Transplantation of Human Intestine Into the Mouse: A Novel Platform for Study of Inflammatory Enterocutaneous Fistulas.

BACKGROUND AND AIMS: Enteric fistulas represent a severe and medically challenging comorbidity commonly affecting Crohn's disease [CD] patients. Gut fistulas do not develop in animal models of the disease. We have used transplantation of the human fetal gut into mice as a novel platform for studying inflammatory enterocutaneous fistulas. METHODS: Human fetal gut segments were transplanted subcutaneously into mature SCID mice, where they grew and fully developed over the course of several months. We first analysed the resident immune cells and inflammatory response elicited by systemic lipopolysaccharide [LPS] in normal, fully developed human gut xenografts. Thereafter, we used immunostaining to analyse fully developed xenografts that spontaneously developed enterocutaneous fistulas. RESULTS: Resident human innate and adaptive immune cells were demonstrated in gut xenografts during steady state and inflammation. The expression of human IL-8, IL-1ß, IL-6, TNF-α, A20, and IkBα was significantly elevated in response to LPS, with no change in IL-10 gene expression. Approximately 17% [19/110] of fully developed subcutaneous human gut xenografts spontaneously developed enterocutaneous fistulas, revealing striking histopathological similarities with CD fistula specimens. Immunohistochemical analyses of fistulating xenografts revealed transmural lymphocytic enteritis associated with massive expansion of resident human CD4+ lymphocytes and their migration into the intraepithelial compartment. Regionally, mucosal epithelial cells assumed spindle-shaped mesenchymal morphology and formed fistulous tracts towards chronic non-healing wounds in the host mouse skin overlying the transplants. CONCLUSIONS: Inflammation and fistulas developed in human gut xenografts lacking IL-10 gene response. This novel model system will enable systematic studies of the inflamed and fistulating human gut in live animals.

Fístula duodenal tras gastrectomía: análisis retrospectivo de 13 nuevos casos / Duodenal fistula after gastrectomy: retrospective study of 13 new cases

Introducción: la fístula del muñón duodenal (FMD) es una de las complicaciones más agresivas tras una gastrectomía. Aunque la incidencia reportada en la literatura es baja, su asociación con una elevada morbimortalidad hace que sea una de las complicaciones más temidas por los cirujanos. Material y métodos: evaluamos de forma retrospectiva todas las FMD acaecidas en nuestro centro tras realizar una gastrectomía programada por neoplasia gástrica, en el periodo comprendido entre enero de 1997 y diciembre de 2014. Analizamos variables demográficas, oncológicas y quirúrgicas, así como la evolución posterior en términos de morbimortalidad y estancia hospitalaria. Resultados: en el periodo que comprende el estudio se realizaron 666 gastrectomías y observamos una FMD en 13 pacientes, lo que supone una incidencia del 1,95%. En 8 casos (61,5%) se efectuó un tratamiento quirúrgico, y en 5 casos (38,5%), un tratamiento conservador. La mortalidad postoperatoria asociada a una FMD fue del 46,2% (6 casos). En el grupo quirúrgico, 3 pacientes presentaron una sepsis grave con fracaso multiorgánico, 2 una hematemesis importante que requirió la realización de hemostasia endoscópica, una evisceración, y un absceso subfrénico que requirió drenaje percutáneo. Seis de los pacientes (75%) fallecieron a pesar del tratamiento quirúrgico, siendo 3 de las muertes en las primeras 24 horas tras la reintervención. Los 2 pacientes que consiguieron sobrevivir tras la reintervención presentaron una estancia de 45 y 84 días respectivamente. En el grupo de tratamiento conservador, la tasa de curación fue del 100%, no observándose complicaciones significativas y siendo la estancia media postoperatoria de 39,5 días (rango, 26-65 días). Conclusión: la FMD constituye una complicación poco frecuente pero asociada a una elevada morbimortalidad. En nuestra experiencia, el manejo conservador ha demostrado mejores resultados en cuanto a morbimortalidad en comparación con el tratamiento quirúrgico (AU)

