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Ileocolonic Healing after Small Ileocecal Resection in Mice: NOD2 Deficiency Impairs Anastomotic Healing by Local
Maria B Witte1, Johannes Saupe2, Johannes Reiner2
1Department of General, Visceral, Thoracic, Vascular and Transplant Surgery, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany.
Abstract:
Ileocecal resection (ICR) is frequently performed in Crohn's disease (CD). NOD2 mutations are risk factors for CD. Nod2 knockout (ko) mice show impaired anastomotic healing after extended ICR. We further investigated the role of NOD2 after limited ICR. C57B16/J (wt) and Nod2 ko littermates underwent limited ICR including 1-2 cm terminal ileum and were randomly assigned to vehicle or MDP treatment. Bursting pressure was measured on POD 5, and the anastomosis was analyzed for matrix turn-over and granulation tissue. Wound fibroblasts from subcutaneously implanted sponges were used for comparison. The M1/M2 macrophage plasma cytokines were analyzed. Mortality was not different between groups. Bursting pressure was significantly decreased in ko mice. This was associated with less granulation tissue but was not affected by MDP. However, anastomotic leak (AL) rate tended to be lower in MDP-treated ko mice (29% vs. 11%, p = 0.07). mRNA expression of collagen-1α (col1 α), collagen-3α (col3 α), matrix metalloproteinase (mmp)2 and mmp9 was increased in ko mice, indicating increased matrix turn-over, specifically in the anastomosis. Systemic TNF-α expression was significantly lower in ko mice. Ileocolonic healing is impaired in Nod2 ko mice after limited ICR by local mechanisms maybe including local dysbiosis.
Insights
NOD2 gene mutations impair healing after ileocecal resection in mice, leading to reduced anastomotic strength. NOD2 deficiency affects matrix turnover and granulation tissue formation, impacting surgical recovery in Crohn's disease models.
Area of Science:
- Gastroenterology
- Surgical Research
- Immunology
Background:
- Ileocecal resection (ICR) is a common surgery for Crohn's disease (CD).
- NOD2 mutations are established risk factors for CD.
- Previous studies showed impaired healing after extended ICR in Nod2 knockout (ko) mice.
Purpose of the Study:
- To investigate the role of NOD2 in anastomotic healing after limited ICR.
- To assess the impact of NOD2 deficiency on surgical outcomes and tissue repair.
- To explore potential therapeutic effects of MDP treatment in Nod2 ko mice.
Main Methods:
- Limited ICR was performed on wild-type (wt) and Nod2 ko mice.
- Animals were treated with vehicle or MDP (muramyl dipeptide).
- Anastomotic bursting pressure, granulation tissue, matrix turnover (collagen, MMPs), and macrophage cytokines were analyzed on post-operative day 5.
Main Results:
- Nod2 ko mice exhibited significantly decreased anastomotic bursting pressure and reduced granulation tissue.
- Increased mRNA expression of collagen and matrix metalloproteinases (MMPs) in ko mice indicated heightened matrix turnover.
- While MDP did not improve bursting pressure, it showed a trend towards reduced anastomotic leak rates in ko mice.
Conclusions:
- NOD2 plays a crucial role in promoting adequate anastomotic healing after limited ICR, independent of systemic TNF-α levels.
- Impaired healing in Nod2 ko mice is likely due to local mechanisms, potentially involving dysbiosis.
- These findings highlight NOD2's importance in intestinal surgical repair and suggest potential therapeutic targets for CD patients with NOD2 mutations.
