deficiency functionally impairs adaptation to short bowel syndrome via alterations of the epithelial barrier function.

Nucleotide-binding oligomerization domain-containing protein 2 () gene mutations are a risk factor for Crohn's disease and also associated with worse outcome in short bowel syndrome (SBS) patients independent of the underlying disease. The aim of this study was to analyze the effect of deficiency on barrier function and stool microbiome after extensive ileocecal resection in mice. Male C57BL6/J wild-type (WT) and -knockout (KO) mice underwent 40% ileocecal resection. Sham control mice received simple transection of the ileum. Clinical outcome was monitored daily. Barrier function was measured with Ussing chambers using FITC-4-kDa-Dextran flux, transmucosal electrical resistance, and dilution potentials. Immunofluorescence of claudin-2 was studied. Composition of the stool microbiome was assessed by 16S rRNA gene sequencing. Resected -KO mice had impaired clinical outcome compared with resected WT mice. This was accompanied by increased stool water contents and increased plasma aldosterone. Histomorphological adaptation was independent of . Barrier function studies revealed impaired sodium to chloride permeability and altered claudin-2 localization in the absence of . Resection induced decreases of bacterial diversity and a shift of bacteriodetes-to-firmicutes ratios. Ileum and cecum resection-induced increase in proteobacteria was absent in -deficient mice. Verrucomicrobia were temporarily increased in -KO mice. Nod2 deficiency functionally impairs adaptation to short bowel syndrome via a lesser increase of epithelial sodium pore permeability, altered epithelial barrier function, and the microbiome. gene mutations are associated with the development of severe short bowel syndrome and intestinal failure. The influence of mutations on intestinal adaptation in experimental short bowel syndrome has not been studied yet. Here, we provide data that deficiency worsens clinical outcome and functional adaptation under SBS conditions in mice, indicating that NOD2 is required for successful adaptation after ileocecal resection.