Introduction: Duodenal stump fistula (DSF) after gastrectomy has a low incidence but a high morbidity and mortality, and is therefore one of the most aggressive and feared complications of this procedure. Material and methods: We retrospectively evaluated all DSF occurred at our hospital after carrying out a gastrectomy for gastric cancer, between January 1997 and December 2014. We analyzed demographic, oncologic, and surgical variables, and the evolution in terms of morbidity, mortality and hospital stay. Results: In the period covered in this study, we performed 666 gastrectomies and observed DSF in 13 patients (1.95%). In 8 of the 13 patients (61.5%) surgery was the treatment of choice and in 5 cases (38.5%) conservative treatment was carried out. Postoperative mortality associated with DSF was 46.2% (6 cases). In the surgical group, 3 patients developed severe sepsis with multiple organ failure, 2 patients presented a major hematemesis which required endoscopic haemostasis, 1 patient had an evisceration and another presented a subphrenic abscess requiring percutaneous drainage. Six patients (75%) died despite surgery, with 3 deaths in the first 24 hours of postoperative care. The 2 patients who survived after the second surgical procedure had a hospital stay of 45 and 84 days respectively. In the conservative treatment group the cure rate was 100% with no significant complications and an average postoperative hospital stay of 39.5 days (range, 26-65 days). Conclusion: FMD is an unusual complication but it is associated with a high morbidity and mortality. In our experience, conservative management has shown better results compared with surgical treatment (AU)

A Practical Predictive Index for Intra-abdominal Septic Complications After Primary Anastomosis for Crohn's Disease: Change in C-Reactive Protein Level Before Surgery.

BACKGROUND: Postoperative intra-abdominal septic complications are difficult to manage in Crohn's disease, which makes prevention especially important. OBJECTIVE: The purpose of this study was to examine the risk factors for intra-abdominal septic complications after primary anastomosis for Crohn's disease and to seek a practical predictive index for intra-abdominal septic complications. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Based on a computerized database of 344 patients with Crohn's disease who underwent primary anastomosis between 2004 and 2013, the patients were placed into an intra-abdominal septic complications group and a group without intra-abdominal septic complications. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors, and the predictive accuracy of possible predictors was assessed using receiver operating characteristic curves. RESULTS: Overall, 39 patients (11.34%) developed intra-abdominal septic complications. Preoperative C-reactive protein level >10 mg/L was found to be an independent risk factor (p < 0.01) for intra-abdominal septic complications. For prediction of intra-abdominal septic complications, receiver operating characteristic curve analysis showed that a C-reactive protein cutoff of 14.50 mg/L provided negative and positive predictive values of 96.84% and 34.07%. In addition, the change in C-reactive protein levels over the 2 weeks before surgery was greater in the intra-abdominal septic complications group than the group with no intra-abdominal septic complications (p < 0.01), and the directions of change were opposite, upward in the former and downward in the latter. Apart from being a risk factor for intra-abdominal septic complications (p < 0.01), receiver operating characteristic curve analysis showed that the change in C-reactive protein levels before surgery had a negative predictive value for intra-abdominal septic complications of 98.66% and a positive predictive value of 76.09%. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Changes in C-reactive protein before surgical treatment of Crohn's disease could serve as a practical predictive index for postoperative intra-abdominal septic complications.

[Nutrition therapy in enterocutaneous fistula; from physiology to individualized treatment]. / Terapia nutricia en fístula enterocutánea; de la base fisiológica al tratamiento individualizado.

