**3. Gut microbiota and obesity mediated type 2 diabetes**

GM has a close association with host obesity, since the increase in total body fat in wild type mice is high when compared to germ free mice consuming more food. Transplanting of cecum-derived microbiota induced an increase in body fat mass and insulin resistance, adipocyte hypertrophy, and increased level of circulating leptin and glucose [78]. Germ free mice when fed with a diet rich in fat and sugar content showed lean phenotype however wild type mice who were fed with the high sugar and high fat diet turned obese. Also the germ free mice showed enhanced insulin sensitivity, leading to improved glucose tolerance and altered cholesterol metabolism diminishing cholesterol storage and increasing cholesterol excretion via fecal route. GM alters intestinal permeability, causes endotoxemia, enhances calorie provision, stimulates endocannabinoid system (eCB), regulates lipid metabolism by increasing activity of lipoprotein lipase and lipogenesis resulting in host obesity. Lipopolysaccharides (LPS), present in the cell membrane of Gram-negative bacteria, stimulate low-grade inflammation and incidence of insulin resistance (IR). LPS reaches the circulation from gut by diffusion either by enhanced intestinal permeability or absorption after association with chylomicron [79]. LPS acts as a ligand for toll-like receptors TLR-4 occurring in immune cells, liver and adipose tissue. LPS activated TLR-4 prompts conformational changes recruiting adapter molecules like myeloid differentiation primary factor MyD88 protein, IL-1 receptor associated kinase IRAK, TNF receptor associated factor TRAF6, and NF-κB inducing kinase NIK, phosphorylating and degrading inhibitor of nuclear factor kappa B kinase IKKB, inhibitor of nuclear factor kappa light chain enhancer of activated B cells NF-κB. Activated NF-κB translocates to the nucleus triggering expression of inflammatory proteins and various pathways like janus kinase JNK, p38 microtubule associated protein kinase MAPK, and extracelluar signal regulated kinase ERK finally resulting in insulin resistance (**Figure 1**). Colonization of *Bifidobacterium infantis* can impair inflammation by altering the intestinal permeability. Excess of lipid in diet enhances exposure to free fatty acids and their derivatives, facilitates endotoxin absorption and increases plasma LPS level termed as "metabolic endotoxemia" (**Table 1**) [80, 81]. Interaction between endogenous lipid and cannabinoid receptor (CB1 and CB2) stimulates adenylate cyclase and MAPK, ERK, and NF-κB pathways, triggering inflammation, insulin resistance and obesity [82]. On the whole GM stimulates the eCB system, enhances intestinal permeability, triggering

*Parasitology and Microbiology Research*

rats induced by high-fructose (**Table 1**) [65].

**conditions**

in inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in adipose tissue and down-regulated forms of GLUT 4 and peroxisome proliferator activated receptor-γ (PPAR-γ) (**Figure 1** and **Table 1**) [58]. Methodical consumption of probiotic yoghurt reduces inflammatory markers such as highsensitivity C-reactive protein levels in pregnant women and T2D [59, 60]. Probiotic strains decrease oxidative stress in pancreatic tissue, reducing inflammation and apoptosis of pancreatic cells [61]. Probiotic strains also lessen LDL cholesterol and total cholesterol in serum by regulating lipid metabolism, reducing the risk of T2D [62]. Consumption of *Lactobacillus casei* Shirota increase lipopolysaccharidebinding protein expression in plasma and diminishing endotoxemia (**Table 1**) [63]. *Bifidobacterium animalis* sub sp. lactis can restrict bacterial translocation in intestine alleviating bacteremia in early stages of T2D (**Table 1**) [64]. Oral administration of *L. casei* can also ameliorate impaired glucose tolerance in hyperinsulinemic

