KRAS　mutations　are　associated　with　poor　prognosis　in　colorectal　cancer　(CRC).　Although　the　association　between　the　gut　microbiota　and　CRC　has　been　extensively　documented,　it　is　unclear　whether　KRAS　mutations　can　regulate　the　gut　microbiota.　Metagenomics　has　identified　changes　in　the　diversity　of　the　gut　microbiota　in　CRC　due　to　KRAS　mutations.　Specifically,　KRAS　mutations　positively　correlate　with　the　abundance　of　the　bacteroides.　Understanding　how　to　regulate　the　classic　carcinogenic　bacterium　within　the　bacteroides,　such　as　enterotoxigenic　bacteroides　fragilis　(ETBF),　to　enhance　treatment　efficacy　of　tumors　is　a　key　focus　of　research.　Mechanistically,　we　found　that　the　reduction　of　miR3655　is　indispensable　for　KRAS　mutation-promoted　proliferation　of　CRC　and　the　abundance　of　ETBF.　miR3655　targets　SURF6　to　inhibit　its　transcription.　Further　transcriptomic　sequencing　revealed　that　SURF6　promotes　intratumoral　colonization　of　ETBF　in　CRC　by　inhibiting　the　nuclear　translocation　and　transcription　levels　of　the　IRF7,　affecting　the　activation　of　the　IFNβ　promoter.　Regulating　miR3655　and　SURF6　can　promote　IFNβ　secretion　in　CRC,　directly　killing　ETBF.　These　data　indicate　that　KRAS　mutations　affect　the　intratumoral　colonization　of　ETBF　in　CRC　through　the　miR3655/SURF6/IRF7/IFNβ　axis.　This　provides　new　potential　strategies　for　treating　CRC　associated　with　KRAS　mutations　or　high　levels　of　ETBF.　©　2024　The　Author(s).　Published　with　license　by　Taylor　&　Francis　Group,　LLC.