Outcome, comorbidity, hospitalization and 30-day mortality after closure of acute perforations and postoperative anastomotic leaks by the over-the-scope clip (OTSC) in an unselected cohort of patients.

BACKGROUND: Acute gastrointestinal (GI) wall defects contain a high risk of morbidity and mortality and may be closed endoscopically by a full-thickness over-the-scope clip (OTSC). METHODS: Unselected consecutive patients presenting with acute non-surgical perforations or postoperative anastomotic leaks or perforations underwent attempted OTSC placement as primary closure method after interdisciplinary consensus in three tertiary referral centres. Their clinical data and intervention characteristics were evaluated in an intention to treat analysis during a 24-month period to assess closure rates, 30-day mortality, hospitalization and comorbidity. RESULTS: In total, 34 patients (16 females, 18 males, 69.5 years) were included with 22 non-surgical perforations and 12 postoperative anastomotic leaks or perforations. Definitive closure of the perforations and leaks was achieved in 26/34 patients (76.5 %). Successful closure of the GI wall defect resulted in a significantly shorter hospital stay (8 days, p = 0.03) and was significantly correlated with comorbidity (r = 0.56, p = 0.005). In the group with OTSC failure, hospitalization was 18 days and 6 of 8 patients (75 %) required immediate surgery. Three deaths occurred in the group with successful OTSC closure due to comorbidity, while one death in the OTSC failure group was related to a refractory perforation. Favourable indications and locations for a successful OTSC procedure were identified as PEG complications, endoscopic or postoperative leaks of stomach, colon or rectum, respectively. CONCLUSIONS: In unselected patients, OTSC was effective for closure of acute GI wall defects in more than 75 % of all patients. Clinical success and short hospitalization were best achieved in patients without comorbidity, but closure of the perforation or the anastomotic leak was found to be not the only parameter relevant for patient outcome and mortality.

["Giant" fibrovascular esophageal polyp]. / "Gigantischer" fibrovaskulärer Polyp des Ösophagus.

Fibrovascular polyps are rare mesenchymal tumors that arise mainly in the cricopharyngeal portion of the esophagus. They may protrude distally to become "giant" pedunculated lesions filling almost the entire esophageal lumen. Histologically they contain varying amounts of adipose, fibrous and vascular tissues and belong to spindle cell lipomas according to the classification of soft tissue tumors. Immediate resection of these benign lesions is warranted as they may be regurgitated and cause asphyxia. These lesions are usually treated by open surgery (left cervicotomy) or, less invasively, by peroral endoscopic surgery. Polyp removal by flexible endoscopy has been described but may be hazardous if its stalk is broad-based. In this report the case of a 73-year-old male with dysphagia is described in whom a "giant" fibrovascular polyp was diagnosed endoscopically and promptly removed surgically by the peroral route. At control endoscopy 14 months later, the asymptomatic patient was free of polyp recurrence.

[Lymphoma-induced antiphospholipid syndrome as a cause of splenic infarction]. / Lymphom-induziertes Antiphospholipidsyndrom als Ursache von Milzinfarkten.

HISTORY AND ADMISSION FINDINGS: A 71-year-old man presented with bilateral sialadenosis of the parotid gland, episodes of fever up to 39 °C, general malaise and weight loss of 5 kg within the last 6 weeks. At physical examination peripheral lymph nodes were not palpable. INVESTIGATIONS: Laboratory studies revealed a normal white blood cell count, anemia and thrombocytopenia. Serum C-reactive protein and lactate dehydrogenase were elevated on admission and rose further. Plasmatic coagulation was characterized by prolonged partial thromboplastin time and reduced prothrombin time. Abdominal computed tomography showed an enlarged spleen with irregular hypodense areas, indicating splenic infarctions. Enlarged lymph nodes were noted at the paraaortic region and in the splenic hilum. DIAGNOSIS: As the patient`s condition deteriorated from day to day a diagnosis had to be enforced. Splenectomy was thus performed which confirmed the CT findings of numerous infarcted areas. A marginal zone lymphoma was found within the splenic hilar lymph nodes. High titer serum antibodies against cardiolipin confirmed the diagnosis of secondary antiphospholipid syndrome (APS). TREATMENT AND COURSE: Oral anticoagulation with phenprocoumone was started; in addition, chemotherapy with rituximab, cyclophosphamide, vincristin and prednisolone (R-CHOP) was initiated. Despite clinical recovery serological markers of APS remained elevated. The lymphoma recurred only six months after chemotherapy had been completed, and the patient died two months later. CONCLUSION: Because of its potentially fatal consequences anticoagulation and treatment of the underlying disease are crucial in secondary APS.

[Segmental necrotizing colitis in a patient with E. coli O104:H4 infection]. / Segmentale nekrotisierende Kolitis bei einem Patienten mit EHEC-Infektion vom Typ O104:H4.

A 29-year-old man presented with abdominal cramps and bloody diarrhoea. Blood tests revealed elevated C-reactive protein (21.3 mg/dL; normal range 0.01 - 0. 82 mg/dL) and white blood cells (28200/µL, normal range 4000 - 10000/µL). Stool tests were negative for enteropathogenic bacteria and Clostridium difficile toxins A/B. Ultrasound and computed tomography showed massive swelling of the transverse colon and right colonic flexure. At endoscopy, circular necrosis of the mucosa was encountered in the proximal segments of the colon whereas distal parts of the organ showed patchy inflammation of minor severity. Extended stool testing identified Escherichia coli type O104:H4 as the causative microorganism. There was no evidence for haemolytic uraemic syndrome. Under conservative treatment the patient recovered clinically, serologically and endoscopically. At follow-up endoscopy, longitudinal ulcers and vital mucosa were present. In this case report the segmental pattern of mucosal necrosis in a patient with EHEC infection is noteworthy.

