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

A side effect of anti-cancer chemotherapy is the development of mucositis, an inflammation of the mucosal epithelial lining. The mechanisms underlying mucositis development and the microbiome are largely unknown. We developed a novel experimental system for gut organ cultures that provides control over drug dosage, luminal flow rate and exposure time[1]. We utilize this system to dissect the 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 cytarabine. We identified several significant changes that must be further investigated. Moreover, intestinal permeability increases after chemotherapy treatment, and has been shown to be one of the hallmarks of mucositis[2]. Therefore, we took advantage of our system to develop an innovative on chip permeability assay, allowing us to test the effect of a chemotherapy-derived microbiome on gut barrier function. Interestingly, we found that certain chemotherapy-disrupted microbes induced an increase in gut permeability, while others didn’t have a significant effect. Those results were confirmed by an in vivo permeability assay, using FITC. Characterizing the bacterial populations that might directly affect gut permeability will allow us to narrow down the molecular mechanism associated with this phenomenon. Additionally, it will 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

[1] (Yissachar et al., Cell. 2017

[2] Sonis et al., Nat Rev Cancer. 2004