**2.5 Role of gut microbiota in maintaining intestinal integrity and metabolic** 

Increased gut permeability provides the relation between high-fat diet and LPS by causing LPS entry into circulation via the portal system in T2D patients [66]. Animal model studies have provided evidence between increased intestinal permeability and progression of obesity and insulin resistance [67, 68]. Consumption of prebiotics increase gut microbiota, rectify intestinal permeability, diminish inflammation, alleviate endotoxemia and ameliorate glucose tolerance [68]. Highfat diet induce decrease in tight junction proteins regulating epithelial integrity of gut lining and gut permeability such as zonula occluden-1 (ZO-1) and occludin. Dietary fatty acids activate toll-like receptor 2 (TLR-2) and toll like receptor 4 (TLR-4) signaling pathways. TLR-4 leads to LPS translocation into intestinal capillaries and induces insulin resistance in mice [69–71]. Altered gut permeability and plasma LPS levels are related with distribution of ZO-1 and occluding and

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**Figure 1.**

*Influence of gut microbiota in various physiological responses [80, 81, 83, 84, 110, 111].*

LPS entry into circulatory system resulting in endotoxemia. Rise in LPS, modulates the integrity of the tight junctions of the intestinal membrane increasing LPS in circulation. Therefore, GM is a complex system having both advantageous and dangerous microbes, and understanding the GM and host integration system provides a generalized idea about the function of each unit of the GM-host system [83, 84].

#### **3.1 Gut microbiota and carbohydrate metabolism during type 2 diabetes**

Bile acids affect glucose homeostasis via activation of nuclear farnesoid X receptor (FXR) and the membrane-bound G protein coupled receptor, TGR5. These receptors are expressed in liver, ileum and pancreas [85]. Some bile acids act as agonists for FXR, and others are FXR antagonists [86–88]. Known FXR agonists are CDCA, lithocholic acid, deoxycholic acid, and cholic acid [89]. The antidiabetic effects exhibited by vertical sleeve gastrectomy, bariatric surgery, occurs through FXR [90]. Also, intestinal FXR agonist treatment can improve insulin sensitivity [91]. In the ileum, activation of FXR leads to the production of fibroblast growth factor-19, a hormone that affects glucose tolerance through mechanisms that are largely independent of insulin [92, 93]. Activation of TGR5 produces glucagon-like peptide-1 (GLP-1) from ileum improves both energy and glucose homeostasis [94]. Activation of FXR in pancreas regulates insulin transport and secretion [95], and protects the islets from lipotoxicity [96]. FXR activation in liver improves insulin sensitivity in T2D patients [97]. The GM can modulate the amount and type of secondary bile acids produced via FXR and TGR5 signaling. GM enzymes such as bile salt hydrolase for deconjugation, 7-alpha dehydroxylase for dihydroxylation and 7α-hydroxysteroid dehydrogenase for epimerization of bile acids are reduced in T2D patients compared to healthy controls [98]. Bile acid concentrations in the circulation show a diurnal pattern since they increase after food intake [99].

#### **3.2 Gut microbiota and lipid metabolism during type 2 diabetes**

Our body metabolism, inflammatory processes and innate immune system are regulated by dietary lipids [100]. The dietary lipids can also act as (proinflammatory) ligands which can bind to nuclear receptors [101]. The nuclear receptors are peroxisome-proliferator-activated receptors (PPAR) and liver X receptors (LXR) which regulate metabolic and inflammatory pathways. Hence the dietary lipids can improve insulin action and down-regulate secretion of pro-inflammatory cytokines [102, 103]. Lipids can also activate G-protein coupled receptors (Gpcr) such as Gpr43 when activated by dietary-metabolite acetate lipolysis in adipocytes is decreased leading to reduced plasma-free fatty acids. Gpr43 can be considered as a potential target for regulation of lipid metabolism [104]. Inflammation and lipid accumulation are characteristic features of atherosclerosis [105]. Recent evidences provide sufficient link between atherosclerosis and GM variety [106]. Short-term antibiotic administration can alter the composition of GM which can convert dietary choline and l-carnitine to trimethylamine (TMA). TMA is later oxidized into TMAO by the action of hepatic Flavin monooxygenases [107]. Dietary choline is highly available in foods rich in lipid phosphatidylcholine, lecithin, such as in eggs, red meat, milk, poultry, liver, and fish [108]. Bile acids are key modulators of lipid and cholesterol metabolism, and they facilitate intestinal absorption and transport of nutrients, vitamins, and lipids. Production of bile occurs in the liver and 95% of bile acids are reabsorbed in the ileum. Later the bile acids are re-absorbed in liver, entering the enterohepatic circulation. GM converts primary bile salts to secondary bile salts by bile acid de-hydroxylation [109]. Bile acids can also result in the release of GLP-1 from enteroendocrine L cells via activation of Takeda G protein coupled receptor-5

