Abstract Background Short bowel syndrome (SBS) is a rare and complex condition that can occur after ileo caecal resection (ICR), which is often performed in Crohn’s disease (CD) patients. The disease outcome depends on the postsurgical anatomy as well as individual risk factors that may impede intestinal adaptation. The objective of this study was to investigate intestinal adaptation following ICR in a CD mouse model. Methods SAMP1/YitFc (SAMP1, n=37) mice with histologically manifest ileitis and parental controls (AKR, n=34) of both sexes were subjected to 40% ICR or transection (sham) at the age of 14-20 weeks. Intestinal continuity was established by end-to-end jejunocolic anastomosis. Clinical data and stool samples were collected for either 7 or 14 days. Histomorphological adaptation and intestinal inflammation were examined by histological evaluation of residual jejunal and colonic sections as well as by analysis of blood parameters and cytokine mRNA expression in mesenteric lymph nodes (MLN). Results This study was the first to examine adaptation in a CD mouse model. At the age of 14 weeks SAMP1 mice exhibited spontaneous ileitis, with characteristics similar to CD (hypertrophy of muscularis, dysplasia of paneth cells, transmural infiltration, villus blunting). Following surgery, SAMP1 mice showed higher mortality after surgery in ICR and sham groups (both 33%) compared to AKR (21% ICR, 0% sham). ICR resulted in the manifestation of SBS, displayed by body weight loss and diarrhea in both strains. SAMP1 mice exhibited a higher food intake and demonstrated less weight loss than AKR mice. However, the level of wellbeing was significantly lower in comparison to AKR after ICR (p<0.0001 d7, d14). Histomorphological adaptation of the remnant jejunum was worse in SAMP1 mice (villus height SAMP1 229 µm vs. AKR 376 µm, p<0.01). Following ICR, SAMP1 mice exhibited normalization of preoperatively increased inflammatory values in the blood (neutropenia, lymphocytosis) and a reduction of Il4 and Infγ mRNA expression in MLN after ICR (p<0.05 SAMP1 vs. AKR). Conclusion The SAMP1/YitFc mouse is a suitable model for investigating the mechanisms of intestinal adaptation under the influence of experimental chronic ileitis. Subsequent research will focus on the alteration of the inflammatory environment and mucus barrier of the remaining bowel following resection in this model.

Abstract Background Ulcerative colitis (UC) and Crohn’s disease (CD) of the colon may cause significant malnutrition by “inflammation-dependent”, and “inflammation-independent” mechanisms. Glucagon-like peptide 2 (GLP-2) is secreted by ileocolonic L cells in response to nutrient intake and promotes small intestinal barrier function. GLP-2 secretion is enhanced after small bowel resection. We hypothesized that loss of GLP-2 secretion by a) genetic ablation, and b) inflammatory ablation through severe DSS-colitis, impairs small intestinal barrier dysfunction in the mouse mid small bowel resection model. Methods The impact of GLP-2 loss on small intestinal barrier function was evaluated using two models. In the first model, gcg knockout (KO) and wild-type (WT) mice underwent 50% mid-small bowel resection (MSBR). In the second model, male C57BL/6J mice were divided into the following groups: non-operated controls +/- DSS, MSBR alone, MSBR with dextran sulfate sodium (MSBR+DSS), and MSBR with DSS plus teduglutide (GLP-2 analogue). Body weight changes, mucosal height, tight junction mRNA expression, and FITC-4kDa-dextran flux were assessed using Ussing chambers. Results The gcg-WT mice did not develop diarrhea during the experimental period, while gcg-KO mice showed significantly increased stool water content two days post-surgery (p < 0.05). Although no other major clinical differences were observed between gcg-WT and KO mice after MSBR, gcg-KO mice exhibited reduced mucosal height and increased FITC-dextran flux, indicating impaired barrier function (p < 0.05). DSS-colitis was less severe in the MSBR-model, compared to non-operated DSS-colitis. However, in the inflammatory model, MSBR+DSS mice experienced significant body weight loss, colon shortening, all of which were significantly mitigated by teduglutide treatment. Teduglutide also improved villus length (p < 0.001) and reduced FITC-dextran permeability (p < 0.05). Claudin-2 expression, which was markedly elevated in MSBR+DSS mice, was significantly reduced with teduglutide treatment. Conclusion Our findings demonstrate that DSS-induced colitis is less severe in the 50% MSBR model. Furthermore, genetic knockout of gcg, i.e. complete ablation of GLP-2 secretion capacity, diminishes resection-triggered barrier- and growth response, while DSS-colitis, i.e. incomplete ablation of GLP-2 secretion capacity, diminishes resection-triggered barrier-, but not growth response. Thus, GLP-2-deficiency with small intestinal barrier dysfunction may be an inflammation-independent mechanism ultimately contributing to malnutrition in severe colitis.

