Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer

Background and aims The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes. Methods A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months. Results Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 x-10(-11)); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 x-10(-12)), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7.

Automated summary

This study investigates the association between gut microbiota, metabolome, and colorectal cancer (CRC). The authors identify specific microbiota clusters, such as cluster 7 containing Fusobacterium nucleatum and Granulicatella adiacens, that are strongly associated with CRC and can predict favorable disease-free survival. They also find that cluster 1 containing Faecalibacterium prausnitzii and Ruminococcus gnavus is negatively associated with cancer and predicts worse disease-free survival. In addition, certain metabolic clusters show associations with CRC, such as Met 1 composed of fatty acids, ceramides, and lysophospholipids, which is negatively associated with CRC, and Met 2 composed of phosphatidylcholine species, nucleosides, and amino acids, which is strongly associated with CRC.