236 of TGF-β signaling pathways in which SMAD proteins are involved. Although butyrate mainly showed antifibrotic effects via reduction of non-canonical TGF-β signaling cascades, there was also a significant increase in the expression of SMAD4 with the addition of butyrate on top of TGF-β treatment.28 We found Anaerostipes bacteria to also be strongly associated with expression of ZNF644, a zinc finger protein that is positively regulated by intracellular zinc concentrations. Depletion of intracellular zinc levels, or even zinc deficiency, may have destabilizing effects on SMAD proteins and thereby impair the TGF-β signaling pathway.29 Mucosal Verrucomicrobiabacteria inversely associatewith expressionof the IBDsusceptibility gene YDJC We observed significant inverse associations between Verrucomicrobia bacteria, of which Akkermansia muciniphila is a well-known member, and the expression of the YDJC gene, which encodes for the YdjC chitooligosaccharide deacetylase homolog (YdjC) protein. This gene has been identified as a shared susceptibility gene for CD, UC and psoriasis.13,30,31 YDJC was originally identified as a celiac disease–associated susceptibility locus, but some SNPs were also associated with CD as well as with pediatric-onset CD.32 YdjC catalyzes the deacetylation of acetylated carbohydrates, an important reaction in the degradation of oligosaccharides.33 YDJC expression has been associated with tumor progression in studies of lung cancer.34,35 The observed inverse association between Akkermansia and YDJC expression may suggest a potential protective role of Akkermansia, as decreased YDJC expression may mitigate its pro-carcinogenic effects. Despite the association between YDJC and the susceptibility to IBD on a genetic level, its precise functional role remains largely unknown.32 Mucosal Alistipes bacteria positively associate with MUC4 expression The bacterial genus Alistipes, belonging to family Rikenellaceae and phylum Bacteroidetes, is a recently discovered bacterial species, of which many have been isolated from the human gut microbiome. The role of Alistipes in health and disease is still unclear. Some evidence indicates that it may confer protective effects to the host, but other studies report pathogenic effects, e.g. in colorectal cancer development. A key factor believed to determine the relative abundance of Alistipes is the dysbiotic state of the gut microbiome.36 In IBD, there is also conflicting data about the pathogenicity of Alistipes species. Alistipes finegoldii has been demonstrated to exert anti-inflammatory effects in experimental models of colitis.37 Likewise, another study found an increased abundance of Alistipes in NOD2-knockout mice that had less severe (TNBS-induced) colitis compared to wild-type mice.38 It has also been reported that Alistipes abundance could increase after taking probiotic supplements, which in turn may protect against hepatocellular cancer growth in an experimental setting.39 However, metagenomic studies have shown that Alistipes abundances were increased in mouse models of spontaneous CD-like ileitis terminalis as compared to wild-type mice, suggesting that Alistipes species may also play a pathogenic role by eliciting segmental ileitis.40,41 MUC4 encodes for mucin 4, a protein found in the glycocalyx present on the intestinal epithelium. Deletion or knockouts of Muc4 have demonstrated protective effects in mouse models, as shown by lower levels of proinflammatory factors and resistance against DSS-induced colitis. It is still Chapter 6
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