Exploring the Role of Pathogen Pattern Recognition Receptors (PRRs) in inflammation and understanding the gut microbiota shift, in sugar rich diet induced Type 2 Diabetes following antibiotic administration

Abstract

Recent studies have shown the role of intestinal microflora as one of the environmental factor for the development of Type 2 Diabetes (T2D), which increase energy extraction, regulate the peripheral metabolism and as a result increase the body mass. Intestinal microflora alteration may have their positive as well as negative impacts in development and protection of T2D. Due to the critical ecological relationships amongst gut microbial communities, it is difficult to clearly demonstrate the role of particular groups of microbiota responsible for the pathogenesis of T2D. In this study, we assessed the shift in major gut phyla Firmicutes, Bacteroidetes and Proteobacteria, to which major proportion of gut bacteria belongs, as well as some of the genera like E. coli, Lactobacillus, Clostridium and Bifidobacteria which have been shown to play important role with respect to metabolic disorders in previous studies, during the progression of High Sucrose Diet induced T2D. During the study Eudragit coated moxifloxacin microspheres (pH 5.5, pH 7.0) targeted to small intestine and colon as well as chitosan was used to modulate the gut microflora. The study was aimed to analyze the effect of altering the gut microbiota in context with insulin sensitivity in sugar rich diet induced diabetic rat models. We observed that pH 5.5 specific antibiotic treated diabetic groups have shown significantly lower levels of Plasma Glucose, SGOT, SGPT, TG, Total Cholesterol, Free Fatty Acids (FFA), Lipopolysaccharide (LPS) and increased level of HDL as well as increased glucose sensitivity (OGTT) as compared to diabetic groups and pH 7.0 specific antibiotic treatment group whereas chitosan treated groups have shown negative effect with respect to insulin sensitivity, and biochemical parameters. These findings were further supported by histopathological studies in which disintegrated structures of small intestine, large intestine and liver steatosis were observed at lesser extent in pH 5.5 treated groups as compared to diabetic, pH 7.0 specific antibiotic and chitosan treated diabetic groups. TLR2 and TLR4 are the important innate immune receptors which play a vital role in pathogenesis of the T2D via sensing the gut microflora. TLR2 and TLR4 expression was found to be increased in colon and liver tissues of diabetic group as compared with control group. TLR4 in small intestine and colon in pH 5.5 treated diabetic groups showed decreased expression, while TLR2 expression was found to be increased as compared with all other groups which can be correlated with decreased LPS level in pH 5.5 treated groups. These findings may suggest that altering the microflora of small intestine may decrease LPS mediated TLR4 expression and improves the insulin sensitivity.