit sugars are readily absorbed in the intestine, whereas disaccharides like
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sucrose, lactose and maltose and complex polysaccharides like starch, pectin and hemicellulose
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needs to be broken down into simple monosaccharides before absorption in the intestine. Polysaccharides are not digested in the upper part of the gastrointestinal tract, but they are
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converted into monosaccharides in the ileum with the help of bacterial enzymes like glycosidases [46]. After ingestion of a carbohydrate rich diet, glucose concentrations in the blood are expected to go up, but it is strongly regulated and kept at a homeostatic level of the two hormones, insulin and glucagon. The upper digestive tract is involved in carbohydrate digestion and its absorption in the blood stream via various specialized proteins known as glucose transporters (GLUTs) located on epithelial cells [18]. To briefly describe glucose absorption in healthy conditions,
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ACCEPTED MANUSCRIPT GLUT proteins transport glucose into β-cells of the islets of Langerhans in the pancreas. Oxidation of the pancreatic glucose stimulates insulin secretion by mechanisms of membrane depolarization and closure of potassium channels, resulting in voltage dependent calcium influx and exocytosis of insulin [21].
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Many studies display the important role of the gut environment in the pathogenesis of
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immunological disorders with multiple mechanisms. The role of gut environment and lymphoid
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tissue associated with the gut are also established for their role in T2D [47]. In addition to T2D, the role of gut microbiome has also been associated with type 1 diabetes (T1D). Reduction in gut
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microbial diversity breaches the cell-to-cell integrity. This defect causes a leaky gut with
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enhanced permeability that leads to intestinal inflammation and reduced or disturbed immune response at gut mucosa. All these factors have an influence in T-cell mediated autoimmunity and
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related autoimmune disorders including T1D [48]. The mucosal surface of the intestinal lining
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represents the largest surface area of any organ in the human body and the lymphatic tissues associated with them are the most extensive immunological organs. The gut being the most
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exposed region to various microbial components and foreign antigens like food plays a very
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crucial role on a host-environment axis of immune education [49].
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T1D is the consequence of the multiple factors, including individual’s genetic makeup, and exogenous environmental and host-related aspects. Hence, the gut microbiome and their involvement in the mucosal immune system play an important role in the progression of severe clinical diseases like T1D [47]. In about 50% of the patients with T1D, human leukocyte antigen type DR4-DQ8 was detected as an indicator for the celiac disease [50, 51]. Role of gut barrier function and reduced oral tolerance in immune related low-grade inflammation in these patients are said to be linked with diabetes. In T1D, there is an absolute insulin deficiency due to T-cell 8
ACCEPTED MANUSCRIPT mediated destruction of pancreatic β cells [52]. In contrast, T2Dis a chronic metabolic abnormality with fasting serum hyperglycemia, insulin non-responsiveness and insulin insufficiency due to reduced insulin secretion from β cells in insulin non-responsive environment [53]. Insulin resistance or non-responsiveness is the failure of cells to sense the normal insulin
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level especially in liver and muscle tissues. Other possible important mechanisms involved in
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T2D are incretin deficiency or non-responsiveness, enhanced lipid catabolism, enhanced
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glucagon availability in the blood, higher salt and water renal retention and other metabolic abnormalities [33, 52].
Studies conducted with high fat diet fed germ free mice,
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conventionalized mice and mice fed with standard diet demonstrated that the metabolic and
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immunological profiles mainly depend on microbial diversity and composition irrespective of type of diet [54]. Mice from same genotype and similar diet pattern may have different glucose
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metabolism patterns (hyperglycemic or hypoglycemic) depending on their gut microbiome
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metabolic functionality [55].
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profile [55]. These findings confirm the interrelationship between the gut microbiome and
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Figure 1: Interplay between diet and the gut microbiome. Regulatory role of diet and
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microbiota in healthy (left) and diabetic conditions (right) have different mechanisms. In T1D, the bacterial population in gut modulates gut-permeability and signaling
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mechanisms, thereby initiating an autoimmune response. In T2D, dysbiosis due to carbohydrate hydrolysis causes low-grade inflammation and decrease in insulin sensitivity.
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ACCEPTED MANUSCRIPT Role of diet in shaping gut flora It is a well-known fact that the gut microbiome has a significant role in digestion of food components and their absorption. Additionally, they also regulate the expression of certain genes in the host. In the previous section, we discussed that the change in dietary pattern can influence
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the gut microbial composition and diversity resulting in a shift in the ratio of Firmicutes to
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Bacteroidetes. An increase of Bacteroidetes population leads to increase the energy yield. There
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are reports demonstrating the reduced numbers of Bifidobacteria in high fat fed mice gut increases endotoxemia. This enhanced endotoxemia can be reversed by prebiotic
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supplementation, which restores Bifidobacteria levels in the mouse gut [56, 57]. There are
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evidences to confirm that Bacteroidetes are more prevalent in the gut of individuals consuming diet rich in animal based foods, whereas Prevotella is dominant in individuals consuming diets
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rich in plant based foods (Fig 2). In addition, gut bacteria produce certain metabolites like
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SCFAs that protect the host from pathogenic bacteria and play other important beneficial roles. In individuals consuming predominantly plant-derived foods, the gut microbiota produce more
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SCFAs, enzymes involved in anabolism and increased synthesis of amylase, glutamate and
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riboflavin (Fig. 2) (58, 59).. On the other hand, consumption of animal derived foods leads to adaptation of gut microbial function towards increased catabolic processes like degradation of
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glycans and amino acids [60]. The role of microbiota with multi gene functions in converting indigestible dietary components like complex polysaccharides to simple sugars may be considered as one of the beneficial mechanisms in the host to extract more energy from the diet [42]. The breakdown of these polysaccharides results in production of SCFAs, i.e., butyrate, propionate and acetate along with some gases like hydrogen, which are further involved in colonic fermentation and enhanced
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ACCEPTED MANUSCRIPT energy harvest [61]. The energy generated from digestion of such indigestible polysaccharides make a negligible contribution to the total energy required by host in comparison to simpler and digestible carbohydrates. Such a small amount of energy derived from complex polysaccharides may not be beneficial for the host directly, but may have an indirect role in the survival of
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commensal bacteria [46], obesity and its related metabolic abnormalities. It is hypothesized that
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butyrates have the ability to decrease calorie intake by inducing satiety, which works through
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shifts in GLP-1 (glucagon like peptide-1) and GIP-1 (gastric inhibitory peptide-1) production [45]. Butyrates are also involved in strengthening of gut integrity by providing energy to
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enterocytes to regulate their survival and proliferation.
