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

Abstract

Compared with wild-type mice, lipocalin-2-/-mice have increased interleukin 22 expression, increased adaptation, and less dysbiosis after 75% small-bowel resection. Moreover, the proinflammatory and anti-adaptive effects of lipocalin-2 can be transferred to germ-free mice via a fecal transplant. 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 þ IL22 þ 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 improves adaptation and restores the normal microbiome after 75% SBR in WT mice.CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.

Distal Small Bowel Resection Yields Enhanced Intestinal and Colonic Adaptation

“…Knockout of lipocalin 2 was also found to promote adaptation. 16 Here, we observed no differences in remnant small bowel expression of lipocalin 2 or IL22 when proximal and distal SBRs were compared (P ¼ 0.4176 and P ¼ 0.6068, data not shown). These disparate findings may be due to several factors including different lengths of resection (75% versus 50%), varied postoperative times for study (1 and 3 week versus 2 and 10 week), and site of resection.…”

“…14 Enhanced physical adaptation has been observed in the presence of dietary fat 15 and interleukin 22 (IL22; mediated by lipocalin 2). 16 The ability to harness and modify these structural and functional changes with measurable impact speaks of the translatability of the SBR model and offers insight on future subjects of manipulation.…”