Abstract Background Anastomotic leakage (AL) is a serious complication after gastrointestinal surgery that seems to occur more frequently in patients with CD than in non-IBD patients. Nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) is a risk gene for CD. We have recently demonstrated that Nod2-deficent mice have impaired anastomotic healing after ileocecal resection (ICR) even in the absence of a Crohn's phenotype. It is not yet understood how CD itself affects anastomotic healing. SAMP1/YitFc mice spontaneously develop Crohn's-like ileitis and show a defect in the NOD2 receptor. With this study we aimed to investigate whether anastomotic healing is altered after ICR in experimental ileitis. Methods SAMP1/YitFc mice (n=17) with histologically manifest ileitis and parental controls (AKR, n=12) were subjected to ICR. Intestinal continuity was established by end-to-end ileocolic anastomosis. On day 5, the strength of the anastomosis was assessed by bursting pressure (BP) measurement. Anastomotic healing was evaluated macroscopically using the anastomotic healing score (AHS). Hydroxyproline content and collagenase activity in the anastomosis were determined. The inflammatory status was determined by mRNA expression of inflammatory cytokines in mesenteric lymph nodes (MLN) and spleen tissue. Results 25% of the AKR mice and 29% of the SAMP1/YitFc mice developed perioperative complications. Leakage rate was not higher in mice with ileitis. Functionally, anastomoses were not impaired in SAMP1/YitFc mice (BP SAMP1 93 mmHg vs. AKR 123 mmHg) and AHS did not differ between the groups. However, mice with ileitis were more prone to microscopic abscess formation. Collagenase activity and hydroxyproline content in the anastomotic tissue did also not differ significantly. Preoperatively, mice with ileitis expressed increased IL4 and INF-γ mRNA levels in the MLN compared to AKR controls. After ICR, the local expression of IL4, TNF-α, lysozyme 1 and IL2 was significantly decreased in SAMP1/YitFc mice (p<0.05 SAMP1 d0 vs. d5, MLN). Resection induced significantly increased expression of IL4, lysozyme 1 and IL2 in the spleen of AKR mice, but not in SAMP1/YitFc mice (p<0.05 AKR ICR vs. SAMP1 ICR d5). Conclusion The SAMP1/YitFc mouse is a suitable model to study mechanisms of anastomotic healing under the influence of experimental chronic ileitis. Ileitis alone was not a risk factor for impaired healing. Ongoing studies address the local effects of therapeutic immunomodulation on the healing process of the anastomoses.

Abstract Background Single-nucleotide polymorphisms (SNP) of the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene are associated with higher risk for Crohn′s disease (CD). It has also been reported that they are more likely to associate with specific phenotypes such as stricturing or perianal disease and the need for resection surgery. The aim of our study was to investigate if these NOD2 variants are associated with higher cumulative bowel damage in Crohn’s disease. Methods We performed NOD2 genotyping in a cohort of 150 patients with CD from a tertiary care center in Germany. The risk polymorphisms SNP 8 (R702W, rs2066844), SNP 12 (G908R, rs2066845), and SNP 13 (1007fs, rs2066847) were screened for. The Lémann-Index (LI) was calculated to estimate digestive tract damage of each patient. Additionally, we collected the following data: age at diagnosis, disease location and behaviour using the Montréal classification, and the disease duration. Results Fifty patients carried at least one of the three SNPs. In the univariate analysis, the LI of patients with at least one risk-SNP was not significantly different from the LI in patients without a risk-SNP (NOD2 WT), 13.62 ± 15.10 vs. 11.57 ± 13.08, p=0.196. Also, after stratification for the single polymorphisms, the LI was not significantly different in patients with vs. patients without SNP. However, variants of NOD2 were associated with a higher LI in patients with non-stricturing, non-penetrating disease behavior (Montréal classification B1), 2.61 ± 2.80 vs. 0.85 ± 1.82, p=0.007. Importantly, in the presence of SNP13 a strong correlation between the LI and disease duration was found, rp = 0.69. In contrast, only a weak correlation was detectable in the presence of NOD2 WT, rs = 0.30 (figure 1). The LI was significantly higher in patients with SNP13 and an early disease onset than in patients who were first diagnosed at a higher age. Conclusion NOD2 risk polymorphisms are associated with a high LI during non-stricturing, non-penetrating disease behaviour. In line with this, we observed higher digestive tract damage in patients with CD diagnosis at a young age in patients with the polymorphism SNP13. Finally, our data suggest that particularly SNP13 predisposes to progressive damage accumulation over the disease course.