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Low-grade inflammation is one of the most important pathophysiological factors resulting in the progression of T2D with hyperglycemia and insulin resistance [62]. Reduction of
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gut microbial diversity leads to increase in pathogenic bacteria, gut inflammation and
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progression of diabetic condition. The gut inflammatory responses include innate immune response mechanism with the use of TLRs and by producing pro-inflammatory cytokines as well
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as by an increase in endotoxemia [63]. These innate immune responses or release of toxic
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compounds such as H2S in the gut milieu can contribute to leaky gut and increased access of microbial components in lumen to the host system resulting in systemic inflammation. In mouse
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model it was demonstrated that high fat diet induced obesity, translocation of intestinal Gramnegative bacteria in the circulatory system, adipose tissue and cause endotoxemia. Remarkably, such effects were reversed by using specific prebiotics and probiotics [63].
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Figure 2: Flowcharts representing the effect of diet pattern on bacterial population in the human gut. The flowchart on the left panel (blue) indicates fiber-rich diet and the right panel (red) indicates fat/protein rich diet.
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ACCEPTED MANUSCRIPT Probiotics and diabetes mellitus There is an overwhelming body of literature on the role of probiotics in human health. The role of specific bacteria in modulating blood glucose levels in DM is known [64]. Several other concepts are proposed to explain the role of probiotics in diabetes. Certain classes of
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probiotic bacteria can provide immune-modulatory effects to counter chronic inflammation
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transpired due to shift in gut microbiome [65-67]. The role of low-grade chronic inflammation is
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well documented in the progression of T2D [62]. Probiotic strains may also enhance IL-10 production, which is a very important regulatory and anti-inflammatory cytokine in diabetic
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mice. Increase in IL-10 is reported to down regulate the pro-inflammatory cytokines like IFN-γ
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and IL-2/IL-1β resulting in prevention of low-grade inflammation and onset of diabetes [63, 67]. In a recent study, use of Lactobacillus reuteri GMNL-263 in high fructose fed rats has been
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found to reduce T2D markers like serum glucose, glycated hemoglobin and c-peptide [64]. The
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same study has also reported that there is a reduction in the inflammatory cytokines Il-6 and TNF-α in adipose tissue along with downregulation of GLUT 4 and PPAR-ϒ. Regular
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consumption of probiotic yoghurt can decrease the inflammatory markers in pregnant women in
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terms of reducing the hs-CRP (high sensitivity C-reactive protein) level, which is also implicated in T2D [68, 69]. In addition to these effects, some of the probiotic strains are able to reduce the
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oxidative stress in pancreatic tissue, thereby minimizing the chronic inflammation and pancreatic cell apoptosis [70].
There are probiotic strains that have been found to reduce LDL cholesterol and total cholesterol in serum by modulating lipid metabolism, which can be considered as a factor for reduction of T2D risk [71]. In a murine model of obesity and T2D, oral administration of Lactobacillus casei Shirota enhanced the lipopolysaccharide-binding protein (LBP) expression in plasma and alleviated the endotoxemia [72]. It was shown that Bifidobacterium animalis subsp. 14
ACCEPTED MANUSCRIPT lactis 420 was able to restrict the bacterial translocation in tissues from intestine and reduce the metabolic bacteremia in early phases of T2D [73]. In a recently published study, administration of L. casei Zhang to high fructose induced hyper-insulinemia rats was found to ameliorate
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impaired glucose tolerance [74].
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Intestinal integrity and metabolic conditions
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A potential mechanism linking high-fat diet and LPS has increased gut permeability, allowing the LPS to enter the circulation via the portal system. Intestinal permeability in human
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T2D is significantly increased compared with matched control subjects [75]. Animal model
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studies have suggested that an increase in intestinal permeability leads to progression of obesity and insulin resistance [76, 77]. However, intake of prebiotics can enrich gut microbiota, improve
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intestinal permeability, suppress inflammation by reducing the level of endotoxemia and also
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improve glucose tolerance [77]. High-fat diet fed mice displayed a reduction in tight junction proteins like zonula occluden-1 (ZO-1) and occludin, responsible for epithelial integrity of the
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gut lining and increase in gut permeability. Dietary fatty acids are thought to activate toll-like
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receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) signaling pathways. TLR-4 is part of the complex that mediates LPS translocation into intestinal capillaries [78] and its activity is
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necessary to induce insulin resistance in mice [79, 80]. Altered gut permeability and plasma LPS levels involve changes in the distribution of ZO-1 and occludin, as well as changes in the endocannabinoid (eCB) system. Gut microbes selectively act to modulate colonic expression of the cannabinoid receptor 1 (CB1), which strongly influences gut permeability through effects on ZO-1 and occludin [81]. It was also observed that changes in the gut microbiota after prebiotic ingestion resulted in
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ACCEPTED MANUSCRIPT reduced gut permeability in obese mice. Gut microbiota exposed to several antibiotics are capable of inducing metabolic endotoxemia in mice fed with high fat diet, which is further associated with increased gut permeability, unregulated pro-inflammatory cytokines, and disturbed metabolic profile of diabetes and obesity (Fig 3). Regulation of the eCB system has
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also been associated with inflammation and diabetes [82, 83]. Modulation of intestinal
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microbiota influences gut eCB expression that might help in controlled gut permeability and
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plasma LPS levels through the CB1 receptor [81].
