Study of the effect of faecal microbiota transfer (FMT) therapy on a preclinical radiation-induced colorectal model
Thesis: Faecal microbial transplantation to reduce radiation-induced colonic epithelial damages: application to Pelvic Radiation disease. Radiotherapy accounts for 60% of treatment strategies for pelvic cancer. The consequences of radiation in the tissues surrounding the tumour can appear several years after radiotherapy. This was described in 2010 as a new pathology: Pelvic Radiation Disease (PRD). In the laboratory, the aim is to develop new therapeutic strategies to reduce the tissue toxicity induced by radiotherapy. Prospective clinical data have shown that during and after pelvic radiotherapy, there is a change in the microbiota in parallel with intestinal complications. This could be described as dysbiosis, a disruption of the symbiotic relationship between the host and the gut microbiota. Our aim is to demonstrate, in a relevant preclinical model, that irradiation leads to changes in the gut ecosystem which ultimately is responsible for the evolution of lesions. We have developed a suitable localised irradiation model using fractionated doses (very similar to the clinical procedure) to obtain irradiation protocols that induce moderate to severe epithelial damage. In collaboration with the Institut National de Recherche Agronomique et Environnement, we analysed the temporal dynamics of (i) the alteration of the faecal microbiota (Shot Gun metagenomic sequencing) and the metabolome (analytical methods based on liquid chromatography-mass spectrometry) and (ii) the host immune and epithelial response by immunostaining. We reported that, depending on the protocol used, irradiation increases the diversity of the microbiota, stimulates the host immune response and alters the tissue over time. We have also shown that faecal microbiota transfer reduces colonic toxicity only in animals with moderate epithelial damage. Existing treatments for PRD are only symptomatic, so this study is of primary clinical interest.
Keywords
- Microbiota
- Radiotherapy
- Irradiation
- Dysbiosis
- Inflammation
Issuing body(s)
- Sorbonne Université
Date of defense
- 05/07/2023
Thesis director(s)
- Fabien Milliat
- Jean-Marc Chatel
- Alexandra Semont
URL of the HAL notice
Version
- 1