A Central Role for Lipocalin-2 in the Adaptation to Short-Bowel Syndrome Through Down-Regulation of IL22 in Mice

作者：Ailan Zhang, Chhinder P. Sodhi, Menghan Wang, Darla Shores, William B. Fulton, Thomas Prindle, Serena Brosten, Elizabeth O’Hare, Alexander R. Lau, Hua Ding, Hongpeng Jia, Peng Lü, James R. White, Justin Hui, Cynthia L. Sears, David J. Hackam, Samuel M. Alaish · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2020 · DOI：10.1016/j.jcmgh.2020.04.006 · 被引用次数：8 · 研究领域：Clinical Nutrition and Gastroenterology、Liver Disease and Transplantation、Immune Response and Inflammation

Background & Aims In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. Methods We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2) -/- , and interleukin 22 (IL22) -/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2 -/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4 + IL22 + laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. Results A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2 -/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22...