235 cells of patients with IBD.16 In the context of T-regs, FOSL2 also appears to be important as it is a determinant of a highly suppressive subpopulation of T-regs in humans that are particularly enriched in the lamina propria of patients with CD, supporting wound healing in the intestinal mucosa.17 Although speculative, bifidobacteria, as well as their metabolites such as butyrate, may potentially confer immune-modulating properties via interaction with FOSL1 expression. Mucosal bifidobacteria positively associate with Krüppel-like factor 2 (KLF2) expression Krüppel-like factor 2 (encoded by KLF2) is a negative regulator of intestinal inflammation, and its expression is found to be reduced in patients with IBD.18 KLF2 also negatively regulates differentiation of adipocytes and strongly inhibits PPAR-γ expression, which prevents differentiation of preadipocytes into adipocytes and thereby prevents adipogenesis.19 KLF2 also plays an important role in endothelial physiology, where it may act as a molecular switch by regulating endothelial cell function in inflammatory disease states.20 Interestingly, KLF2 modifies the traffickingof T-regs, as increased KLF2 expression inT-regs promotes the induction of peripheral immunological tolerance, whereas, in the absence of its expression, T-regs are unable to effectively migrate to secondary lymphoid tissues.21 Indeed,, it was demonstrated in mouse experiments that mice developed IBD in the presence of KLF2-deficient T-regs, which were unable to prevent colitis by disrupted co-trafficking of effector and regulatory T cells. In light of these considerations, mucosal bifidobacteria may confer beneficial immune-modulating properties by upregulating KLF2 expression, thereby stimulating T-reg migration and contributing to immunological selftolerance in the context of IBD. Mucosal Anaerostipes bacteria positively associate with host SMAD4 expression Anaerostipes, which belong to the Lachnospiraceae family, are anaerobic bacteria that are wellknown butyrate-producers. Butyrate serves as the primary energy source for colonic epithelial cells and is characterized by anti-inflammatory and anti-carcinogenic properties. SMAD4 is an important intracellular effector of the TGF-β superfamily of proteins. These proteins have important functions in alleviating intestinal inflammation and maintenance of gut mucosal homeostasis. Haploinsufficiency of SMAD4 in mice and humans has been associated with an increased susceptibility to colonic inflammation.22 In patients with CD, reduced epithelial protein levels of SMAD4 were observed that associated with disease activity, indicating defective mucosal TGF-β signaling during active intestinal inflammation. In an experimental animal study, mice with an epithelial deletion of Smad4 presented with macroscopic invasive adenocarcinoma of the distal colon and rectum three months after DSS-induced colitis.23 Indeed, SMAD4 mutations in humans are linked to juvenile polyposis syndrome and associated with poor disease outcome in several types of cancer.24-27 Using RNA-seq analysis, a strong inflammatory expression profile was observed after SMAD4 deletion, with expression of various inflammatory cytokines and chemokines, including CCL20. In addition, it was demonstrated that CCL20 could be repressed by SMAD4 in colonic epithelial cells, proving that TGF-β signaling could block the induction of CCL20 expression to protect against the development of colitis-associated cancer. In an experimental study involving human hepatic stellate cells, butyrate was demonstrated to be protective against diet-induced nonalcoholic steatohepatitis and liver fibrosis via suppression Mucosal host-microbe interactions in IBD
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