Revealing the Antagonistic Interactions of Faecalibacterium prausnitzii and Bacteroides fragilis in Colorectal Cancer.

Abstract

Maladaptation of host-microbe metabolic interactions plays a crucial role in development of colorectal cancer (CRC). However, remains a lack of comprehensive studies using multi-omics analysis to illustrate host-microbe metabolic interactions in CRC. We collected and analyzed 440 stool samples from a discovery cohort in Shanghai China (255 patients with CRC and 185 healthy controls). Each sample was subjected to metagenomic sequencing and nontargeted liquid chromatography mass spectrometry. Fresh-frozen specimens of tumors and matched adjacent normal mucosae were extracted from 62 patients with CRC, and whole exome sequencing and RNA sequencing were performed to explore host genomic patterns and host-microbe metabolic interactions. Finally, relationships detected in the discovery cohort were validated against independent cohorts, organoid models, and mice experiments. The relationship between disrupted microbial homeostasis and CRC progression is characterized by Bacteroides fragilis enrichment and reduction of Faecalibacterium prausnitzii. F prausnitzii metabolizes tryptophan into picolinic acid (PIA) via the enzyme 2-amino-3-carboxymuconate semialdehyde decarboxylase, with PIA exerting an antagonistic effect on enterotoxigenic B fragilis-mediated tumor progression. Mechanistically, enterotoxigenic B fragilis up-regulates the expression of genes associated with poor differentiation and recurrence, namely TCERG1 and CKAP2, and PIA induces tumor cell apoptosis by down-regulating these 2 genes. Independent validation cohorts and murine models corroborated that a tryptophan-rich diet effectively elevates circulating PIA levels, suggesting its potential as an anticancer dietary intervention. Our research characterized a representative microbe-metabolite-host regulatory pathway occurring in CRC, namely the F prausnitzii-PIA-TCERG1/CKAP2 axis antagonizing enterotoxigenic B fragilis-induced CRC progression. As a treatment option, we highlight the therapeutic potential inherent in a tryptophan-rich diet and in manipulating microbial composition targeting the F prausnitzii-PIA axis to prevent CRC.