TY - JOUR T1 - Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900592 VL - 3 IS - 6 SP - e201900592 AU - Yu Shimizu AU - Kiminori Nakamura AU - Aki Yoshii AU - Yuki Yokoi AU - Mani Kikuchi AU - Ryuga Shinozaki AU - Shunta Nakamura AU - Shuya Ohira AU - Rina Sugimoto AU - Tokiyoshi Ayabe Y1 - 2020/06/01 UR - https://www.life-science-alliance.org/content/3/6/e201900592.abstract N2 - 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. ER -