# Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment
## 3 Microbiota in CRC
### Influence of Microbiota on Conventional CRC Therapy  
In conventional CRC therapy, chemotherapeutic agents and radiation are used and, due to their insufficiency, co-treatment with supplements, phytopharmaceuticals or feces transplantation, with its influence on the microbiome, are becoming increasingly interesting. Chemotherapeutics have been utilized for decades to treat a variety of human tumors and still represent typical first-line treatment for CRC [152], but are also used in combination with fluoropyrimidine-based substances and oxaliplatin as well as irinotecan [153] at the advanced, non-resectable CRC stage. Nonetheless, a substantial number of patients are likely to experience treatment-related morbidity and mortality due to these medications [152]. Given that CRC develops in close neighborhood to gut bacteria, new research has focused on how the gut microbiota influences the efficacy and toxicity of existing chemotherapeutic treatments [146]. Traditional CRC medicines such as irinotecan, 5-FU and cyclophosphamide have been demonstrated to alter the microbiome diversity of mice in pre-clinical models as well as in human patients. However, it is still unclear how this affects the prognosis, as some research revealed conflicting results when it comes to the role of microbiota in therapy. For example, in an animal experiment, germ-free mice were much more resistant [154] to powerful anti-cancer agent irinotecan [155] and had a higher lethal dose than holoxenic mice [154]. This could be due to the development of metabolites that are harmful to drugs as a consequence of bacterial metabolism. The authors have not thoroughly investigated the ultimate cause of death of these mice and did not identify the crucial bacterial species that accounted for this phenomenon. However, interestingly, irinotecan's major side effect of diarrhea correlating with intestinal damage was very rarely observed in germ-free mice compared to holoxenic animals [154], while irinotecan-treated patients often show severe diarrhea as a side effect. In their liver, irinotecan is converted to its active form, human topoisomerase I poison SN-38, and then inhibited by DP-glucuronosyltransferase by adding Glc (SN-38-G) [156]. This inactive compound is revived by GUS in the colon, resulting in acute poisoning. [PERSON] et al. discovered the GUS enzymes responsible for SN-38 reactivation in the human gut using a combination of proteomics and bioinformatic analysis on human feces samples under the consideration that SN-38 is a harmful metabolite of irinotecan [148]. Meanwhile, it is known that removing Glc from SN38-G causes SN38 reactivation, leading to the described disadvantages for the patients. Inhibition of the GUS enzyme synthesis thereby minimizes intestinal damage and maintains irinotecan's anti-cancer activity [156]. These findings imply that the presence of some bacteria is responsible for an increase in treatment-associated adverse effects leading to the assumption that gut microbiome can influence therapeutic efficacy. Surprisingly, bacteria appear to have a dual function in cancer treatment, with studies reporting a synergistic impact of microbiota and therapeutic efficacy, while some others demonstrate the presence of bacteria as an barrier for the efficacy of drug [153]. With regard to diseases of the digestive organs, research is constantly being conducted into the potential effects of nutritional supplements. More than a decade ago, it was shown that supplementing a high-inulin or oligofructose diet inhibited the growth of a transplantable tumor in a mouse model. Inulin and oligofructose are fructans that have been found to increase Bifidobacterium proliferation in the stomach. The inclusion of these supplements to the animals' food increased the efficacy of six different chemotherapy medicines, namely 5-FU, doxorubicin, vincristine, cyclophosphamide, methotrexate as well as cytarabine, implying a prebiotic impact of inulin and oligofructose [157].