Changes in the gut microbiota due to prebiotic feeding reduce gut permeability in obese
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mice. Studies have demonstrated the regulation of gut permeability though the localization of
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tight junction proteins via eCB systems. Cani et al. [62] investigated the role of CB1 receptor in obese mice by inhibiting the receptor and found the increased localization and distribution of
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occludin and ZO-1 proteins. Glucose tolerance in rat model was found to be improved during
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activation of cannabinoid CB2 receptor and blocking of CB1 receptor that acts as CB2 receptor agonists [84]. Lactobacillus supplementation has been positively correlated with expression of
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CB2 receptor, whereas the association was negative with Clostridium spp. [85]. In rodents,
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levels [86].
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several probiotics showed regulation of intestinal microbiota through CB2 receptor expression
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Figure 3. Schematic view of gut microbiota under healthy and diseased conditions
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(dietary antigen-induced inflammation and insulin resistance). Intestinal microbiota changes with alteration in dietary pattern resulting in increased gut permeability at
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epithelial layers due to downregulation of junction protein expressions. This action
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increases systemic LPS level and metabolic endotoxemia results in insulin resistance.
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ACCEPTED MANUSCRIPT Gut Microbiome and antibiotics Use of antibiotics not only limits the activity of pathogenic bacteria, but also the commensal microbial population living in the gut. Several reports suggest that a shift in the gut microbial population due to antibiotic usage may be associated with progression of DM [52].
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Antibiotic treatment could modulate fat-mass and SCFAs levels [90]. List of important
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antibiotics and their effect on gut microbiome are summarized in Table 1. Infants with the onset
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of diabetes are characterized with less diversity of gut microbiome due to over-usage of antibiotics. This transformation has been considered as pre-diabetic microbial signature. Under
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this state, there is a decrease in Bifidobacteria spp. and an increase in Bacteroides spp. when
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compared with genetically susceptible infants, but with no diabetes [91].
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Alteration of gut microbiome by the use of antibiotic provide protection from virus induced T1D [92]. Segmented filamentous bacterial group (SFB) has been anticipated to give
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protection by inducing proliferation of protective T-helper type 17 (Th17) cell populations in the
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small intestine [92]. Conversely, understanding the relationship between the gut microbiome and T1D is very limited. Although many reports indicate the benefits of antibiotics in treating T1D,
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there is no information on gut physiology, leaky gut, LPS translocation, endotoxemia and
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inflammation both in T1D patients and in animal models [93].
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Table1. Changes in the gut microbiome due to the use of clinically important antibiotics
Clarithromycin plus metronidazole
Meropenem Streptomycin
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Ticarcillin
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Gentamicin
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Erythromycin
Enterococci ↓↑, Streptococci ↓↑, and anaerobic bacteria ↓↑, Bacteroides spp.↓; Short-chain fatty acids↓ Streptococci↓, Enterococci↓, Enterobacteria↓ Staphylococci↑, Anaerobes↑ Enterobacter spp.↓ Enterobacteria↓, streptococci↓, Clostridia↓, Bacteroides spp.↓, Gram-vecocci↓ Ruminococcaceae↓, Bacteroidaceae↑ Enterococci ↓ Enterococci ↓, E. coli ↓, Lactobacilli ↓, Bifidobacteria ↓, Enterobacteria ↑ Yeasts ↑, Bacteroidetes ↑, Proteobacteria ↑
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Clindamycin
Actinobacteria↓
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Tigecycline
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Reference [94] [95] [96] NA
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Ciprofloxacin
Bacterial population shift Enterobacter spp.↑ Enterobacter spp.↓ Anaerobes↑, Enterobacteria ↓ NA Enterobacteria↓, Short-chain fatty acid (SCFA) producers↓
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Antibiotic Ampicillin Amoxicillin Cefotaxime Chloramphenicol
[97], [98] [99]
[98, 100, 101]
[102] [94] [103] [104] [105] [106]
Notes: ↑ increase; ↓ decreases, ↓↑ Changes in bacterial population, spp. Species, NA, not available
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ACCEPTED MANUSCRIPT Future prospects and challenges The increased prevalence of obesity and related metabolic disorders like diabetes, atherosclerosis, and NAFLD (non-alcoholic fatty liver disease) have become a serious public health concern across the globe. Changing dietary habits, sedentary life and increased work
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pressure seems to be a major factor for the development and rapid progression of metabolic
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diseases. Recent reports have established that gut microbiota play a major role in the
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development and progression of diabetes. Reduction in intestinal barrier function and increase in membrane permeability with leaky guts, favor the translocation of Gram-negative bacteria to the
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systemic circulation and elevating LPS levels which in turn results in metabolic endotoxemia in
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obese and diabetic individuals.
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The low-grade inflammation due to endotoxemia clearly indicates the possibility of gut microbial metabolites in initiating metabolic disturbances and subsequent disorders like T2D.
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The shift in the bacterial population in the gut influences host energy harvest and metabolism.
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These outcomes indicate that specific bacterial molecular targets involved in the regulation of diabetes or related diseases should be investigated further for the better management of clinical
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complications. Several studies have shown the difference in animal models as well as in humans
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in the prevalence of bacterial population between diabetic and control subjects. However, further research is needed to identify specific phyla, class, genera or species of gut bacteria with variable correlations and metabolic phenotypes. The gut microbiome can be disturbed or modified with numerous host or environmental factors starting from host genotype, diet, stress or medications. Even changes in circadian rhythm may have influence in the regulation gut microbes [107]. Therefore, tightly controlled human and animal studies are warranted to explain these complex issues of microbiome and disease 20
ACCEPTED MANUSCRIPT interrelationship. New generation -omics approaches like metagenomics, transcriptomic, and metabolomics can be extensively explored for elucidating the molecular basis of metabolic interactions between specific microbes and healthy or disease subjects. This multidisciplinary approach will be helpful in understanding the functions of established microbial groups of the
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gut microbiota in the controls as well as patients with diabetes related disorders.