Enterocutaneous fistula is the most common of all intestinal fistulas. Is a condition that requires prolonged hospital stay due to complications such as electrolyte imbalance, malnutrition, metabolic disorders and sepsis. Nutritional support is an essential part of the management; it favors intestinal and immune function, promotes wound healing and decreases catabolism. Despite the recognition of the importance of nutrition support, there is no strong evidence on its comprehensive management, which can be limiting when establishing specific strategies. The metabolic imbalance that a fistula causes is unknown. For low-output fistulas, energy needs should be based on resting energy expenditure, and provide 1.0 to 1.5 g/kg/d of protein, while in high-output fistulas energy requirement may increase up to 1.5 times, and provide 1.5 to 2.5 g/kg of protein. It is suggested to provide twice the requirement of vitamins and trace elements, and between 5 and 10 times that of Vitamin C and Zinc, especially for high-output fistulas. A complete nutritional assessment, including type and location of the fistula, are factors to consider when selecting nutrition support, whether is enteral or parenteral nutrition. The enteral route should be preferred whenever possible, and combined with parenteral nutrition when the requirements cannot be met. Nutritional treatment strategies in fistulas may include the use of immunomodulators and even stress management.

Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release.

Diamine oxidase (DAO) is abundantly expressed in mammalian small intestine catalyzing the oxidative breakdown of polyamines and histamine. The aim of this study was to determine the relationship between stimulation of intestinal diamine oxidase secretion with intestinal fat absorption and histamine release. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated and intraduodenal tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic DAO activity and protein secretion were analyzed by radiometric assay and Western blot, respectively. Lymphatic histamine concentration was measured by ELISA. Infusion of Liposyn II (4.43 kcal/3 ml) resulted in a ~3.5-fold increase in lymphatic DAO protein secretion and DAO activity, peaking at 1 h and lasting for 3 h. Liposyn II infusion also increased the lymphatic histamine release, a substrate for DAO. To determine the relationship of DAO release with histamine release, histamine was administered intraperitoneally (10 mg/kg) in fasting rats and resulted in a significant doubling in lymphatic DAO activity, supporting a link between histamine and DAO. In addition, ip administration of the histamine H4 receptor antagonist JNJ7777120 significantly reduced the Liposyn II-induced DAO output by 65.9%, whereas H(1) (pyrilamine maleate), H(2) (ranitidine), and H(3) (thioperamide maleate) receptor antagonists had little effect. We conclude that DAO secretion may contribute to the catabolism of histamine released during fat absorption and this is probably mediated through the histamine H(4) receptor.

Interleukin-13 and transforming growth factor ß synergise in the pathogenesis of human intestinal fistulae.

OBJECTIVE: Epithelial to mesenchymal transition (EMT) seems to play an important role in the pathogenesis of fistulae, a common clinical complication of Crohn's disease (CD). TGFß and interleukin-13 (IL-13) have been correlated with the onset of EMT-associated organ fibrosis and high levels of TGFß have been shown in transitional cells (TCs) lining CD fistula tracts. This study investigated whether IL-13 could be involved in the pathogenesis of CD-associated fistulae. DESIGN: Protein or mRNA levels in HT29 intestinal epithelial cells (IECs) or colonic lamina propria fibroblasts (CLPFs) were studied by western blotting or real-time PCR. CLPFs were isolated from non-inflammatory disease controls or patients with CD with or without fistulae and IL-13 levels were analysed in surgically removed fistula specimens by immunohistochemistry. RESULTS: TGFß induced IL-13 secretion in CLPFs from patients with fistulising CD. In fistula specimens high levels of IL-13 were detected in TCs covering fistula tracts. In HT29 IEC monolayers, IL-13 induced SLUG and ß6-integrin mRNA, which are associated with cell invasion. HT29 spheroids completely disintegrated when treated with TGFß for 7 days, whereas IL-13-treated spheroids did not show morphological changes. Here, TGFß induced mRNA expression of SNAIL1 and IL-13, whereas IL-13 elevated SLUG and ß6-integrin mRNA. An anti-IL-13 antibody was able to prevent IL-13-induced SLUG expression in HT29 IECs. CONCLUSIONS: TGFß induces IL-13 expression and an EMT-like phenotype of IECs, while IL-13 promotes the expression of genes associated with cell invasion. These findings suggest that TGFß and IL-13 play a synergistic role in the pathogenesis of fistulae and inhibition of IL-13 might represent a novel therapeutic approach for fistula treatment.

Metabolic and nutritional support of the enterocutaneous fistula patient: a three-phase approach.

