Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice

Yu Shimizu,Yuki Yokoi,Rina Sugimoto,Tokiyoshi Ayabe,Aki Yoshii,Ryuga Shinozaki,Shunta Nakamura,Shuya Ohira,Kiminori Nakamura,Mani Kikuchi

doi:10.26508/lsa.201900592

Abstract

Crohn's disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

Highlights

The intestinal tract harbors an immense number of bacteria, the intestinal microbiota, which are involved in many aspects of host physiology, that includes energy metabolism [1], immune system regulation [2], and nervous system development [3]
Histological analysis with hematoxylin and eosin (HE) staining was conducted to assess the relationship between disease progression and Paneth cells in SAMP1/YitFc mice, which develop spontaneous ileitis by 20 wk of age which resembles that of Crohn’s disease (CD) patients [37]
Dysbiosis with reduced diversity observed in the SAMP1/YitFc mice is consistent with previous studies of the intestinal microbiota of CD patients from the Americas, Europe, and Japan [31, 46, 47, 48]

Summary

Introduction

The intestinal tract harbors an immense number of bacteria, the intestinal microbiota, which are involved in many aspects of host physiology, that includes energy metabolism [1], immune system regulation [2], and nervous system development [3]. Α-Defensins, a major family of mammalian antimicrobial peptides, are known regulators of the intestinal microbiota. These ~4-kD basic peptides are characterized by evolutionally conserved Cys residue positions that are invariantly spaced to form disulfide bonds between CysI-CysVI, CysII-CysIV, and CysIII-CysV [5]. Oral administration of Crp prevents severe dysbiosis in mouse graftversus-host disease [13, 14], indicating that Paneth cell α-defensins secreted into the intestinal lumen contribute to innate immunity and to maintenance of intestinal homeostasis by regulating the intestinal microbiota [15, 16]

Methods

Results

Conclusion