Acknowledgments and Declarations: P.T. is supported by programme grant funding from Department of Biotechnology, Govt. of India (Ramalingaswami Fellowship) and Translational
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Health Science and Technology Institute (Department of Biotechnology, Govt. of India). S.S. is supported by a post-doctoral fellowship women (PDFW) awarded by the University Grant
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Commission (UGC, India). Both the authors had a significant role in content, structure and review of manuscript. The authors thank Dr. Pragyan Acharya (AIIMS, New Delhi), Dr.
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Bhabatosh Das (THSTI, Faridabad) and Dr. Thandavaryan Ramamurthy (THSTI, Faridabad) for
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reviewing the manuscript.
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The authors declare that they have no conflict of interest.
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Sapna Sharma, Prabhanshu Tripathi PII: DOI: Reference:
S0955-2863(18)30307-3 doi:10.1016/j.jnutbio.2018.10.003 JNB 8077
To appear in:
The Journal of Nutritional Biochemistry
Received date: Revised date: Accepted date:
1 April 2018 17 September 2018 3 October 2018
Please cite this article as: Sapna Sharma, Prabhanshu Tripathi , Gut microbiome and type 2 diabetes: Where we are and where to go?. Jnb (2018), doi:10.1016/j.jnutbio.2018.10.003
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ACCEPTED MANUSCRIPT Gut microbiome and type 2 diabetes: where we are and where to go?
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Authors: Sapna Sharma1, Prabhanshu Tripathi2*
Affiliations: 1Gene Regulation Laboratory,
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School of Biotechnology, Jawaharlal Nehru University,
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New Delhi, 110067, India
Centre for Human Microbial Ecology, Translational Health Science, and Technological
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Institute, NCR Biotech Science Cluster, 3rd Milestone Gurgaon-Faridabad Expressway,
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Faridabad, Haryana 121001, India
*Corresponding Author
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Prabhanshu Tripathi, PhD
Ramalingaswami Fellow (Scientist D), CHME Division, Translational Health Science and Technological Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad–Gurgaon Expressway Faridabad, Haryana 121001 Email: [email protected] Phone- +91-129-2876474
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ACCEPTED MANUSCRIPT Abstract Type 2 diabetes mellitus (T2D) is a highly prevalent metabolic disorder characterized by an imbalance in blood glucose level, altered lipid profile and high blood pressure. Genetic constituents, high fat and high-energy dietary habits and a sedentary lifestyle are three major
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factors that contribute to high risk of T2D. Several studies have reported gut microbiome
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dysbiosis as a factor in rapid progression of insulin resistance in T2D that accounts about 90% of
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all diabetes cases worldwide. The gut microbiome dysbiosis may reshape intestinal barrier functions and host metabolic and signaling pathways, which are directly or indirectly related to
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the insulin resistance in T2D. Thousands of the metabolites derived from microbes interact with
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the epithelial, hepatic and cardiac cell receptors that modulate host physiology. Xenobiotics including dietary components, antibiotics and non-steroidal anti-inflammatory drugs (NSAIDS)
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strongly affect the gut microbial composition and can promote dysbiosis. Any change in the gut
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microbiota can shift the host metabolism towards increased energy harvest during diabetes and obesity. However, the exact mechanisms behind the dynamics of gut microbes and their impact
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on host metabolism at the molecular level are yet to be deciphered. We reviewed the published
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literature for better understanding of the dynamics of gut microbiota, factors that potentially induce gut microbiome dysbiosis and their relation to the progression of T2D. Special emphasis
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was also given to understand the gut microbiome induced breaching of intestinal barriers and/or tight junctions and their relation to insulin resistance.
Keywords: Diabetes mellitus, gut microbiome, dysbiosis, T2D, SCFAs, tight junctions, gut permeability, intestinal integrity.
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ACCEPTED MANUSCRIPT Introduction Metabolic disorders are a group of health disorders that include type 2 diabetes mellitus (T2D), cardiovascular disease (CVD) and other such disorders that are diagnosed by monitoring defined biochemical, clinical and metabolic factors. Metabolic disorders can also be defined by a
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combination of obesity with hypertension, elevated fasting hyperglycemia, triglycerides, low-
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density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol in
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plasma [1].
A continuous increase in the prevalence of obesity (BMI ≥ 30kg/m2) and related
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metabolic diseases are a big challenge in developed countries [2]. A recent report estimated that
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about 42% of the US adult population will be obese by 2020 [3]. Prevalence of obesity and related metabolic diseases are also a major public health burden in developing countries [4].
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Obesity leads to various life threatening non-communicable diseases, including CVD and T2D,
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which are major contributing factors towards premature deaths worldwide [5]. In the developing countries T2D alone contributes ~80% premature mortality due to metabolic disorders [6].
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World Health Organization (WHO) has projected that T2D could be one of the top ten potent
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reasons of death worldwide by 2030 [7]. Globally, 347 million people are affected by DM and in more than 36 million cases, the syndrome is undiagnosed [8, 9]. In the past 3-4 decades, due to
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changes in lifestyles, diet patterns, less physical activities and exposure to adverse environmental factors the prevalence of diabetes has dramatically increased [10]. India, the second most populous country in the world with a huge burden of malnutrition and poor quality of life is also facing obesity and other health related problems [11]. The size of the Indian population and fast growing economy may provide a reasonable platform for studying the impact of obesity on metabolic diseases such as CVD and T2D [12, 13]. In the past, traditional Indian culture and dietary habits limited the influence of western/modern lifestyle 3
ACCEPTED MANUSCRIPT limiting the incidences of metabolic diseases like obesity and diabetes that are considered to be associated with such lifestyle [14]. However, the changes in the socioeconomic status of urban life have now become the leading cause of lifestyle-related diseases in India [15]. Such alterations in lifestyle include changes in dietary habits, sedentary life and improper medications.
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Previously, obesity and its related metabolic diseases have been correlated with heredity,
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lifestyle and certain environmental factors.
