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  • Artesunate br Possible promoters of inflammatory

    2019-07-24


    Possible promoters of inflammatory bowel disease (IBD) The human gut is filled with trillions of microorganisms and the most prevalent bacterial species are Bacteroidetes and Firmicutes [23]. A study by De Filippo and colleagues compared the gut microbiota of two groups of children coming from an African rural village and Florence, Italy. The diet of the African group was mostly vegetarian, rich in fibres and plant polysaccharides, whereas the Italian diet contained predominantly fat and animal proteins. The faecal microbiota of the African cohort consisted of a large quantity of Bacteroidetes and reduced Firmicutes, together with an abundance of Prevotella and Xylanibacter bacteria, that are known to digest cellulose and promote uptake energy. In contrast, the Italian children had an abundance of Firmicutes and limited numbers of cellulose degrading bacteria species [24]. Subsequent studies have established differences in gut microbiome between geographic regions and age [25,26]. Moreover, apart from geographical differences, the gut microbiome and energy produced is influenced by diet. By example, during obesity, the proportion of Bacteroidetes and Firmicutes is reversed and Firmicutes levels increased by 50% [27], and the microbiome has a greater capacity to generate energy from food compared to lean individuals [28]. Considering that the above, alterations in the metabolic products of gut microbiota has been described to modulate the integrity of the epithelial layer and the gut immune response. An important contributor is butyrate a short-chain fatty Artesunate (SCFA), that is a product of plant polysaccharides fermentation [23]. A low concentration of butyrate, enhances the integrity of the intestinal barrier, whereas a high concentration promotes epithelial cell death [29,30]. The production of another SCFA, acetate increases protection against the enteropathogen Escherichia coli 0157:H7 by maintaining epithelial barrier function and restricting the translocation of bacterial toxins to the blood supply [31]. Mechanistically, a study by Maslowski et al., demonstrated that the binding of SCFA to the G-protein coupled receptor 43 (GPR43) resolved inflammatory responses in colitis, arthritis and asthma, whereas, GPR43 deficient mice had increased inflammation [32]. Helicobacter hepaticus, a commensal bacterium can promote colitis in mice. This effect was ablated by the addition of Bacteroides fragilis, due to the production of a single polysaccharide A (PSA), while mice provided with purified PSA showed reduced inflammation [33]. These results show that molecules produced by the bacterial microbiota can modulate the balance between colonic health and disease. Consistent with this data and translating to IBD patients, the microbiota of CD and UC patients has been shown to differ substantially to non-IBD controls. Specifically, it has been observed in one IBD cohort that Bacteroidetes and SCFA producing bacteria are depleted, and Actinobacteria and Proteobacteria are increased [34]. These data also suggest that possible treatment strategies for some forms of IBD could be accelerated by resolving the microbiological imbalances. Taken together these results show that diet modifies the natural microflora and creates dysbiosis. This in turn promotes an inappropriate inflammatory response leading to an imbalance in local pro- and anti-inflammatory factors and become a factor in promoting IBD [35]. Nevertheless, as shown above given the inconclusive clinical data connections between obesity and IBD in patients, it is arguable that dysbiosis generated through a western diet is not the only factor. A possible and additive scenario through which IBD risk could ensue is in individuals with inherited genetic mutations, that in the presence of a western diet lead to altered immune responses and increased intestinal permeability.
    Genetic change linked with promoting IBD Large population cohorts with IBD have been examined for genetic mutations through GWAS [36]. A meta-analysis of six GWAS for UC resulted in the identification of candidate genes that could provide important insights into the disease process. Some of these included components of the immune system: interleukin 1 receptor (IL1R2); two receptors for interleukin-8 (IL8RA/B); interleukin-7 receptor (IL7R); interleukin-12B (IL12B); PR domain containing 1 (PRDM1), a master transcriptional regulator of plasma cells and a transcriptional repressor of the interferon-β (IFN-β) promoter, and cell adhesion: guanine nucleotide binding protein (G protein) alpha 12 (GNA12), a membrane bound GTPase that plays an important role in tight junction assembly in epithelial cells [37].