| सारांश: | <p>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. Our previous study showed that high fibre diets sensitised RT112 xenografts to irradiation by modifying the gut microbiota and this phenotype was positively correlated with Bacteroides acidifaciens (BA) abundance. As the gut microbiota can enhance anti-tumoural immune responses, I hypothesised that dietary fibre manipulation and its effects on the gut microbiota can radiosensitise tumours via microbiota secretion of metabolites and/or immunomodulation.</p>
<p>In preclinical mouse experiments, psyllium plus resistant starch (RS) or psyllium plus inulin significantly decreased tumour size (P=0.007 and <0.001, respectively) and they enhanced tumour control when combined with ionising radiation (IR; P<0.001 and 0.028, respectively) compared to 0.2% cellulose.</p>
<p>Psyllium plus inulin raised Bifidobacterium abundance (P<0.001), CD8+ cell numbers (P=0.024), and caecal inosine levels (P<0.001), which have been shown to enhance immunotherapy efficacy. There was a significant correlation between immune response and tumour control versus Clostridiales order abundance. Systemic GM-CSF (granulocyte-macrophage colony-stimulating factor) and IL-2 cytokines levels were increased by IR. The caecal butyrate level was associated with the tumour control in the psyllium plus inulin group of both non-irradiated and irradiated mice (P=0.041). It is noted that threitol also negatively correlated with IR response. Psyllium plus RS increased several metabolite levels that have anti-tumourigenic properties, and significantly radiosensitised the tumours (P=0.004). 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 (SCFAs, P<0.001), and prevented the delayed weight gain seen with 0.2% cellulose after IR.</p>
<p>We previously found that inulin enhanced the relative abundance of BA. Based on cell experiments, the supernatants of co-cultures of BA and Faecalibactrium prausnitzii (FP, butyrate-producer) conferred greater cytotoxicity than BA alone (P<0.001) or co-cultures of Bifidobacterium (acetate-producer) and FP (P<0.001), and also increased histone acetylation levels. Bacterial supernatants of BA+FP increased DNA damage and delayed DNA repair following 2 Gy IR (P<0.05) and increased radiosensitivity of bladder tumour cells (P=0.008 at 8 Gy). Overall, I demonstrated that dietary fibre supplements radiosensitised bladder tumours, with associated gut microbiota modification and enhancement of immune responses and metabolite levels. Since psyllium plus either RS or inulin achieved a more favourable therapeutic ratio with improved tumour control with decreased side effects, I propose that dietary fibre supplements may be useful adjuncts to radiotherapy in patients with pelvic malignancy.</p>
|
|---|