Abstract
BackgroundPatients with pelvic malignancies often receive radiosensitising chemotherapy with radiotherapy to improve survival; however, this is at the expense of increased normal tissue toxicity, particularly in elderly patients. Here, we explore if an alternative, low-cost, and non-toxic approach can achieve radiosensitisation in mice transplanted with human bladder cancer cells. Other investigators have shown slower growth of transplanted tumours in mice fed high-fibre diets. We hypothesised that mice fed a high-fibre diet would have improved tumour control following ionising radiation (IR) and that this would be mediated through the gut microbiota.ResultsWe investigated the effects of four different diets (low-fibre, soluble high-fibre, insoluble high-fibre, and mixed soluble/insoluble high-fibre diets) on tumour growth in immunodeficient mice implanted with human bladder cancer flank xenografts and treated with ionising radiation, simultaneously investigating the composition of their gut microbiomes by 16S rRNA sequencing. A significantly higher relative abundance of Bacteroides acidifaciens was seen in the gut (faecal) microbiome of the soluble high-fibre group, and the soluble high-fibre diet resulted in delayed tumour growth after irradiation compared to the other groups. Within the soluble high-fibre group, responders to irradiation had significantly higher abundance of B. acidifaciens than non-responders. When all mice fed with different diets were pooled, an association was found between the survival time of mice and relative abundance of B. acidifaciens. The gut microbiome in responders was predicted to be enriched for carbohydrate metabolism pathways, and in vitro experiments on the transplanted human bladder cancer cell line suggested a role for microbial-generated short-chain fatty acids and/or other metabolites in the enhanced radiosensitivity of the tumour cells.ConclusionsSoluble high-fibre diets sensitised tumour xenografts to irradiation, and this phenotype was associated with modification of the microbiome and positively correlated with B. acidifaciens abundance. Our findings might be exploitable for improving radiotherapy response in human patients.
Highlights
Patients with pelvic malignancies often receive radiosensitising chemotherapy with radiotherapy to improve survival; this is at the expense of increased normal tissue toxicity, in elderly patients
Dietary fibre structures align with phenotypes of specific microbes that differ in their metabolic pathways [10]
Our mouse samples contained more than 104 bacterial Colony formation unit (CFU) which appeared to override contaminating species in the sample microbial communities (Fig. 1b)
Summary
Patients with pelvic malignancies often receive radiosensitising chemotherapy with radiotherapy to improve survival; this is at the expense of increased normal tissue toxicity, in elderly patients. New approaches to radiosensitisation are urgently required One such approach might be to modify the intake of dietary fibre by supplements before and during radiotherapy or current standard chemoradiation schedules, which would be a very cost-effective strategy, not expected to add to normal tissue toxicity [3, 4]. Wei et al showed slower growth rates of subcutaneous lymphoma xenografts in mice fed a high-fibre diet (8%) compared to mice on a low-fibre diet, with similar findings in both immune-deficient and immune-competent models [5] This was associated with increased plasma and tumour butyrate levels, but the authors did not investigate the effects of the diet on the gut microbiome. Other metabolites including small intermediate and end by-products of endogenous metabolic pathways, products of microbe-host co-metabolism, and exogenous signals arising from diet, drugs, and other environmental stimuli might be important [11]
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