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**4.1 Antibiotics**

*An Insight into the Changing Scenario of Gut Microbiome during Type 2 Diabetes*

**3.3 Gut microbiota composition during type 2 diabetes**

(TGR5) (**Figure 1**). This phenomenon affects insulin secretion sensitivity [110]. Bile acids have another receptor called farnesoid X receptor (FXR) present in liver, intestine, and pancreatic beta cells [111]. Hence, bile acids improve our metabolism in the long term after bariatric surgery by enhancing intestinal hormone secretion.

The GM of T2D patients exhibit low population of Firmicutes and Clostridia and high ratio of Bacteroidetes:Firmicutes (**Table 1**) [112, 113]. However, the GM of T2DM and obese patients are not always identical because the GM of obese patients show decreased Bacteroidetes:Firmicutes ratio [113–115, 118]. GM of T2DM patients also show low population of butyrate-producing bacteria. Shortchain fatty acids (SCFAs) like butyrate, acetate, and propionate are fermented from dietary fiber in large intestine by GM. SCFAs regulate energy metabolism, immune responses and tumorigenesis in gut. Butyrate is the energy source for colonic epithelial cells. Butyrate perpetuates intestinal integrity and thereby avert translocation of Gram-negative intestinal bacteria across the lumen of the gut. This phenomenon ultimately leads to endotoxemia triggering a low-grade inflammation

The major risk factors behind T2D are genetic predisposition, less physical activity, fetal programming, obesity and altered GM [114, 116]. Total weight of GM in the distal gut is about 1.5 kg and it is considered as a microbial organ. The GM consists of embers from Bacteria, Archaea, Eukarya and viruses, but a large part of the population includes anaerobic bacteria. 90% of the bacterial species present in gut are grouped into the two bacterial phyla Firmicutes (Gram-positive) and Bacteroidetes (Gram-negative) (**Table 1**) [15, 16]. An average adult fosters a minimum of 160 bacterial species and a set of genes in the GM is obligatory for proper functioning of the GM [15]. The GM gives protection from disease causing pathogens and facilitates the immune system. GM also help in production of vitamin K and many B-vitamins like folate, vitamin B12. Metagenomic studies about sequencing of T2D patients exhibit dysbiotic GM and less butyrate-producing bacteria (*Roseburia* species and *Faecalibacterium prausnitzii*). Metabolic disorders like obesity and impaired glucose metabolism are related with an altered ratio of Firmicutes and Bacteroidetes [118–120]. Populations of Proteobacteria and particularly *Escherichia coli* are also high in T2D patients (**Table 1**) [113, 121]. Gram-negative bacteria contribute to inflammatory lipopolysaccharides (LPS) stimulating pro-inflammation, during T2D and obesity. Oral administration of metformin, a widely used drug for T2D elevates populations of Enterobacteriaceae and lowers populations of *Clostridium* and *Eubacterium*. Metformin also increases the populations of *Akkermansia* sp. in high-fat diet-fed mice, hence improving glucose metabolism [122]. Oral administration of *Akkermansia muciniphila* also improves metabolic dysfunctions like endotoxemia and adipose tissue inflammation (**Table 1**) [122, 123]. Hence metformin can be used as a potent drug in improvising the GM content in T2D patients, managing glucose tolerance and inflammation.

**4. Modulation of gut microbiota to cure type 2 diabetes**

Antibiotics have become very popular for elimination of pathogenic bacteria. However, antibiotics are also harmful to the local population of beneficial GM. Hence excess use of antibiotics must be prevented for healthy maintenance of

*DOI: http://dx.doi.org/10.5772/intechopen.90697*

during T2D [15, 113, 115].

(TGR5) (**Figure 1**). This phenomenon affects insulin secretion sensitivity [110]. Bile acids have another receptor called farnesoid X receptor (FXR) present in liver, intestine, and pancreatic beta cells [111]. Hence, bile acids improve our metabolism in the long term after bariatric surgery by enhancing intestinal hormone secretion.
