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

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

[76]. Also probiotics control GM through CB2 receptor expression [77].

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

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

endocannabinoid (eCB) system. Gut microbes selectively modify expression of the cannabinoid receptor 1 (CB1) in colon also affecting zona occluding ZO-1 and occludin [72]. Administration of probiotics changes the gut microbiota resulting in reduced gut permeability in obese mice. Antibiotic exposure induces metabolic endotoxemia in mice fed with high-fat diet, along with increased gut permeability, secretion of proinflammatory cytokines, and incidence of diabetes and obesity (**Figure 1**). Modulation of the eCB system is connected with inflammation and diabetes [72, 73]. Moderation of GM controls eCB expression in gut, thereby regulating gut permeability and plasma LPS levels through the CB1 receptor [72]. Changes in the gut microbiota due to prebiotic feeding reduce gut permeability in obese mice. Modulation of gut permeability occurs through the distribution of tight junction proteins through eCB systems [55]. Activation of cannabinoid CB2 receptor and blocking of CB1 receptor improves glucose tolerance [74, 75]. *Lactobacillus* administration is positively correlated with expression of CB2 receptor, and *Clostridium* spp. is negatively correlated with CB2 expression (**Table 1**)

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

**Figure 1.**

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

*An Insight into the Changing Scenario of Gut Microbiome during Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.90697*

endocannabinoid (eCB) system. Gut microbes selectively modify expression of the cannabinoid receptor 1 (CB1) in colon also affecting zona occluding ZO-1 and occludin [72]. Administration of probiotics changes the gut microbiota resulting in reduced gut permeability in obese mice. Antibiotic exposure induces metabolic endotoxemia in mice fed with high-fat diet, along with increased gut permeability, secretion of proinflammatory cytokines, and incidence of diabetes and obesity (**Figure 1**). Modulation of the eCB system is connected with inflammation and diabetes [72, 73]. Moderation of GM controls eCB expression in gut, thereby regulating gut permeability and plasma LPS levels through the CB1 receptor [72]. Changes in the gut microbiota due to prebiotic feeding reduce gut permeability in obese mice. Modulation of gut permeability occurs through the distribution of tight junction proteins through eCB systems [55]. Activation of cannabinoid CB2 receptor and blocking of CB1 receptor improves glucose tolerance [74, 75]. *Lactobacillus* administration is positively correlated with expression of CB2 receptor, and *Clostridium* spp. is negatively correlated with CB2 expression (**Table 1**) [76]. Also probiotics control GM through CB2 receptor expression [77].