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Eukaryotes, bacteria and archaea residing in the gut are collectively known as the gut microbiota. Inclusion of gut environment and the inhabiting microbial genome represent the gut
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microbiome in which bacteria are the major constituents in the gut. Several studies identified
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that changes in the quantity and diversity of gut microbiota have significant importance in the progression of many metabolic disorders [16, 17]. Human gut microbiota provide protection to
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the host against pathogens by competing for space and nutrition or by refining and improving
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the immune system. They also play crucial role in maintaining the intestinal integrity/homeostasis of gut epithelial lining and metabolizing the xenobiotics including drugs
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[18-21]. Adjunct therapy with probiotic (live, beneficial commensal bacteria) species like
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Lactobacillus and Bifidobacterium has been in use for a long time [22, 23]. In addition, to probiotics, resistant fibers that promote the growth of beneficial bacteria are consumed as
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functional foods or “prebiotics” [24]. In contrast to beneficial component of gut microbiota, the imbalance or dysbiosis can cause numerous disease conditions or can worsen the severity of diseases like ulcerative colitis, Crohn’s disease, inflammatory bowel disease and colorectal cancer [25-29]. The dysbiosis has also been linked to several antipathy and metabolic diseases like food allergy, obesity and diabetes and non-alcoholic steatohepatitis (NASH) [30-33]. A recent study has
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ACCEPTED MANUSCRIPT shown the relationship between the gut microbial profiles in children and their nutritional status by clustering of potentially pathogenic microbes into a distinct hub in the severely malnourished gut [34]. Due to the intricate association between gut microbiota and health, a comprehensive
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account on species diversity and their functional mechanism(s) needs to be elucidated further
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for diagnostic and therapeutic purposes. In a recent study, it was shown that certain bacterial
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species could significantly improve the symptom scores in T2D mouse models by reversing several metabolic dysfunctions, including the gain in fat mass, metabolic endotoxemia, tissue
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inflammation, and insulin secretion and sensitivity [35]. In this review, we summarize the role
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and mechanisms of gut microbiota in obesity and related metabolic disorders and future
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prospects.
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Diabetes and current approaches for its management In recent years, management of diabetes using symptom-based medicines against
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hyperglycemia or insulin resistance (such as metformin, sitagliptin, and pioglitazone) and
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medicines for diabetes-related complications like adipose inflammation, have drawn considerable attention. Metformin being advantageous in controlling hyperglycemia without
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inducing side effects like hypoglycemia or weight gain or any cardiovascular complication is the first choice for clinicians to treat T2D patients [36]. This drug has been frequently prescribed as an insulin sensitizer for controlling insulin resistance and lowering the fasting insulin level in plasma. Metformin primarily works by blocking respiratory chain complexes mediated by mitochondria resulting in reduced glucose production in liver [37]. Intermittent treatment of T2D cases with metformin were found to have increased serum bile acids and their conjugates, with a
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ACCEPTED MANUSCRIPT decrease in glucagon like protein-1 (GLP-1) [38]. Metformin helps in metabolism and the gut microbiota. Many studies conclude that metformin induces GLP-1 secretion and serum bile acid suppression and correlate well with changes in Bacteroidetes/Firmicutes ratio [39, 40]. Some
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studies have reported very interesting facts about metformin, such as its capacity to induce mucin
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expression similar to Akkermansia muciniphila [40]. Both Akkermansia and metformin
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administration to mice fed on high fat diet are associated with a decrease in IL-1β and IL-6 expression in adipose tissue. These reports provide evidence about the similarity between
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Akkermansia and metformin in improving the metabolic profile by lowering tissue inflammation
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in diet-induced obesity [40]. Apparently, the bacterial population regulates the metabolism
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Gut microbiota and its functions
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during hyperglycemic conditions along with metformin action.
Targeted metagenomics studies have revealed that approximately 90% of the bacterial
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species present in the gut of adults belongs to phyla Bacteroidetes (Gram-negative) and
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Firmicutes (Gram-positive) [41, 42]. Depending on the anatomy, abiotic environment and diversified functions of different parts of the gut, the microbial composition may also broadly
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differ. A healthy adult harbors 500-1000 bacterial species at a time and there can be 1012-1014 colony forming units (CFU) in the whole gut with a mass weight of about 1-2 kg [43]. The colon alone contains approximately 109-1012 CFU/ml followed by 101-103 CFU/ml in jejunum and 104108 CFU/ml in the ileum [44]. Transfer of microbiota takes place in utero or during birth and achieves stability at around 2 years of age. In addition to host genetics and environmental factors early exposure to microbes
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ACCEPTED MANUSCRIPT during birth play an important role in regulating the composition of gut microbiota. Exposure to (i) vaginal microbiome during normal delivery, (ii) skin microbiota during cesarean sections, exclusive breast-feeding or formula feeding and (iii) antibiotics in neonatal and early childhood also play a significant role in shaping the stable gut microbiome. The gut microbiota both
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directly and indirectly facilitates various vital functions of the human host, including digestion of
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complex dietary foods, harvesting energy from indigestible carbohydrates, vitamin synthesis and
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development of immune cells. Various metabolites like short-chain fatty acids (SCFAs)
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involved in the maintenance of human health [45].
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generated by the colonic microbiota from resistant starch modulate various signaling pathways
Gut microbiota and carbohydrate metabolism
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The regular diet of a healthy individual contains a large fraction of carbohydrates that
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include monosaccharides, disaccharides, as well as complex polysaccharides. Common sugars like cane sugar and fruit sugars are readily absorbed in the intestine, whereas disaccharides like
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sucrose, lactose and maltose and complex polysaccharides like starch, pectin and hemicellulose
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needs to be broken down into simple monosaccharides before absorption in the intestine. Polysaccharides are not digested in the upper part of the gastrointestinal tract, but they are
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converted into monosaccharides in the ileum with the help of bacterial enzymes like glycosidases [46]. After ingestion of a carbohydrate rich diet, glucose concentrations in the blood are expected to go up, but it is strongly regulated and kept at a homeostatic level of the two hormones, insulin and glucagon. The upper digestive tract is involved in carbohydrate digestion and its absorption in the blood stream via various specialized proteins known as glucose transporters (GLUTs) located on epithelial cells [18]. To briefly describe glucose absorption in healthy conditions,
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ACCEPTED MANUSCRIPT GLUT proteins transport glucose into β-cells of the islets of Langerhans in the pancreas. Oxidation of the pancreatic glucose stimulates insulin secretion by mechanisms of membrane depolarization and closure of potassium channels, resulting in voltage dependent calcium influx and exocytosis of insulin [21].
