Increased D-Neopterin biosynthesis in gut microbiome promoted colonic carcinogenesis after ampicillin or amoxicillin treatment

Background: Emerging data have manifested that antibiotic-induced perturbations can potentially increase susceptibility to colorectal cancer (CRC), while the underlying mechanism is still unclear. Results: : Herein we established the humanized microbiome mice transplanted with feces and hematopoietic stem cells from CRC patients to explore how ampicillin or amoxicillin contributed to colorectal cancer progression. Metagenomics and untargeted metabolomics analyses have suggested the effect of ampicillin or amoxicillin on colonic tumorigenesis is correlated with an alteration of gut microbiota and increased levels of the microbiota-derived metabolite D-Neopterin ( P < 0.05). Then D-Neopterin is evidenced to activate the expressions of IGF2BP1 and ARG1 in myeloid-derived suppressor cells (MDSCs) by scRNA-seq. Moreover, IGF2BP1 was determined to maintain the stability of ARG1 transcript by binding to three m6A sites of ARG1‐3’UTR in the sorted MDSCs. Conclusion: In essence, this study has identified the important role of ampicillin or amoxicillin-induced increase of D-Neopterin in enhancing colorectal cancer proliferation. It thus implicates that therapeutic regimen of CRC patients should eliminate the application of ampicillin or amoxicillin.