pylori is no longer detected, even when seropositivity suggests prior infection [136]. These observations have led to the proposal of an alternative model for H. pylori carcinogenesis in which the deterioration of the gastric niche, driven by long-term H. pylori host interaction, causes

dysbiosis with the expansion of cancer-provoking oropharyngeal and intestinal Raf targets pathobionts [137]. Dysbiosis of the intestinal microbiota or its physical interaction with hematopoietic cells following barrier damage can both regulate inflammation (reviewed in [132, 133] and be a cause of cancer [138-140]. IL-18 has been shown to mediate mucosal protective mechanisms [141]. In particular, mice that are unable to produce, process, or respond to IL-18 (e.g., deficient in IL-18, IL-18R, MyD88, inflammasomes, or inflammasome signaling molecules) are characterized by intestinal dysbiosis and elevated susceptibility to chemically induced colon carcinogenesis

and nonalcoholic steatohepatatis [141-143]. The intestinal dysbiosis in these mice is characterized by the proportional expansion of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7, and colon carcinogenesis can be transferred to healthy mice by cohousing or fecal transfer [143]. SCFAs, such as butyrate, which are bacterial products derived from the fermentation of dietary fibers in the colon, have been shown to induce IL-18 production in intestinal epithelial cells by activating the GPR109a receptor, and also to act directly on DCs, macrophages, and T cells [44]. SCFAs have also been Opaganib purchase shown to induce the expansion of Treg cells, producing the anti-inflammatory cytokine IL-10, thus

suppressing colonic inflammation and carcinogenesis [44, 46]. IL-18 in turn favors mucosal tissue repair by regulating the production and availability of IL-22 [144]. IL-22 is produced by innate lymphoid cells in the intestinal lamina propria and, through activation of STAT3, induces epithelial cell proliferation and production of antibacterial peptides [145]. Thus, IL-22 favors epithelial repair and, depending on the extent of mucosal damage in the different experimental models, it may be pro- or anticarcinogenic [144-147]. Furthermore, in addition to having decreased IL-18 production by enterocytes, mice deficient for the NOD-like receptor-related Florfenicol protein 6 inflammasome have also been shown to have defective autophagy in goblet cells and abrogated mucus secretion into the large intestinal lumen [148]. These mice are therefore unable to clear enteric pathogens from the mucosal surface and are susceptible to persistent infection. Mice genetically deficient for other immunologically relevant genes, such as Tlr5, Il10, Tbx1, and Rag2, also show susceptibility to colitis and colon carcinogenesis due to gut dysbiosis, which can be transferred to healthy mice [149]. Many individual microbes have been associated with colorectal cancer either in human studies or in experimental animals.