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Many studies display the important role of the gut environment in the pathogenesis of
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immunological disorders with multiple mechanisms. The role of gut environment and lymphoid
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tissue associated with the gut are also established for their role in T2D [47]. In addition to T2D, the role of gut microbiome has also been associated with type 1 diabetes (T1D). Reduction in gut
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microbial diversity breaches the cell-to-cell integrity. This defect causes a leaky gut with
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enhanced permeability that leads to intestinal inflammation and reduced or disturbed immune response at gut mucosa. All these factors have an influence in T-cell mediated autoimmunity and
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related autoimmune disorders including T1D [48]. The mucosal surface of the intestinal lining
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represents the largest surface area of any organ in the human body and the lymphatic tissues associated with them are the most extensive immunological organs. The gut being the most
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exposed region to various microbial components and foreign antigens like food plays a very
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crucial role on a host-environment axis of immune education [49].
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T1D is the consequence of the multiple factors, including individual’s genetic makeup, and exogenous environmental and host-related aspects. Hence, the gut microbiome and their involvement in the mucosal immune system play an important role in the progression of severe clinical diseases like T1D [47]. In about 50% of the patients with T1D, human leukocyte antigen type DR4-DQ8 was detected as an indicator for the celiac disease [50, 51]. Role of gut barrier function and reduced oral tolerance in immune related low-grade inflammation in these patients are said to be linked with diabetes. In T1D, there is an absolute insulin deficiency due to T-cell 8
ACCEPTED MANUSCRIPT mediated destruction of pancreatic β cells [52]. In contrast, T2Dis a chronic metabolic abnormality with fasting serum hyperglycemia, insulin non-responsiveness and insulin insufficiency due to reduced insulin secretion from β cells in insulin non-responsive environment [53]. Insulin resistance or non-responsiveness is the failure of cells to sense the normal insulin
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level especially in liver and muscle tissues. Other possible important mechanisms involved in
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T2D are incretin deficiency or non-responsiveness, enhanced lipid catabolism, enhanced
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glucagon availability in the blood, higher salt and water renal retention and other metabolic abnormalities [33, 52].
Studies conducted with high fat diet fed germ free mice,
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conventionalized mice and mice fed with standard diet demonstrated that the metabolic and
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immunological profiles mainly depend on microbial diversity and composition irrespective of type of diet [54]. Mice from same genotype and similar diet pattern may have different glucose
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metabolism patterns (hyperglycemic or hypoglycemic) depending on their gut microbiome
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metabolic functionality [55].
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profile [55]. These findings confirm the interrelationship between the gut microbiome and
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Figure 1: Interplay between diet and the gut microbiome. Regulatory role of diet and
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microbiota in healthy (left) and diabetic conditions (right) have different mechanisms. In T1D, the bacterial population in gut modulates gut-permeability and signaling
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mechanisms, thereby initiating an autoimmune response. In T2D, dysbiosis due to carbohydrate hydrolysis causes low-grade inflammation and decrease in insulin sensitivity.
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ACCEPTED MANUSCRIPT Role of diet in shaping gut flora It is a well-known fact that the gut microbiome has a significant role in digestion of food components and their absorption. Additionally, they also regulate the expression of certain genes in the host. In the previous section, we discussed that the change in dietary pattern can influence
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the gut microbial composition and diversity resulting in a shift in the ratio of Firmicutes to
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Bacteroidetes. An increase of Bacteroidetes population leads to increase the energy yield. There
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are reports demonstrating the reduced numbers of Bifidobacteria in high fat fed mice gut increases endotoxemia. This enhanced endotoxemia can be reversed by prebiotic
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supplementation, which restores Bifidobacteria levels in the mouse gut [56, 57]. There are
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evidences to confirm that Bacteroidetes are more prevalent in the gut of individuals consuming diet rich in animal based foods, whereas Prevotella is dominant in individuals consuming diets
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rich in plant based foods (Fig 2). In addition, gut bacteria produce certain metabolites like
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SCFAs that protect the host from pathogenic bacteria and play other important beneficial roles. In individuals consuming predominantly plant-derived foods, the gut microbiota produce more
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SCFAs, enzymes involved in anabolism and increased synthesis of amylase, glutamate and
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riboflavin (Fig. 2) (58, 59).. On the other hand, consumption of animal derived foods leads to adaptation of gut microbial function towards increased catabolic processes like degradation of
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glycans and amino acids [60]. The role of microbiota with multi gene functions in converting indigestible dietary components like complex polysaccharides to simple sugars may be considered as one of the beneficial mechanisms in the host to extract more energy from the diet [42]. The breakdown of these polysaccharides results in production of SCFAs, i.e., butyrate, propionate and acetate along with some gases like hydrogen, which are further involved in colonic fermentation and enhanced
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ACCEPTED MANUSCRIPT energy harvest [61]. The energy generated from digestion of such indigestible polysaccharides make a negligible contribution to the total energy required by host in comparison to simpler and digestible carbohydrates. Such a small amount of energy derived from complex polysaccharides may not be beneficial for the host directly, but may have an indirect role in the survival of
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commensal bacteria [46], obesity and its related metabolic abnormalities. It is hypothesized that
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butyrates have the ability to decrease calorie intake by inducing satiety, which works through
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shifts in GLP-1 (glucagon like peptide-1) and GIP-1 (gastric inhibitory peptide-1) production [45]. Butyrates are also involved in strengthening of gut integrity by providing energy to
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enterocytes to regulate their survival and proliferation.
