Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation

Yosuke Kurashima,Masako Morimoto,Yuki Goda,Kaoru Shimada,Ai Sasou,Yoshikazu Yuki,Natsumi Seki,Koji Hase,Yun Gi Kim ,Hideki Iijima,Toshihiko Suzuki,Masahira Hattori,Yutaka Inagaki,Kazuya Kawano,Takaaki Kigoshi,Hiroshi Ohno,Yukinobu Saito ,Fujimi Arai,Wataru Suda,Sayuri Murasaki,Hiroshi Ashida,Hiroshi Kiyono

doi:10.1038/s41467-021-21277-2

Abstract

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF–dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn’s diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas–intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

Highlights

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD)
We found that microfold cells (M cells) in follicle-associated epithelium of Peyer’s patches express glycoprotein 2 (GP2), which acts as a transcytotic receptor for type 1 fimbrial adhesin (FimH), a component of type 1 pili, expressed by E. coli and Salmonella typhimurium[18,19,20]
GP2 was detected in the pancreas but not in the luminal compartment of the stomach, which is consistent with a previous report that GP2 is expressed by pancreatic acinar cells[15]

Summary

Introduction

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). The pancreas–intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation. Inflammatory bowel diseases, such as Crohn’s disease (CD) and ulcerative colitis (UC), are associated with dysregulation of the intestinal mucosal barrier and dysbiosis[1,2,3]. Several lines of evidence show a high prevalence of mucosal-associated commensal bacteria, including Escherichia coli, adherent-invasive E. coli, in CD patients and that these bacteria play a key role in the pathogenesis of CD9. We identify a biological function of pancreatic GP2 in the harsh environment of the intestinal tract, controlling bacterial attachment and penetration for intestinal homeostasis

Methods

Results

Conclusion