Einleitung Die Ileozökalresektion (ICR) ist die am häufigsten durchgeführte Resektion bei Patienten mit Morbus Crohn (MC). Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) ist ein Risikogen für MC. Der Funktionsverlust von NOD2 geht in NOD2-defizienten Mäusen nicht mit einem Crohn-Phänotyp einher, weist aber eine schlechtere Anastomosenheilung auf. SAMP1/YitFc (SAMP1) Mäuse bilden spontan eine Crohn-ähnliche Ileitis aus und weisen einen Defekt des NOD2 Rezeptors auf. Es ist unklar, wie sich die Crohn-ähnliche Entzündung auf die Anastomosenheilung auswirkt.

Ziel/Aim GLP-2-Pharmakotherapie erhöht durch Induktion von Zottenwachstum die intestinale Absorptionskapazität. Ein weiterer, weniger gut untersuchter Effekt pharmakologischer GLP-2-Stimulation ist die Relaxation der Gallenblasenmotilität. Der Einfluss von GLP-2- auf den nach Darmresektion gestörten enterohepatischen Kreislauf und den damit verbundenen Farnesoid X (Gallensäuren-)Rezeptor (FXR)-abhängigen Gallensäurenmetabolismus ist bisher nicht untersucht.

Einleitung Die Ileocoecalresektion (ICR) ist die am häufigsten durchgeführte Resektion bei Patienten mit M. Crohn. Die Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) Genmutation stellt ein Risiko für die Entwicklung von M. Crohn dar. Patienten mit NOD2 Mutationen haben ein schlechteres outcome in verschiedenen klinischen Situationen. In früheren Studien konnten wir zeigen, dass eine erweiterte ICR in Nod2-defizienten Mäusen mit einer schlechteren Anastomosenheilung einhergeht. Der molekulare Mechanismus ist bislang jedoch noch nicht verstanden.

Effects of a Protein Optimized Diet Combined with Moderate Resistance Training on the Postoperative Course in Older Patients with Hip Fracture

Darmversagen (DV) ist die Unfähigkeit des Darms die Protein-, Energie- und/oder Flüssigkeits- und Elektrolytbilanz aufrecht zu erhalten mit resultierender Notwendigkeit zur parenteralen Substitution (PS). Darminsuffizienz (DI) ist der diätetisch kompensierte Zustand. Beim resektionsbedingten Kurzdarmsyndrom werden der PS-Bedarf und die Adaptationsfähigkeit wesentlich durch die funktionelle Anatomie bestimmt (Typ-I – Jejunostoma, Typ-II – jejunocolische Anastomosose, Typ-III – jejuno-ileo-colonische Anastomose).

Teduglutide wird beim chronischen Darmversagen eingesetzt, um die parenterale Ernährung zu reduzieren und infusionsfreie Tage zu gewinnen. Durch die GLP-2-Stimulation wird ein trophischer Effekt erreicht und die Aufnahme von Natrium und Wasser verbessert. Ob die im Jejunum durch Claudin-10 und -15 vermittelte Natriumselektivität der parazellulären Tight Junction beeinflusst wird, ist unklar.

Einleitung: Als physiologische Reaktion auf eine umfangreiche Darmresektion kommt es zur intestinalen Adaptation mit einer im Verlauf verbesserten Resorption von Nährstoffen, Flüssigkeit und Elektrolyten. NOD2 ist ein intrazellulärer Rezeptor für bakterielle Zellwandbestandteile. Eine Mutation von NOD2 stellt unabhängig von einem M. Crohn einen Risikofaktor für die Entwicklung eines Darmversagens im Sinne einer verschlechterten Adaptation dar, wobei die Mechanismen hierfür nicht bekannt sind.

Einleitung: Das Kurzdarmsyndrom ist ein komplexes Krankheitsbild nach ausgedehnter Dünndarmresektion. NOD2-Mutationen sind unabhängig von der Grunderkrankung Risikofaktor für die Entwicklung eines Darmversagens, ohne dass die Mechanismen hierfür bekannt sind. In einem murinen Kurzdarmmodell zeigen NOD2-/--Tiere einen schlechteren klinischen Verlauf. Da NOD2-Mutationen mit intestinalen Barrieredefekten assoziiert sind, haben sie möglicherweise Anteil an dieser eingeschränkten Adaptation.

