biostudies-literatureSun JFundamental Research Funds for the Central UniversitiesNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)5778https://www.ebi.ac.uk/biostudies/studies/S-EPMC11237007biostudies-literatureUnknown15(1)Antimicrobial proteins contribute to host-microbiota interactions and are associated with inflammatory bowel disease (IBD), but our understanding on antimicrobial protein diversity and functions remains incomplete. Ribonuclease 4 (Rnase4) is a potential antimicrobial protein with no known function in the intestines. Here we find that RNASE4 is expressed in intestinal epithelial cells (IEC) including Paneth and goblet cells, and is detectable in human and mouse stool. Results from Rnase4-deficient mice and recombinant protein suggest that Rnase4 kills Parasutterella to modulate intestinal microbiome, thereby enhancing indoleamine-2,3-dioxygenase 1 (IDO1) expression and subsequently kynurenic and xanthurenic acid production in IECs to reduce colitis susceptibility. Furthermore, deceased RNASNature communicationsRibonuclease 4 functions as an intestinal antimicrobial protein to maintain gut microbiota and metabolite homeostasis.PMC1123700732071289Li HXu NZhu ZHu ZChen MZhou WPing ZBai RSheng JZhu JGe XLuo LSun DWang WSun JXu ZfalseRibonuclease 4 functions as an intestinal antimicrobial protein to maintain gut microbiota and metabolite homeostasis.Antimicrobial proteins contribute to host-microbiota interactions and are associated with inflammatory bowel disease (IBD), but our understanding on antimicrobial protein diversity and functions remains incomplete. Ribonuclease 4 (Rnase4) is a potential antimicrobial protein with no known function in the intestines. Here we find that RNASE4 is expressed in intestinal epithelial cells (IEC) including Paneth and goblet cells, and is detectable in human and mouse stool. Results from Rnase4-deficient mice and recombinant protein suggest that Rnase4 kills Parasutterella to modulate intestinal microbiome, thereby enhancing indoleamine-2,3-dioxygenase 1 (IDO1) expression and subsequently kynurenic and xanthurenic acid production in IECs to reduce colitis susceptibility. Furthermore, deceased RNAS2024-01-01T00:00:00Z2024 Jul2026-06-01T13:30:43.131Z2025-04-05T15:47:47.306ZS-EPMC112370073898725910.1038/s41467-024-50223-1