Deciphering the role of the gut microbiome in the development of chemotherapy-induced mucositis, using a novel gut organ culture system

The main side effect of anti-cancer chemotherapy is the development of mucositis, a severe inflammation of the mucosal epithelial lining throughout the GI tract, which affects 80% of the patients undergoing high-dose chemotherapy. The molecular mechanisms underlying mucositis development and the role of microbiome are largely unknown. We developed a novel experimental system for gut organ cultures that provides absolute control over the drug dosage, luminal flow rate and exposure time (Yissachar et al., Cell. 2017). In our laboratory, we utilize the versatility of this unique system to dissect the immediate-early intestinal responses to chemotherapy in the presence of endogenous microbiota, or chemotherapy-disrupted microbiota, which might be associated with long-term development of gut inflammation. We used transcriptional profiling of whole gut tissues, and their sub-cellular components, following ex-vivo introduction of low and high dose of cytarabine and we identified a number of significant changes in neuronal factors and immune pathways that must be further investigated. Moreover, intestinal permeability increases after chemotherapy treatment, and has been shown to be one of the hallmarks of the third and fourth phases of mucositis (Sonis et al., Nat Rev Cancer. 2004). Therefore, we took advantage of the gut organ culture to develop an innovative on chip permeability assay, that allows us to test the effect of chemotherapy and chemotherapy-derived microbiome on gut barrier function. Interestingly we found that certain chemotherapy-disrupted microbiota induced an increase in gut permeability, while others didn’t have a significant effect. Those results were confirmed by a well established in vivo permeability assay, using fluorescent-labeled dextrans. Characterizing the bacterial populations that might directly affect gut permeability will allow us to narrow down the molecular mechanism associated with this phenomenon and promote new therapeutic approaches to restore the balance between gut bacteria and the immune system during chemotherapy, ameliorate intestinal inflammation, and boost anti-cancer therapy.