# Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment
## 2 Bacterotherapy in CRC Treatment
### Mechanisms Used in Bacterotherapy in CRC
#### 2.1.1 Bacterotherapy for Modulating Innate Immunity  
Our immune system plays a crucial role in the protection and defense against cancer development [46]. Here, it is of great importance to understand the duality of the immune system composed of a defensive and a reparative mode. While the defensive mode promotes the production of immune cells, the reparative mode stimulates the secretion of immune suppressive cytokines, and growth factors among others, thus facilitating cell invasion. Bacteria can interact either as pathogens or as compounds of the \"normal\" flora, whereby pathogenic interaction of bacteria triggers immune system activity in several ways, described in the following section [36; 47; 48]. _Activation of Inflammasome Pathways_  
One mechanism the immune system is activated by, is represented by the stimulation of inflammasome pathways, triggered by bacteria. Previous investigation on the \(\Delta\)ppGpp _Salmonella typhimurium_ strain, which is defective in the synthesis of ppGpp (regulates virulence gene expression), demonstrated its tumor-targeting activity in CRC mouse models by activating inflammasome pathways, leading to suppression of tumor cell released signals and significantly increased levels of the pro-inflammatory cytokine IL-1B in the tumors, resulting in tumor growth inhibition [38; 49]. Another mechanism stimulating the inflammasome pathway besides direct activation through the strain of \(\Delta\)ppGpp _Salmonella typhimurium_ revealed, was demonstrated by the secretion of ATP from damaged cancer cells attacked by \(\Delta\)ppGpp _Salmonella typhimurium_, leading to NLRP3 inflammasome activation in macrophages [38]. Moreover, in another study of \(\Delta\)ppGpp _Salmonella typhimurium_, researchers found evidence that the bacterial strain shows tumor-targeting ability and that primary as well as even metastatic CRC could be suppressed in mice [50]. Based on this background, the mechanism of activating the inflammasome by bacterial strains can be considered as an efficient therapeutic strategy to make use of in bacterotherapy in CRC treatment. _Activation of Anti-Tumor T-cell Responses_  
Another mechanism that has been demonstrated to inhibit tumor development refers to anti-tumor effectors T-cell responses. Here, _Escherichia coli_, an anaerobic bacteria strain, was found to be indirectly involved in CRC clearance via activating as the host's defense mechanism, leading to T-lymphocyte production. These, in turn, greatly contribute to tumor-protective activity by CD8\({}^{+}\) and CD4\({}^{+}\) T-cells acting as major effectors in the immunological response against tumors as previously shown in CRC mouse models [38]. Importantly, it was proven via depletion experiments that CD8\({}^{+}\) T-cells were the only effectors during the induction phase, thus responsible for tumor clearance, while both, CD8\({}^{+}\) and CD4\({}^{+}\), were involved in the memory phase. In addition, the anti-tumor T-cell effectors (CD4\({}^{+}\) and CD8\({}^{+}\)) were found to suppress newly set tumors, whereby CD8\({}^{+}\) T-cells were even able to destroy already established CRC [38]. Moreover, in another study CD4\({}^{+}\) and CD25\({}^{+}\) regulatory T-cells have been shown to reduce the risk of colon cancer, underlining the potential of bacteria triggered T-cell responses as a novel CRC treatment approach [51]. _Activation of Cytokine-Triggered Tumor Necrosis_  
Tumor-colonizing bacteria describe specific anaerobic bacteria species that invade and are able to grow in solid tumors because damaged circulation and necrosis found in tumors present necessary condition for anaerobic bacteria to grow and replicate [52; 53; 54; 55]. In a study of [PERSON] et al. the administration of anaerobic _Salmonella enterica serovar Typhimurium_ to cancer mouse models showed that through hemorrhaging a remarkable increase in bacterial flushing into the solid tumor and subsequent necrosis could be detected, which is associated with TNF-\(\alpha\) secretion and its capability to destroy vascular endothelial cells.