Pelvic cancers are amongst the most frequently diagnosed cancers worldwide. Half of the patients undergoing pelvic radiotherapy report a wide diversity of complications, which reduce patients’ quality of life and add an additional burden to the healthcare system. Currently, there are no effective therapies available to mitigate these injuries, which is partly due to a lack of insight into the events causing intestinal mucositis and dysbiosis. Apart from traditional pharmacological compounds, there is a need for research on adjuvant therapies. This PhD dissertation explored the potential of Limnospira indica PCC 8005 as innovative treatment strategy for pelvic irradiation-induced mucositis and dysbiosis, in comparison to well-studied probiotic Lacticaseibacillus rhamnosus GG ATCC 53103. To achieve this overarching goal, first, a new in vivo irradiation-gut-microbiome model was implemented. Herein, the structural and functional impact of local, pelvic irradiation on the intestinal ecology of healthy mice was characterized so that side effects encountered by patients following pelvic radiotherapy were mimicked. Pelvic irradiation (12 Gy) evoked structural and functional changes in the intestine, which secondarily resulted in a microbiome shift. Members of Ruminococcacceae, Lachnospiraceae and Porphyromonodaceae were differentially impacted and identified as biomarkers for pelvic irradiation. Subsequently, unprocessed, fresh biomass of L. indica PCC 8005 or L. rhamnosus GG were investigated for their effect on the gut microbiome of healthy mice. Both food supplements appeared to transiently shift the microbial community, characterized by a higher relative abundance of butyrate producing members of the Lachnospiraceae and Porphyromonadaceae families, respectively. This could indicate a potential for both supplements to sustain or restore the intestinal ecology following pelvic irradiation-induced intestinal mucositis. | XIII Therefore, a randomized, placebo-controlled preclinical trial was set up in which daily supplementation with fresh L. indica PCC 8005 and L. rhamnosus GG before and after 12 Gy irradiation of the pelvis was investigated in our newly implemented in vivo irradiation-gut-microbiome model. They were evaluated for their radioprotective effects on both the intestinal tissue as well as the fecal microbial community. Both could not confer barrier protection. However, L. rhamnosus GG was attributed some anti-inflammatory capacities by partly reducing mucosal myeloperoxidase levels. In addition, L. rhamnosus GG appeared more effective in preventing pelvic irradiation-induced dysbiosis when compared to L. indica PCC 8005. In conclusion, this PhD dissertation contributed to a better understanding of the pathogenesis of pelvic irradiation-induced mucositis and dysbiosis. Furthermore, we obtained insights in the capacity of Lacticaseibacillus rhamnosus GG ATCC 53103, and to a lesser extent Limnospira indica PCC 8005, to grant radioprotection. This work thus provides evidence to further explore the potential of both food supplements as a mitigating agent counteracting pelvic irradiation-induced intestinal mucosal inflammation and resultant dysbiosis.
|Qualification||Doctor of Science|
|Date of Award||10 Jan 2022|
|State||Published - 10 Jan 2022|