Ribonuclease 4 functions as an intestinal antimicrobial protein to maintain gut microbiota and metabolite homeostasis

Jun Sun, Muxiong Chen, Zhen Hu, Ningqin Xu, Wenguang Wang, Zejun Ping, Jiayi Zhu, Desen Sun, Zhehao Zhu, Hangyu Li, Xiaolong Ge, Liang Luo, Wei Zhou, Rongpan Bai (), Zhengping Xu () and Jinghao Sheng ()
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Jun Sun: Zhejiang University School of Medicine
Muxiong Chen: Zhejiang University School of Medicine
Zhen Hu: Zhejiang University School of Medicine
Ningqin Xu: Hangzhou Normal University
Wenguang Wang: Zhejiang University School of Medicine
Zejun Ping: Zhejiang University School of Medicine
Jiayi Zhu: Zhejiang University School of Medicine
Desen Sun: Medical School of Ningbo University
Zhehao Zhu: Zhejiang University
Hangyu Li: Zhejiang University
Xiaolong Ge: Zhejiang University School of Medicine
Liang Luo: Zhejiang University School of Medicine
Wei Zhou: Zhejiang University School of Medicine
Rongpan Bai: Zhejiang University School of Medicine
Zhengping Xu: Zhejiang University School of Medicine
Jinghao Sheng: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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 RNASE4 levels are observed in the intestinal tissues and stool from patients with IBD, correlating with increased stool Parasutterella. Our results thus implicate Rnase4 as an intestinal antimicrobial protein regulating gut microbiota and metabolite homeostasis, and as a potential diagnostic biomarker and therapeutic target for IBD.

Date: 2024
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DOI: 10.1038/s41467-024-50223-1

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