Background. Intestinal transplantation is a treatment option for intestinal failure. Although nephrotoxic medication after transplantation is a major cause for posttransplant renal insufficiency, it remains unclear why kidney dysfunction is particularly frequent after intestinal transplantation.Methods. This study analyzed messenger RNA expression of NHE3, DRA, and CFTR in 404 biopsies obtained between day 2 and 1508 from the terminal ileum of 10 adult intestinal transplant recipients.Results. The time courses of immunosuppression and glomerular filtration rate were correlated. In the first posttransplant year, expression of NHE3 and DRA, which mediate NaCI absorption, was diminished to a greater degree than that of CFTR, which mediates chloride secretion. Reduced NHE3 and DRA expression was associated with high tacrolimus trough levels. Titration of tacrolimus to low levels by year 2 was paralleled by partially restored NHE3 and DRA expression. In cell culture experiments, similar effects of tacrolimus on transporter expression were detected. In patients, both reduced tacrolimus levels and recovery of NHE3 and DRA expression were associated with stabilization of renal function.Conclusions. Our data strongly suggest that tacrolimus impairs absorption of NaCI and water from the transplanted ileum, leading to volume depletion and impaired renal function. This may be reversible by reduction of tacrolimus to lower levels without increased rates of rejection or chronic graft failure.

Einleitung: Beim Kurzdarmsyndrom und beim Darmversagen sind enterale und parenterale Ernährung die Basis der Therapie. Die rekonstruktive Chirurgie vermag die anatomische Situation zu verbessern. Die Darmtransplantation stellt gegenwärtig eine Therapieoption beim drohenden Scheitern der parenteralen Ernährung dar. Methodik: Es wurde eine systematische Literatursuche zum Kurzdarmsyndrom und zum Darmversagen, gekoppelt mit einer Literatursuche zur enteralen und parenteralen Ernährung, zur rekonstruktiven Chirurgie und zur Darmtransplantation durchgeführt. In der Arbeitsgruppe wurden auf dieser Basis Empfehlungen formuliert und hinsichtlich der Empfehlungsstärke bewertet. Sie wurden anschließend in einem Delphi-Verfahren und einer Konsensuskonferenz vorgestellt, diskutiert und verabschiedet. Ergebnisse: Die Leitlinie bezieht sich spezifisch auf das Kurzdarmsyndrom bei Erwachsenen. Sie enthält einen allgemeinen Teil mit Definitionen sowie Empfehlungen zur Dokumentation der anatomischen Situation und des Ernährungszustands, zur Indikation, Zusammensetzung und Durchführung einer parenteralen Ernährung (unter besonderer Berücksichtigung der meist im Vordergrund stehenden Flüssigkeits- und Elektrolytverluste), zu den Prinzipien der spezifischen Diät, zu den Kathetern und deren Infektionsmanagement, zur spezifischen und symptomatischen Pharmakotherapie, zur rekonstruktiven Chirurgie und zur Darmtransplantation. Schlussfolgerung: Kontrollierte Studien sind beim Darmversagen spärlich wegen der Seltenheit des Krankheitsbilds und der großen individuellen Unterschiede. Die prognostizierte Kurzdarmsituation auf der Basis einer möglichst detailliert beschriebenen anatomischen Ausgangssituation stellt die Indikation zur Ernährungsintervention dar. Die ergänzend intendierte, individualisierte parenterale Ernährung, die Prophylaxe und Therapie der Komplikationen und die rekonstruktiv-operativen Ansätze sollen konsequent umgesetzt werden. Spezifische und symptomatische pharmakologische Ansätze können ebenfalls genutzt werden. Die Darmtransplantation stellt eine Option beim drohenden Scheitern der parenteralen Ernährung dar.

Einleitung: Nach einer Dünndarmtransplantation (DTx) kommt es meist zu einer verschlechterten Nierenfunktion. Deshalb kommt der Resorption von NaCl und Wasser aus dem transplantierten Darm eine besondere Bedeutung zu, um die prärenale Komponente möglichst stabil und günstig zu halten. Es existieren keine Daten nach DTx zur Expression der Ionentransporter, die die NaCl-Resorption und die Chlorid-Sekretion im Ileum und damit die Wasserhomöostase vermitteln (NHE3, DRA und CFTR).