BACKGROUND: The care and outcome of enterocutaneous fistula (ECF) have improved greatly over several decades due to revolutionary advances in nutrition, along with dramatic improvements in the treatment of sepsis and the critically ill. However, as the collective experience with damage control surgery has matured, the frequent development of enteroatmospheric fistula (EAF) in the "open abdomen" patient has emerged as an even more vexing problem. Despite our best efforts, ECF and especially EAF continue to be highly morbid conditions, and sepsis and malnutrition remain the leading causes of death. Aggressive nutritional and metabolic support is the most significant predictor of outcome with ECF and EAF. RESULTS: Discussion of the historical advances in nutritional therapy and their impact on ECF, as well as review of the classification of ECF and EAF, provides a framework for the suggested phased strategy that specifically targets the nutritional and metabolic needs of the ECF/EAF patient. These three phases include (1) diagnosis, resuscitation, and early interval nutrition; (2) definition of fistula anatomy, drainage of collections, nutritional assessment and monitoring, and placement of feeding access; and (3) definitive nutritional management, including pharmacologic adjuncts. Early nutritional support with parenteral nutrition followed by transition to enteral nutrition is advocated, including the merits of delivery of enteral nutrition via the fistula itself, known as fistuloclysis. CONCLUSION: Aggressive nutritional therapy is necessary to reverse the catabolic state associated with ECF/EAF patients. Once established, it allows proper time, preparation, and planning for definitive management of the fistula, and in many cases provides the support for spontaneous closure.

Cellular infiltration and cytokine expression correlate with fistulizing state in Crohn's disease.

The purpose of this study was to determine the degree of infiltration of different cell subpopulations (tissue dendritic macrophages, T-helper cells, cytotoxic T lymphocytes, monocytes, neutrophils, and B cells) and the expression of the cytokines interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) in inflamed and noninflamed resected tissues from Crohn's disease (CD) and non-CD patients. Twenty-one resected full-thickness intestinal tissue specimens representing 13 subjects (8 CD and 5 non-CD patients) were included in this study. Sections of 20 µm in thickness were cut and then stained using immunohistochemistry. The sections were analyzed using confocal laser scanning microscopy (CLSM). Patterns of staining for inflamed CD and noninflamed CD tissues versus non-CD tissues demonstrated significant differences in the macrophage and T-helper subpopulations. Surprisingly, the T-helper subset was decreased significantly in the inflamed CD sections compared to the noninflamed CD and non-CD sections. The staining patterns also suggested differences in the expression of both IL-12 and TNF-α between the groups, with cytokine overexpression directly relating to the fistulizing state in CD patients. Cytokine expression is upregulated in chronic CD patients; therefore, the degree of inflammation and tissue damage in CD is dependent on the expression of specific cytokines within the tissue. Differentiation of cell subpopulations may be important for establishing a direct relationship with each state of CD (inflammatory, stricturing, and fistulizing states).

Prospective study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas.

BACKGROUND: Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF. METHODS/DESIGN: Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed. DISCUSSION: This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls. TRIAL REGISTRATION: ISRCTN44000447.

Spontaneous hepaticoduodenal fistula functioning like a bilioenteric anastomosis following bile duct injury: case report.

Bile duct injury is a serious complication of laparoscopic cholecystectomy. We report a case of spontaneous hepaticoduodenal fistula following bile duct injury. Initially, Roux-en-Y hepaticojejunostomy had been planned for the patient, but as the patient did not show any symptoms or findings of biliary obstruction, we preferred a non-operative management. The fistula allowed adequate biliary drainage, and the patient has been followed regularly by the outpatient clinic with good clinical results for approximately five years.

Effects of recombinant human growth hormone on enterocutaneous fistula patients.

