Association of Bacteroides acidifaciens relative abundance with high-fibre diet-associated radiosensitisation

Funding Information: This work was funded by Cancer Research UK Programme grant C5255/ A23755 and Wellcome Trust Investigator Award 209397/Z/17/Z. The funding body had no role in the design of the study; in the collection, analysis, and interpretation of data; or in the writing of the manuscript. Acknowledgements We thank Professor Simon Kroll and Dr. Anderson Ryan for their very helpful comments. We thank Dr. Jia-Yu Ke at Research Diets, Inc. for formulation of the mouse diets, Dr. Lisa Folkes for assistance with the faecal butyrate quantification, and Omega Bioservices (Georgia, USA) for the 16S rRNA gene sequencing on a MiSeq platform.Peer reviewedPublisher PD

The role of dietary supplements, including biotics, glutamine, polyunsaturated fatty acids and polyphenols, in reducing gastrointestinal side effects in patients undergoing pelvic radiotherapy : A systematic review and meta-analysis

Funding Information: This work was supported by Cancer Research UK Programme grant [C5255/A23755]. Chee Kin Then’s DPhil is funded by the Clarendon Fund, Balliol College and CRUK. The funding body had no role in the study design, collection, analysis, interpretation of data or in writing the manuscript.Peer reviewedPublisher PD

How do tumours outside the gastrointestinal tract respond to dietary fibre supplementation?

Peer reviewedPublisher PD

SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells

Funding Information: This work was funded by CRUK Programme Grant C5255/A23755. Acknowledgements Mass spectrometry analysis was performed in the MS laboratory at the Target discovery institute—NDM (Oxford) led by Benedikt M. Kessler. We thank Drs. Eva McGrowder and Blaz Groselj for processing of primary bladder tumour samples to produce cell-free extracts. Data availability The LC-MS/MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE48 partner repository with the dataset identifier PXD017964 and 10.6019/PXD017964.Peer reviewedPublisher PD

Exploiting dietary fibre and the gut microbiota in pelvic radiotherapy patients

ACKNOWLEDGEMENTS We thank Mrs Pat Bain for her assistance in creating Fig. 1. Funding Information: AEK’s salary is funded by Friends of ANCHOR and the University of Aberdeen Development Trust. CKT’s DPhil was funded by the Clarendon Fund, Balliol College, Oxford and Cancer Research UK. JK’s summer research project was funded by a Royal College of Radiologists’ Summer Undergraduate Research Fellowship. The authors received no specific funding for this work.Peer reviewedPublisher PD

p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation

Funding Information: This work was funded by Cancer Research UK (CRUK) program grant C5255/A23755 to A.E.K. Medical Research Council UK (MRC) program grant MC_PC 12001/1 (MC_UU_00001/1) and Breast Cancer Now (Grant No. 2019DecPR1406) to K.R. S.K. was supported by the MRC Oxford Institute of Radiation Oncology (OIRO) CRUK studentship. We thank Dr. Sovan Sarkar (Department of Oncology, University of Oxford) for generously providing DR-GFP U2OS cells. We thank Diogo Dias (Ludwig Cancer Research Institute, University of Oxford) for his technical advice on HR and SSA assays and assistance with the analysis. We thank Dr. Lisa Folkes and Alix Hampson for the high-performance liquid chromatography (HPLC) analysis of CB-5083 concentration in tissue extracts from CD-1 nude mice bearing subcutaneous RT112 tumors. We also thank the Oxford Radcliffe Biobank for providing us with human tissue sections.Peer reviewedPublisher PD

Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity.

Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy

Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity

Acknowledgements We thank Professor William Kim (University of North Carolina, Chapel Hill) for his generous gift of the UPPL1591 cell line. We thank Dr. Mark Hill (Department of Oncology, University of Oxford) for assistance with irradiation procedures, and Dr. Jia-Yu Ke and Dr. Vijay Indukuri (Research Diets, Inc.) for formulation of the mouse diets. We thank Dr. Graham Horgan (James Hutton Research Institute, Aberdeen) for statistical advice. We thank Grampian Biorepository at Aberdeen Royal Infirmary for providing the faecal samples from cancer patients.Peer reviewe

Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity

Background: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. Result: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. Conclusion: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. C3P3Z-i-BEWcsPG8U_9P4fVideo Abstrac

Sequencing of the 16S rRNA gene of the gut microbiota in mice treated with a high fibre diet as a potential endogenous mechanism of radiosensitisation

New non-toxic radiosensitisers are needed in the treatment of muscle-invasive bladder cancer because elderly patients are very vulnerable to chemotherapy-related toxicity of currently available radiosensitisers. Histone deacetylase (HDAC) inhibition is a promising mechanism of radiosensitisation. Tumour cells can accumulate butyrate which is produced by the gut microbiota via fibre fermentation to sufficient levels to cause HDAC inhibition, due to the Warburg effect. This has been seen when mice were treated with high-fibre diets. I hypothesise that the gut microbiota in mice fed a high fibre diet provide a sufficiently high systemic butyrate level for this to act as an endogenous mechanism of radiosensitisation. The specific aims are to examine the impact of the diet on the microbiome, and subsequently correlate diet-induced microbiome changes with tumour growth and response to radiation treatment. RT112 xenografts were used in this study. 16S rRNA gene sequencing was performed on a MiSeq platform and metagenomic analysis was conducted using a QIIME2 platform. The faecal (n=59) and caecal (n=59) microbiomes from mice were similar and they shared the 3 major taxa (&gt; 80% abundance): Bacteroidales, Clostridiales and Verrucomicrobiales. Significantly higher abundance of Bacteroides acidifaciens (p &lt; 0.001) existed in the gut microbiome of mice fed soluble high fibre (HF) for 2 weeks. Principal coordinate analysis showed a notable clustering effect within groups, indicating that diet indeed modified the faecal microbiome. Survival analysis by log-rank test showed soluble HF conferred survival benefits with delayed tumour growth after irradiation (n = 32, p = 0.045). Comparison of the gut microbiome of responders (n = 4) and non-responders (n = 4) to irradiation in the soluble HF group revealed higher abundance of B. acidifaciens in responding mice (p &lt; 0.05). Predictive metagenomic profiling showed gut microbiota in responders to be enriched for carbohydrate metabolism. To investigate the correlation between specific bacterial taxa and tumour response to irradiation, all mice fed different diets (n = 32) were pooled together. Univariate linear regression revealed a statistically significant positive correlation between the survival time of mice and abundance of the B. acidifaciens (R2 = 0.528, P &lt; 0.001). In conclusion, high fibre diets sensitised RT112 xenografts to irradiation by modifying the gut microbiome and this phenotype was associated with higher relative abundance of B. acidifaciens. Therefore, B. acidifaciens could be a potential radiosensitiser in bladder cancer.</p