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Low-grade inflammation is one of the most important pathophysiological factors resulting in the progression of T2D with hyperglycemia and insulin resistance [62]. Reduction of
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gut microbial diversity leads to increase in pathogenic bacteria, gut inflammation and
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progression of diabetic condition. The gut inflammatory responses include innate immune response mechanism with the use of TLRs and by producing pro-inflammatory cytokines as well
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as by an increase in endotoxemia [63]. These innate immune responses or release of toxic
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compounds such as H2S in the gut milieu can contribute to leaky gut and increased access of microbial components in lumen to the host system resulting in systemic inflammation. In mouse
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model it was demonstrated that high fat diet induced obesity, translocation of intestinal Gramnegative bacteria in the circulatory system, adipose tissue and cause endotoxemia. Remarkably, such effects were reversed by using specific prebiotics and probiotics [63].
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Figure 2: Flowcharts representing the effect of diet pattern on bacterial population in the human gut. The flowchart on the left panel (blue) indicates fiber-rich diet and the right panel (red) indicates fat/protein rich diet.
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ACCEPTED MANUSCRIPT Probiotics and diabetes mellitus There is an overwhelming body of literature on the role of probiotics in human health. The role of specific bacteria in modulating blood glucose levels in DM is known [64]. Several other concepts are proposed to explain the role of probiotics in diabetes. Certain classes of
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probiotic bacteria can provide immune-modulatory effects to counter chronic inflammation
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transpired due to shift in gut microbiome [65-67]. The role of low-grade chronic inflammation is
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well documented in the progression of T2D [62]. Probiotic strains may also enhance IL-10 production, which is a very important regulatory and anti-inflammatory cytokine in diabetic
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mice. Increase in IL-10 is reported to down regulate the pro-inflammatory cytokines like IFN-γ
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and IL-2/IL-1β resulting in prevention of low-grade inflammation and onset of diabetes [63, 67]. In a recent study, use of Lactobacillus reuteri GMNL-263 in high fructose fed rats has been
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found to reduce T2D markers like serum glucose, glycated hemoglobin and c-peptide [64]. The
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same study has also reported that there is a reduction in the inflammatory cytokines Il-6 and TNF-α in adipose tissue along with downregulation of GLUT 4 and PPAR-ϒ. Regular
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consumption of probiotic yoghurt can decrease the inflammatory markers in pregnant women in
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terms of reducing the hs-CRP (high sensitivity C-reactive protein) level, which is also implicated in T2D [68, 69]. In addition to these effects, some of the probiotic strains are able to reduce the
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oxidative stress in pancreatic tissue, thereby minimizing the chronic inflammation and pancreatic cell apoptosis [70].
There are probiotic strains that have been found to reduce LDL cholesterol and total cholesterol in serum by modulating lipid metabolism, which can be considered as a factor for reduction of T2D risk [71]. In a murine model of obesity and T2D, oral administration of Lactobacillus casei Shirota enhanced the lipopolysaccharide-binding protein (LBP) expression in plasma and alleviated the endotoxemia [72]. It was shown that Bifidobacterium animalis subsp. 14
ACCEPTED MANUSCRIPT lactis 420 was able to restrict the bacterial translocation in tissues from intestine and reduce the metabolic bacteremia in early phases of T2D [73]. In a recently published study, administration of L. casei Zhang to high fructose induced hyper-insulinemia rats was found to ameliorate
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impaired glucose tolerance [74].
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Intestinal integrity and metabolic conditions
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A potential mechanism linking high-fat diet and LPS has increased gut permeability, allowing the LPS to enter the circulation via the portal system. Intestinal permeability in human
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T2D is significantly increased compared with matched control subjects [75]. Animal model
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studies have suggested that an increase in intestinal permeability leads to progression of obesity and insulin resistance [76, 77]. However, intake of prebiotics can enrich gut microbiota, improve
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intestinal permeability, suppress inflammation by reducing the level of endotoxemia and also
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improve glucose tolerance [77]. High-fat diet fed mice displayed a reduction in tight junction proteins like zonula occluden-1 (ZO-1) and occludin, responsible for epithelial integrity of the
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gut lining and increase in gut permeability. Dietary fatty acids are thought to activate toll-like
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receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) signaling pathways. TLR-4 is part of the complex that mediates LPS translocation into intestinal capillaries [78] and its activity is
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necessary to induce insulin resistance in mice [79, 80]. Altered gut permeability and plasma LPS levels involve changes in the distribution of ZO-1 and occludin, as well as changes in the endocannabinoid (eCB) system. Gut microbes selectively act to modulate colonic expression of the cannabinoid receptor 1 (CB1), which strongly influences gut permeability through effects on ZO-1 and occludin [81]. It was also observed that changes in the gut microbiota after prebiotic ingestion resulted in
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ACCEPTED MANUSCRIPT reduced gut permeability in obese mice. Gut microbiota exposed to several antibiotics are capable of inducing metabolic endotoxemia in mice fed with high fat diet, which is further associated with increased gut permeability, unregulated pro-inflammatory cytokines, and disturbed metabolic profile of diabetes and obesity (Fig 3). Regulation of the eCB system has
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also been associated with inflammation and diabetes [82, 83]. Modulation of intestinal
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microbiota influences gut eCB expression that might help in controlled gut permeability and
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plasma LPS levels through the CB1 receptor [81].
Changes in the gut microbiota due to prebiotic feeding reduce gut permeability in obese
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mice. Studies have demonstrated the regulation of gut permeability though the localization of
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tight junction proteins via eCB systems. Cani et al. [62] investigated the role of CB1 receptor in obese mice by inhibiting the receptor and found the increased localization and distribution of
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occludin and ZO-1 proteins. Glucose tolerance in rat model was found to be improved during
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activation of cannabinoid CB2 receptor and blocking of CB1 receptor that acts as CB2 receptor agonists [84]. Lactobacillus supplementation has been positively correlated with expression of
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CB2 receptor, whereas the association was negative with Clostridium spp. [85]. In rodents,
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levels [86].
