Integration of constraint-based modelling with faecal metabolomics reveals large deleterious effects ofFusobacteriaspecies on community butyrate production

Summary Integrating constraint-based community modelling with population statistics, we introduce new theoretical concepts for interrogating the metabolic functions of the microbiome, applying them to a public metagenomic dataset consisting of 365 colorectal cancer cases (CRC) and 251 healthy controls. We found that 1) glutarate production capability was significantly enriched in CRC microbiomes and mechanistically linked to lysine fermentation in Fusobacteria species, 2) acetate and butyrate production potentials were lowered in CRC, 3) Fusobacteria presence had large negative ecological effects on community butyrate production in CRC and healthy controls. Validating the model predictions against faecal metabolomics, our in silico frameworks correctly predicted in vivo species metabolite correlations with high accuracy. In conclusion, highlighting the value of combining statistical association studies with in silico modelling, this study delivers insights on the metabolic role of Fusobacteria in the gut, while providing a proof of concept for the validity of constraint-based community modelling.