Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity

Abstract

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of pro-inflammatory genes may be effective in the prevention of metabolic syndrome.

Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic and immune-based diseases

“…Particularly, Crohn's disease may be caused or aggravated by bacteria like Firmicutes (Fecalibacterium prausnitzii) and Escherichia coli [35]. Evidence exists that Firmicutes:Bacteriodetes ratio is elevated in irritable bowel syndrome, obesity, type 2 diabetes mellitus (T2D) and insulin resistance [36]. It is unascertained why the same ratio has been found increased in old age [37], however a greater diversity of microbiota was associated with a healthier status in elderly with respect to that found in younger adults [38].…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…43 Moreover, the methylation of 7 CpGs in the promoter of the gene coding for the inflammatory molecule Toll-like receptor (TLR)-2 was significantly lower in T2DM patients compared with controls, and this difference was associated with marked variation in the composition of gut microbiota. 44 Inflammation has also been recognized as the pathogenic link between obesity and T2DM. Indeed, it is remarkable that obese individuals are not all alike in terms of susceptibility to metabolic diseases and, hence, cardiovascular risk.…”

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

“…In NOD and BBDP mice treated with probiotics, there is an increase in the tight-junction protein claudin coupled with reduced systemic inflammation outlining the importance of gut-derived action on mucosal barrier wall functionality in diabetes associated inflammation [28,42,68]. One study also identified that gut-microflora-mediated epigenetic changes to the TLRs in the gut epithelium could regulate the immune response affecting the diabetic phenotype [69] …”