PhD | Fecal microbiotal transplantation as a method for improving the outcomes of the dual radio-...

Recent data suggest a strong association between the gut microbiome and the development of colorectal cancer (CRC), one of the world’s most widely identified malignancies. A significant shift in composition was reported when comparing the gut microbiome of CRC patients with healthy individuals, a phenomenon commonly referred to as dysbiosis. Particularly, Enrichment of several bacterial species, including Fusobacterium nucleatum, Peptostreptococcus anaerobius and enterotoxigenic Bacteroides fragilis, have been identified to contribute to colorectal carcinogenesis, protecting tumor from immune attack, and promoting chemoresistance in CRC patients which consequently leads to treatment failure or disease recurrence. Radiotherapy plays an adjunctive role in the treatment of CRC, after the initial surgery. Yet radiotherapy has been known to cause itself intestinal dysbiosis, coinciding with mucositis and radiation-induced ulceration which eventually can lead to diarrhea, rectal bleeding, epithelial destruction and an eventual treatment interruption or the need for additional treatment. A promising approach for the treatment of CRC is cancer immunotherapy, including checkpoint inhibitors such as anti-PD1 (Golshani et al 2020, Therap Adv Gastroenterol, Sánchez-Alcoholado et al 2020). Yet the efficiency of immune checkpoint inhibitors in patients is heterogeneous and there is increasing evidence that the intestinal microbiota is a major player influencing the outcome of cancer immunotherapy. Immunotherapy is being explored in conjunction with radiotherapy for the treatment of colorectal cancer. This dual therapy offers a promising strategy to improve outcomes (particularly with immunotherapy lower responsiveness).

Microbiome therapy via faecal microbiota transplantation (FMT) was able to protect from radiation‐induced toxicity in mice and is being applied in clinical trial to improve the responsiveness to immunotherapy in CRC patients. To date, microbial modification through FMT was never introduced with the dual therapy of immunotherapy and irradiation. Thus it is not clear whether this will result in improved treatment outcome, lesser side-effects and tumour burden when combined together. Yet, there is a need to obtain pre-clinical evidence that such combined treatment will be more beneficial for the treatment outcome and side-effects. In this study we aim to assess the combined beneficial effect of microbiome therapy (FMT) for immunotherapy (anti PD-1) in CRC mouse model after exposure to radiotherapy in terms of treatment outcome and side-effects. We hypothesis that microbial profiling will be able to stratify CRC mice into responders and non-responders (in term of immuno-therapy efficiency) and sensitive/resistant in term of radiation induce toxicity. Additionally we hypothesis that microbial induced modifications using FMT will improve the treatment outcomes and reduce the side effects of the dual immuno/radio-therapies.