AIM: To explore the effects of recombinant human growth hormone (rhGH) on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula. METHODS: Eight patients with enterocutaneous fistulas received recombinant human growth hormone (10 microg/d) for 7 d. Image analysis and immunohistochemical techniques were used to analyse the expression of proliferating cell nuclear antigen (PCNA) in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7. RESULTS: Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 (24.93 +/- 3.41%, 30.46 +/- 5.24% vs 12.92 +/- 4.20%, P < 0.01). These changes were accompanied by the significant improvement of villus height (500.54 +/- 53.79 microm, 459.03 +/- 88.98 microm vs 210.94 +/- 49.16 microm, P < 0.01), serum levels of total proteins (70.52 +/- 5.13 g/L, 74.89 +/- 5.16 g/L vs 63.51 +/- 2.47 g/L, P < 0.01), albumin (39.44 +/- 1.18 g/L, 42.39 +/- 1.68 g/L vs 35.74 +/- 1.75 g/L, P < 0.01) and fibronectin (236.3 +/- 16.5 mg/L, 275.8 +/- 16.9 mg/L vs 172.5 +/- 21.4 mg/L, P < 0.01) at day 4 and 7, and prealbumin (286.38 +/- 65.61 mg/L vs 180.88 +/- 48.28 mg/L, P < 0.05), transferrin (2.61 +/- 0.12 g/L vs 2.41 +/- 0.14 g/L, P < 0.05) at day 7. Nitrogen excretion was significantly decreased at day 7 (3.40 +/- 1.65 g/d vs 7.25 +/- 3.92 g/d, P < 0.05). No change was observed in the body weight. CONCLUSION: Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.

Nutrition and management of enterocutaneous fistula.

BACKGROUND: The management of enterocutaneous fistula is challenging, with significant associated morbidity and mortality. This article reviews treatment, with emphasis on the provision and optimal route of nutritional support. METHODS: Relevant articles were identified using Medline searches. Secondary articles were identified from the reference lists of key papers. RESULTS AND CONCLUSION: Management of enterocutaneous fistula should initially concentrate on correction of fluid and electrolyte imbalances, drainage of collections, treatment of sepsis and control of fistula output. The routine use of somatostatin infusion and somatostatin analogues remains controversial; although there are data suggesting reduced time to fistula closure, there is little evidence of increased probability of spontaneous closure. Malnutrition is common and adequate nutritional provision is essential, enteral where possible, although supplemental parenteral nutrition is often required for high-output small bowel fistulas. The role of immunonutrition is unknown. Surgical repair should be attempted when spontaneous fistula closure does not occur, but it should be delayed for at least 3 months.

Infliximab therapy improves the bone metabolism in fistulizing Crohn's disease.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of inflammatory bowel diseases and bone resorption as well. Limited data exist about the effect of anti-TNF-alpha infliximab on bone metabolism in inflammatory-type Crohn's disease (CD). AIM: Our aim was to evaluate the effect of infliximab treatment on rapid changes of bone metabolism in fistulizing CD patients. METHODS: 27 patients with fistulizing CD were treated with three series of infliximab. Serum osteocalcin (OC) and beta-CrossLaps (bCL) were measured before administration of each infliximab infusion. 54 patients with inactive CD were controls. RESULTS: In treated patients, there were significant differences in bCL concentrations on days 0 and 14 (p < 0.01) and days 0 and 42 (p < 0.05). OC levels increased significantly between day 0 and 42 (p < 0.05). The values of bCL and OC of control groups differed from serum levels in active patients before the treatment, but not on day 42. Bone markers improved significantly in responder patients, but not in non-responders. CONCLUSION: The beneficial effect of infliximab to the bone metabolism is more expressive in patients whose fistulizing disease improves with this therapy. Our results suggest that TNF-alpha has an important role in the alteration of bone metabolism in fistulizing CD patients.

[Nutritional therapy in children during perioperative period]. / Nutritivnaia terapiia u detei v perioperatsionnom periode.

The efficiency of nutritive therapy was analyzed in cases of 37 patients with gastrointestinal pathologies. Group 1 comprised 12 patients with fistulas of different etiologies and localizations; and group 2 comprised 15 patients with esophageal pathologies, including 7 children with esophageal atresia and 8 children with post-burn cicatricial stenosis of the esophagus. A method of nutrition-status correction by means of both enteral and parenteral feeding is suggested on the basis of examination findings comprising both clinical and laboratory-and-instrumental data. Preparations for parenteral feeding, i.e. 10-20% fatty emulsions, 10% amino acids solutions and 15-20% glucose solutions, were made use of. Enteral diets: semi-element oligopeptide solutions, like Nutrilon pepti TSC, Alphare. Balanced mixtures: sour-milk Nan, AL 110, Nutrizon, Nutridrink. Practical recommendations were defined, on the basis of study results, as to the therapeutic feeding schemes during the in-hospital treatment stages.

Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease.

BACKGROUND: Fistulae are a troublesome complication of Crohn's disease but little is known of the final effector molecules responsible for matrix degradation. Although matrix metalloproteinases (MMPs) have been strongly implicated in tissue injury in Crohn's disease, their role in fistula formation is unknown. AIM: To determine the expression pattern of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in fistulae of patients with Crohn's disease. PATIENTS AND METHODS: Resected fistula specimens were obtained from patients with Crohn's disease (n = 11) and classified according to the predominant histological features-that is, acute versus chronic inflammation. Patients with fistulae due to other diseases (n = 9) and normal colon (n = 5) served as controls. MMP and TIMP protein expression was measured by single or double labelled immunohistochemistry, and mRNA expression by in situ hybridisation. MMP activity was measured by gelatin zymography. RESULTS: Compared with normal colon, strong MMP-3 expression was consistently observed in fistulae in Crohn's disease, irrespective of the stage of inflammatory activity. MMP-3 transcripts and protein were localised in large mononuclear cells and fibroblasts. MMP-9 transcripts and protein were expressed in granulocytes and only in fistulae with acute inflammation. Staining for MMP-1 and MMP-7 was weak and negative for MMP-10, whereas MMP-2 was equally expressed in normal colon and fistulae. TIMP-1, TIMP-2, and TIMP-3 expression was low in all samples. Similar expression patterns were found in fistulae of the disease control group. Fistulae also expressed active MMP-2 and MMP-9, as measured by gelatin zymography. CONCLUSION: MMP-3 and MMP-9 are markedly upregulated in intestinal fistulae and may contribute to fistula formation through degradation of the extracellular matrix, irrespective of the underlying disease process.

Response, relapse and mucosal immune regulation after infliximab treatment in fistulating Crohn's disease.

BACKGROUND: Infliximab reduces mucosal inflammation in some, but not all, patients with Crohn's disease. AIM: To monitor clinical data and changes in mucosal cytokine levels after infliximab treatment to identify differences between responders and non-responders. METHODS: Twenty-six patients with fistulating Crohn's disease received three infliximab infusions at weeks 0, 2 and 6. Follow-up was for 1 year and included clinical examination, colonoscopy, ano-rectal ultrasound and magnetic resonance imaging. Biopsies were taken at weeks 0, 8, 26 and 52. Cell cultures were established and analysed for tumour necrosis factor-alpha, interferon-gamma and interleukin-10 levels, and related to clinical status and fistula healing. RESULTS: Eleven of 15 patients (73%) with active disease (Crohn's disease activity index > 150) obtained remission (Crohn's disease activity index < 150) at 8 weeks. In in vitro cell cultures, there was reduced tumour necrosis factor-alpha and interleukin-10 production at week 26, with the latter persistent throughout the study period. When the disease deteriorated or relapsed, there was increased interferon-gamma production in in vitro cell cultures. Fistula healing was associated with reduced production of interferon-gamma, tumour necrosis factor-alpha and interleukin-10. CONCLUSIONS: Infliximab down-regulates mucosal immune activation in Crohn's disease. Monitoring of mucosal cytokine levels after infliximab treatment by whole biopsy cultures may be useful as interleukin-10, tumour necrosis factor-alpha and interferon-gamma production are different in responders and at relapse.

Role of somatostatin-14 and its analogues in the management of gastrointestinal fistulae: clinical data.