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several probiotics showed regulation of intestinal microbiota through CB2 receptor expression
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Figure 3. Schematic view of gut microbiota under healthy and diseased conditions
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(dietary antigen-induced inflammation and insulin resistance). Intestinal microbiota changes with alteration in dietary pattern resulting in increased gut permeability at
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epithelial layers due to downregulation of junction protein expressions. This action
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increases systemic LPS level and metabolic endotoxemia results in insulin resistance.
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ACCEPTED MANUSCRIPT Gut Microbiome and antibiotics Use of antibiotics not only limits the activity of pathogenic bacteria, but also the commensal microbial population living in the gut. Several reports suggest that a shift in the gut microbial population due to antibiotic usage may be associated with progression of DM [52].
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Antibiotic treatment could modulate fat-mass and SCFAs levels [90]. List of important
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antibiotics and their effect on gut microbiome are summarized in Table 1. Infants with the onset
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of diabetes are characterized with less diversity of gut microbiome due to over-usage of antibiotics. This transformation has been considered as pre-diabetic microbial signature. Under
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this state, there is a decrease in Bifidobacteria spp. and an increase in Bacteroides spp. when
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compared with genetically susceptible infants, but with no diabetes [91].
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Alteration of gut microbiome by the use of antibiotic provide protection from virus induced T1D [92]. Segmented filamentous bacterial group (SFB) has been anticipated to give
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protection by inducing proliferation of protective T-helper type 17 (Th17) cell populations in the
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small intestine [92]. Conversely, understanding the relationship between the gut microbiome and T1D is very limited. Although many reports indicate the benefits of antibiotics in treating T1D,
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there is no information on gut physiology, leaky gut, LPS translocation, endotoxemia and
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inflammation both in T1D patients and in animal models [93].
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Table1. Changes in the gut microbiome due to the use of clinically important antibiotics
Clarithromycin plus metronidazole
Meropenem Streptomycin
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Ticarcillin
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Gentamicin
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Erythromycin
Enterococci ↓↑, Streptococci ↓↑, and anaerobic bacteria ↓↑, Bacteroides spp.↓; Short-chain fatty acids↓ Streptococci↓, Enterococci↓, Enterobacteria↓ Staphylococci↑, Anaerobes↑ Enterobacter spp.↓ Enterobacteria↓, streptococci↓, Clostridia↓, Bacteroides spp.↓, Gram-vecocci↓ Ruminococcaceae↓, Bacteroidaceae↑ Enterococci ↓ Enterococci ↓, E. coli ↓, Lactobacilli ↓, Bifidobacteria ↓, Enterobacteria ↑ Yeasts ↑, Bacteroidetes ↑, Proteobacteria ↑
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Clindamycin
Actinobacteria↓
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Tigecycline
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Reference [94] [95] [96] NA
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Ciprofloxacin
Bacterial population shift Enterobacter spp.↑ Enterobacter spp.↓ Anaerobes↑, Enterobacteria ↓ NA Enterobacteria↓, Short-chain fatty acid (SCFA) producers↓
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Antibiotic Ampicillin Amoxicillin Cefotaxime Chloramphenicol
[97], [98] [99]
[98, 100, 101]
[102] [94] [103] [104] [105] [106]
Notes: ↑ increase; ↓ decreases, ↓↑ Changes in bacterial population, spp. Species, NA, not available
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ACCEPTED MANUSCRIPT Future prospects and challenges The increased prevalence of obesity and related metabolic disorders like diabetes, atherosclerosis, and NAFLD (non-alcoholic fatty liver disease) have become a serious public health concern across the globe. Changing dietary habits, sedentary life and increased work
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pressure seems to be a major factor for the development and rapid progression of metabolic
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diseases. Recent reports have established that gut microbiota play a major role in the
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development and progression of diabetes. Reduction in intestinal barrier function and increase in membrane permeability with leaky guts, favor the translocation of Gram-negative bacteria to the
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systemic circulation and elevating LPS levels which in turn results in metabolic endotoxemia in
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obese and diabetic individuals.
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The low-grade inflammation due to endotoxemia clearly indicates the possibility of gut microbial metabolites in initiating metabolic disturbances and subsequent disorders like T2D.
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The shift in the bacterial population in the gut influences host energy harvest and metabolism.
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These outcomes indicate that specific bacterial molecular targets involved in the regulation of diabetes or related diseases should be investigated further for the better management of clinical
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complications. Several studies have shown the difference in animal models as well as in humans
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in the prevalence of bacterial population between diabetic and control subjects. However, further research is needed to identify specific phyla, class, genera or species of gut bacteria with variable correlations and metabolic phenotypes. The gut microbiome can be disturbed or modified with numerous host or environmental factors starting from host genotype, diet, stress or medications. Even changes in circadian rhythm may have influence in the regulation gut microbes [107]. Therefore, tightly controlled human and animal studies are warranted to explain these complex issues of microbiome and disease 20
ACCEPTED MANUSCRIPT interrelationship. New generation -omics approaches like metagenomics, transcriptomic, and metabolomics can be extensively explored for elucidating the molecular basis of metabolic interactions between specific microbes and healthy or disease subjects. This multidisciplinary approach will be helpful in understanding the functions of established microbial groups of the
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gut microbiota in the controls as well as patients with diabetes related disorders.
Acknowledgments and Declarations: P.T. is supported by programme grant funding from Department of Biotechnology, Govt. of India (Ramalingaswami Fellowship) and Translational
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Health Science and Technology Institute (Department of Biotechnology, Govt. of India). S.S. is supported by a post-doctoral fellowship women (PDFW) awarded by the University Grant
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Commission (UGC, India). Both the authors had a significant role in content, structure and review of manuscript. The authors thank Dr. Pragyan Acharya (AIIMS, New Delhi), Dr.
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Bhabatosh Das (THSTI, Faridabad) and Dr. Thandavaryan Ramamurthy (THSTI, Faridabad) for
Conflict of interest
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reviewing the manuscript.
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The authors declare that they have no conflict of interest.
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