膳食纤维摄入改变DIET试验中的胆汁酸代谢谱——一项在接受免疫治疗的黑色素瘤患者中进行的随机双盲膳食干预研究

Background: Dietary fiber is associated with response to immune checkpoint blockade (ICB) in melanoma. We previously conducted the DIET trial (NCT04645680) which was a fully controlled feeding study comparing a high fiber versus a healthy control diet in melanoma patients receiving ICB. The trial revealed that high fiber diet is feasible and safe, and patients on high fiber diet demonstrated a numerically higher response rate. Herein, we report a secondary objective of the effects of dietary intervention on systemic metabolism. Methods: Melanoma patients (n=45) initiating ICB were randomized (2:1), following a 1-week equilibration, to either a high fiber (30 g/d fiber ramped-up biweekly via whole foods to 50 g/d) or a healthy control diet (20 g/d fiber) for the study duration (up to 10 weeks). Longitudinal blood specimens were collected at baseline and at each infusion (when treated locally) for up to three cycles during the study. Sera from 43 patients were processed for untargeted metabolomics and bile acid (BA) profiling using LC-MS/MS methods. Current analysis focuses on comparison of paired samples from patients in the high fiber (n=6) and the control arm (n=8) collected during equilibration vs week 1-4, reflecting a dietary fiber 30-40 g/day in the high fiber arm. Results: The untargeted metabolomics analyses revealed changes in BAs and glycine- and taurine- conjugated derivates to be reduced in the high fiber arm compared to control (Wilcoxon rank sum test p<0.05). Targeted BA profiling confirmed a decrease in unconjugated secondary BAs and secondary-to-primary BA ratios, which may influence anti-tumor immunity. Specifically, our findings suggest that dietary fiber reduced gut microbiota mediated biotransformation of secondary BAs (deoxycholic acid, lithocholic acid and ursodeoxycholic acid) from primary BAs (cholic acid and chenodeoxycholic acid). Conjugated to unconjugated BA ratios were also decreased in the high fiber arm, suggesting potentially reduced hepatic BA conjugation. Furthermore, in mouse avatar models of melanoma, fecal microbiota transplant was performed using paired fecal specimens (pre vs post high fiber diet) from participants in the DIET trial. Post-high fiber diet recipients showed improved ICB response and decreased secondary-to-primary BA ratios in the circulation (n=5) compared to pre-high fiber diet recipients. Conclusion: Consistent with prior controlled feeding studies in other settings, our collective findings from circulating metabolites suggested that dietary fiber intervention modulates microbiome mediated secondary BA synthesis and conjugation linked to ICB response. These findings warrant further mechanistic studies in preclinical models and in larger cohort of patients.