Restriction lift date: 2024-09-30
The microbiome in causation, detection, and treatment of cancer
Murphy, Clodagh Leonie
University College Cork
This thesis addresses the aspects of the gut microbiota in the causation, detection, and treatment of cancer. The microbiota in cancer extends beyond causation and risk acting both locally in the gut but also signalling and modifying immune responses beyond the gastrointestinal tract. This can influence the bioavailability, toxicity, and effectiveness of cancer therapies. Firstly, the microbial geography of the colorectal tumour is profiled. This is the first study that showing that the microbiota of an individual colorectal tumour is very similar throughout the entire tumour tissue. Diseased tissue was also comparable to the adjacent normal tissue. This strengthens previous assumptions in the literature that a single biopsy was representative of the colorectal tumour as a whole and that in CRC, a microbial field change occurs throughout the colon. Secondly, the gut microbiota in patients along the colorectal cancer trajectory from precancerous adenomatous polyps to colorectal cancer at endoscopy, at surgery and post-surgery are profiled. The microbiota of all groups differs from those of healthy controls. The post-operative group were closest to the healthy control group in terms of microbial similarity, but the post-operative microbiome never completely normalises. We hypothesise that the partial persistence of the field change in the microbiota seen at CRC diagnosis into the post-operative period may be a continuing risk factor for CRC recurrence. Switching to the theme of the microbiota in the treatment of cancer, the microbiota of patients with stage 4 metastatic melanoma treated with immunotherapy treatment is profiled. There were 11 sequence-based bacterial taxa that were differentially abundant between patients who responded to immunotherapy and treatment non-responders. Similarly, the differential abundance of nine sequence-based bacterial taxa was associated with development of side effects. Using bioinformatic prediction of the functional pathways differentially abundant in patients who develop side effects, three flagellar proteins were identified. Flagellar proteins are potent immune system activators which may give some insight into the mechanism of immune-mediated side-effects that occur with immunotherapy. Continuing the theme of the microbiome in treatment of cancer, Chapter 5 looks at a newly discovered role for Bifidobacterium 195 (Bif195) in reducing small intestinal aspirin induced damage as viewed on video capsule endoscopy in a large international placebo-controlled trial. Aspirin is commonly used for its chemoprotective effect in patients with cancer but can cause serious gastrointestinal side effects. Bif195 may be co-prescribed in the future to reduce these side effects. The findings of this thesis raise the possibility of use of microbial patterns to predict cancer outcomes. Similarly, it questions if microbiome manipulation is possible to induce more favourable treatment results. Faecal microbiota transplantation (FMT) is a possible method of microbiome manipulation. However, safety concerns regarding transmission of infection and possible inflammatory and metabolic phenotypes limits its present use in immunocompromised patients with cancer.
Microbiome , Cancer
Murphy, C. L. 2021. The microbiome in causation, detection, and treatment of cancer. MD Thesis, University College Cork.