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Dietary fibre intake and the gut microbiota have been shown to modulate the efficacies of immunotherapy and chemotherapy treatments, but there have been very few studies in radiotherapy. We previously found that high fibre diets sensitised RT112 xenografts to irradiation by modifying the gut microbiota in immunocompromised mice. As prebiotics can enhance anti-cancer immunity, we hypothesised that dietary fibre and its modification of the gut microbiota can radiosensitise tumours via microbiota secretion of metabolites and/or immunomodulation, in immunoproficient mice.

C57BL/6 mice were inoculated in the flank with UPPL 1591 mouse bladder tumour cells when starting low (0.2% cellulose) and high fibre (5% psyllium, 5% psyllium plus 10% resistant starch/10% inulin) diets (N=30) and tumours allowed to grow to 100 mm3. In another cohort, the tumours were irradiated with 6 Gy ionising radiation (IR) when they reached 100 mm3 (N=60) and allowed to grow up to 700 mm3. Gut microbiota, metabolomics, and immunity analyses were performed by using 16S rRNA sequencing, ion chromatography-mass spectrometry and IHC. For normal tissue studies, mice received 10-14 Gy (N=84, acute) or 5x5Gy (N=40, late) IR to their lower abdomen, and intestines were studied by crypt assay at 3.75 days.

Psyllium plus inulin significantly decreased tumour (P=0.007) and delayed tumour growth following IR (P<0.001) compared to 0.2% cellulose. It raised Bifidobacterium relative abundance up to 40% (P<0.001) and intratumoural CD8+ cell numbers (P=0.0129 compared to psyllium plus RS). Post-IR, tumour control positively correlated to Lachnospiraceae family abundance (R2=0.534, P=0.016) and caecal butyrate levels (P=0.041). In responders to psyllium plus inulin, increased cytokine and receptor and T cell functional pathways and decreased exhausted CD8+ cells in tumours were found. Psyllium plus RS significantly radiosensitised the tumours compared to 0.2% cellulose and psyllium (P=0.004 and <0.001) and this positively correlated to Bacteroides genus abundance (R2=0.573, P=0.011). Although local immunity was suppressed, psyllium plus RS increased the caecal isoferulic acid level (R2=0.472, P=0.028), associated with a favourable response. Gut microbes also involved in tumour control by psyllium plus resistant starch included Peptostreptococcaceae family, Parasutterella and Faecalibaculum genera, and Muribulaceae family. Furthermore, the two diets mitigated the radiation injury caused by 14 Gy in intestinal crypt assays (P=0.08 and 0.011). All psyllium-containing diets increased caecal short-chain fatty acids (P<0.001), and prevented the delayed weight gain seen with 0.2% cellulose after IR.

Since psyllium plus either RS or inulin improved the radiation therapeutic ratio, prebiotics may be useful in pelvic cancer patients receiving radiotherapy.