Somatostatin-14 and its analogue octreotide both exert inhibitory effects on gastrointestinal secretions and may therefore be beneficial in the treatment of gastrointestinal fistulae. There are no studies that have compared these two drugs directly and hence this paper aims to review studies that are available for each drug. There are only six controlled studies that have examined the effects of somatostatin-14 and octreotide on fistula output reduction, three for each drug. All studies compared conservative therapy and the drug in combination with conservative therapy. Of the somatostatin-14 studies, two showed a significant effect on output (p<0.05) and the other demonstrated an output reduction on day 1 that was twice that in the control group (NS). Of the octreotide studies, one showed a significant effect (p<0.01) and the other two showed no effect of the drug on output. No study with either drug has demonstrated an increase in the number of patients that have achieved closure. However, a positive effect on the time to achieve closure has been found. Of the five controlled studies with somatostatin-14, all showed a significant reduction in time to closure. Of the two controlled studies with octreotide, one showed a significant reduction (p=0.002) and the other showed no difference. Due to the limited number of trials, a definitive evaluation of the efficacies of somatostatin-14 and octreotide in the treatment of gastrointestinal fistulae is not possible. However, currently available information seems to suggest a considerable benefit of somatostatin-14 when administered in association with standard conservative treatment, but this needs to be confirmed in a large prospective controlled study.

Stimulation of jejunal synthesis of apolipoprotein A-IV by ileal lipid infusion is blocked by vagotomy.

We examined the role of vagal innervation in lipid-stimulated increases in expression and synthesis of intestinal apolipoprotein A-IV (apoA-IV). In rats with duodenal cannulas and superior mesenteric lymph fistulas given duodenal infusions of lipid emulsion, vagotomy had no effect on either intestinal lipid transport, lymphatic apoA-IV output, or jejunal mucosal apoA-IV synthesis. In rats with jejunal Thiry-Vella fistulas, ileal lipid infusion elicited a twofold stimulation of apoA-IV synthesis without affecting apoA-IV mRNA levels; vagotomy blocked this increase in apoA-IV synthesis. Direct perfusion of jejunal Thiry-Vella fistulas produced 2- to 2.5-fold increases in both apoA-IV synthesis and mRNA levels in the Thiry-Vella segment; these effects were not influenced by vagal denervation. These results suggest two mechanisms whereby lipid stimulates intestinal apoA-IV production: 1) a vagal-dependent stimulation of jejunal apoA-IV synthesis by distal gut lipid that is independent of changes in apoA-IV mRNA levels and 2) a direct stimulatory effect of proximal gut lipid on both synthesis and mRNA levels of jejunal apoA-IV that is independent of vagal innervation.

Nutrient regulation of human intestinal sugar transporter (SGLT1) expression.

BACKGROUND: The activity of most intestinal nutrient transporters is adaptively regulated by the type and amounts of nutrients entering the intestinal lumen. The concentration and activity of the intestinal Na+/glucose cotransporter (SGLT1) are regulated by dietary sugars in most animal species. The activity and abundance of SGLT1 in biopsy specimens removed from human jejunal regions exposed to, and having limited access to, luminal nutrients have been measured and compared. AIMS: To study the effects of luminal nutrients on the expression of SGLT1 in the human intestine. PATIENT AND METHODS: Brush border membrane vesicles (BBMV) were prepared from biopsy specimens removed from the intestine of a 50 year old man who had developed a high output jejunal fistula, and adjacent mucosal fistula, a condition present for 12 months after surgery for a strangulated hernia. BBMV prepared from intestine exposed to luminal nutrients, and from dysfunctional intestine with a limited exposure to nutrients, were used to measure Na+ dependent glucose transport and abundance of SGLT1 protein. RESULTS: The levels of SGLT1 activity and abundance in the BBMV prepared from control biopsy specimens were similar to those found in BBMV prepared from the intestine of healthy individuals. BBMV from the dysfunctional intestine, exposed to limited levels of luminal nutrients, had reduced levels of SGLT1 activity. This reduction in SGLT1 activity and abundance was above that associated with any villus atrophy, as assessed by the abundance/activity of lactase and villin concentrations. CONCLUSIONS: These data indicate that the activity and expression of SGLT1 in human intestine is maintained by the presence of luminal nutrients.