This study identifies P. bifermentans and Dubosiella sp. as potential gut microbiota signatures in hnRNPI KO mice. KO mice were more susceptible to exacerbated colitis during the DSS challenge. Additionally, bacterial metabolites produced by P. bifermentans and D. newyorkensis may influence colon health in hnRNPI KO mice. Predicted pathway analysis from 16S rRNA gene sequencing revealed significant differences in pathways related to human diseases, including cancer. Finally, this study demonstrates that genetic aberrations, specifically hnRNPI KO, disrupt gut microbiota eubiosis, exacerbate colitis, and may potentially increase cancer risk.