NOD2 mutations are associated with the development of intestinal failure in the absence of Crohn's disease

Schäffler, Holger; Schneider, Nina; Hsieh, Chih-Jen; Reiner, John M.; Nadalin, Silvio; Witte, Maria; Königsrainer, Alfred; Blumenstock, Gunnar; Lamprecht, Georg

doi:10.1016/j.clnu.2013.02.014

Cited by 20 publications

(14 citation statements)

References 32 publications

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“…Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) dysfunction is a well-known risk factor for the development of Crohn's disease [6][7][8]. In addition, it is a risk factor for insufficient adaptation and intestinal failure, independent of the underlying disease [9,10]. We have recently reported that extensive ileocecal resection induces severe intestinal failure in Nod2 knockout mice compared to wt mice through mechanisms involving impaired epithelial barrier function and microbiome alterations [11].…”

Section: Introductionmentioning

confidence: 99%

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

et al. 2020

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Background In short bowel syndrome, epithelial surface loss results in impaired nutrient absorption and may lead to intestinal insufficiency or intestinal failure. Nucleotide oligomerization domain 2 (Nod2) dysfunction predisposes to the development of intestinal failure after intestinal resection and is associated with intestinal barrier defects. Epithelial barrier function is crucial for intestinal absorption and for intestinal adaptation in the short bowel situation. Aims The aim of the study was to characterize the effects of the GLP-2 analogue Teduglutide in the small intestine in the presence and absence of Nod2 in a mouse model of short bowel syndrome. Methods Mice underwent 40% ICR and were thereafter treated with Teduglutide versus vehicle injections. Survival, body weight, stool water, and sodium content and plasma aldosterone concentrations were determined. Intestinal and kidney tissue was examined with light and fluorescence microscopy, Ussing chamber studies and quantitative PCR in wild type and transgenic mice. Results Teduglutide reduced intestinal failure incidence in Nod2 k.o. mice. In wt mice, Teduglutide attenuated intestinal insufficiency as indicated by reduced body weight loss and lower plasma aldosterone concentrations, lower stool water content, and lower stool sodium losses. Teduglutide treatment was associated with enhanced epithelial paracellular pore function and enhanced claudin-10 expression in tight junctions in the villus tips, where it colocalized with sodium-glucose cotransporter 1 (SGLT-1), which mediates Na-coupled glucose transport. Conclusions In the SBS situation, Teduglutide not only maximizes small intestinal mucosal hypertrophy but also partially restores small intestinal epithelial function through an altered distribution of claudin-10, facilitating sodium recirculation for Na-coupled glucose transport and water absorption. Keywords Short bowel syndrome • Mouse model • Ussing chamber • Teduglutide • Barrier function • Nucleotide oligomerization domain 2 Abbreviations GLP-2 Glucagon-like peptide 2 Nod2 Nucleotide oligomerization domain 2 RAAS Renin-angiotensin-aldosterone system PS Parenteral support

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Section: Introductionmentioning

confidence: 99%

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

et al. 2020

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“…Since this effect was found in patients with an ileostoma and in those with a colostoma, the lower frequency of colonic CD in patients with NOD2 mutations cannot explain this result. In a previous study we showed that NOD2 was associated with the development of intestinal failure in the absence of CD . For the authors it remains unclear why patients with a NOD2 gene mutation have a significantly lower risk of receiving an ostomy.…”

Section: Discussionmentioning

confidence: 98%

“…In a previous study we showed that NOD2 was associated with the development of intestinal failure in the absence of CD. 26 For the authors it remains unclear why patients with a NOD2 gene mutation have a significantly lower risk of receiving an ostomy.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the NOD2 gene are associated with a specific phenotype and lower anti‐tumor necrosis factor trough levels in Crohn's disease

Schäffler

Geiss

Gittel

et al. 2018

J of Digest Diseases

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Objective Nucleotide‐binding oligomerization domain‐containing protein 2 (NOD2) gene mutations are known to be an important risk factor in the pathogenesis of Crohn's disease (CD). Specific disease phenotypes are associated with the presence of NOD2 gene mutation. One treatment option is to use an anti‐tumor necrosis factor (TNF)‐α agent. Therapeutic drug monitoring (TDM) is usually performed in cases of a loss of response. Our aim was to explore whether NOD2 gene mutations have an effect on the disease phenotype, vitamin D levels, and on TDM in CD patients. Methods This was a retrospective genotype–phenotype association study on NOD2 gene mutations in 161 patients with CD. Results Altogether 55 (34.2%) patients carried at least one mutant allele of NOD2. NOD2 gene mutations were associated with ileocecal disease, ileocecal resection, stricturing and perianal disease, and patients with NOD2 gene mutation had significantly less frequent colonic disease and received an ostomy less frequently. TDM in patients with NOD2 gene mutation showed more frequent anti‐TNF trough levels in the subtherapeutic range and lower anti‐TNF trough levels than in NOD2 wild‐type (WT) patients. Conclusions CD patients with NOD2 gene mutation have a specific clinical phenotype and they may require higher doses of anti‐TNF agents to achieve sufficient anti‐TNF trough levels. They may therefore benefit from a proactive TDM than a reactive approach. This could be another step in the direction of personalized medicine.

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“…Tetradecanoyl phorbol acetate-induced sequence 7 (Tis7) has been characterized to mediate adaptive responses in the intestine and deletion of Tis7 reduces survival in a mouse model of short bowel syndrome [18]. Based on findings in two intestinal transplantation cohorts we have found an increased frequency of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations in patients with short bowel syndrome who did not have Crohn's disease, suggesting that NOD2 plays a role in adaptation [19][20][21]. Interestingly and unexpectedly heterozygosity of the transmembrane tyrosine kinase receptor Ret, which is required for development of the enteric nervous system, leads to enhanced intestinal adaptation after massive small bowel resection [22].…”

Section: Mechanisms Of Adaptationmentioning

confidence: 95%

Nutritional strategies to enhance adaptation in intestinal failure

Lamprecht

Bodammer

2016

Current Opinion in Organ Transplantation

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NOD2 mutations are associated with the development of intestinal failure in the absence of Crohn's disease

Cited by 20 publications

References 32 publications

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

Mutations in the NOD2 gene are associated with a specific phenotype and lower anti‐tumor necrosis factor trough levels in Crohn's disease

Nutritional strategies to enhance adaptation in intestinal failure

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