Novel findings on the metabolic effects of the low glycaemic carbohydrate isomaltulose (Palatinose).

The slow digestible disaccharide isomaltulose (iso; Palatinose) is available as novel functional carbohydrate ingredient for manufacturing of low glycaemic foods and beverages. Although basically characterised, various information on physiological effects of iso are still lacking. Thus, the objective of the present study was to expand scientific knowledge of physiological characteristics of iso by a set of three human intervention trials. Using an ileostomy model, iso was found to be essentially absorbed, irrespective of the nature of food (beverage and solid food). Apparent digestibility of 50 g iso from two different meals was 95.5 and 98.8 %; apparent absorption was 93.6 and 96.1 %, respectively. In healthy volunteers, a single dose intake of iso resulted in lower postprandial blood glucose and insulin responses than did sucrose (suc), while showing prolonged blood glucose delivery over 3 h test. In a 4-week trial with hyperlipidaemic individuals, regular consumption of 50 g/d iso within a Western-type diet was well tolerated and did not affect blood lipids. Fasting blood glucose and insulin resistance were lower after the 4-week iso intervention compared with baseline. This would be consistent with possible beneficial metabolic effects as a consequence of the lower and prolonged glycaemic response and lower insulinaemic burden. However, there was no significant difference at 4 weeks after iso compared with suc. In conclusion, the study shows that iso is completely available from the small intestine, irrespective of food matrix, leading to a prolonged delivery of blood glucose. Regular iso consumption is well tolerated also in subjects with increased risk for vascular diseases.

[Solitary liver tumor as a manifestation of polyarteritis nodosa]. / Solitärer Lebertumor als Manifestation der Panarteriitis nodosa.

HISTORY: A 65-year-old female was admitted with fever of unknown origin. DIAGNOSTIC PROCEDURES: Abdominal computed tomography showed a solid mass (7.5 cm in diameter) with central fluid, located in the right lobe of the liver. Fine-needle aspiration cytology was unremarkable. Further work-up procedures for suspected liver abscess included colonoscopy, which surprisingly revealed adenocarcinoma at 13 cm from the anal orifice. THERAPY AND CLINICAL COURSE: Both lesions in the rectum and liver were resected. While a moderately differentiated (G2) adenocarcinoma of the rectosigmoid junction (stage T3/ N0) was confirmed, histology of the hepatic mass showed liver infarction due to polyarteritis nodosa of the medium-sized arteries. Treatment with 20 mg/d prednisolone was initiated and tapered off over the next three months. The clinical course after discontinuation of corticosteroids was unremarkable over a 6-month follow-up. CONCLUSION: It is suggested that polyarteritis nodosa of the liver occurred in this patient as a paraneoplastic phenomenon and subsided after resection of colorectal cancer and short-term immunosuppression with prednisolone.

Improved metabolic control after 12-week dietary intervention with low glycaemic isomalt in patients with type 2 diabetes mellitus.

The polyol isomalt (Palatinit) is a very low glycaemic sugar replacer. The effect of food supplemented with isomalt instead of higher glycaemic ingredients like sucrose and/or starch hydrolysates on metabolic control in patients with type 2 diabetes was examined in this open study. Thirty-three patients with type 2 diabetes received a diet with foods containing 30 g/d isomalt instead of higher-glycaemic carbohydrates for 12 weeks. Metformin and/or thiazolidindiones were the only concomitant oral antidiabetics allowed during the study. Otherwise, the participants maintained their usual diet during the test phase, but were instructed to refrain from additional sweetened foods. Before start, after 6 weeks and 12 weeks (completion of the study), blood samples were taken and analysed for clinical routine parameters, metabolic, and risk markers. Thirty-one patients completed the study. The test diet was well accepted and tolerated. After 12 weeks, significant reductions were observed for: glycosylated haemoglobin, fructosamine, fasting blood glucose, insulin, proinsulin, C-peptide, insulin resistance (HOMA-IR), and oxidised LDL (an atherosclerosis risk factor). In addition, significant lower nonesterified fatty acid concentrations were found in female participants. Routine blood measurements and blood lipids remained unchanged. The substitution of glycaemic ingredients by isomalt and the consequent on reduction of the glycaemic load within otherwise unchanged diet was accompanied by significant improvement in the metabolic control of diabetes. The present study is in agreement with findings of previous reported studies in human subjects demonstrating beneficial effects of low glycaemic diets on glucose metabolism in patients with diabetes mellitus type 2.

SNP-Array genotyping and spectral karyotyping reveal uniparental disomy as early mutational event in MSS- and MSI-colorectal cancer cell lines.

In this study nine colorectal cancer cell lines were analysed by 10K SNP-arrays and spectral karyotyping (SKY). Complex chromosomal alterations and breakpoints of deleted or translocated fragments found by SKY could further be characterized by SNP-array analysis. Interestingly many monoallelic regions identified by SNP-array analysis display no copy number alterations, representing uniparental disomy (UPD). It was demonstrated that UPD seems to be involved in activation of early-acting tumor suppressor genes in MSS- (APC, CDKN2A) and MSI- (MLH1, MSH2, APC, CDKN2A) colorectal cancer cell lines. Genes involved later on in the adenoma-carcinoma sequence (i.e. TP53/SMAD4) were not found to be inactivated by UPD. Furthermore, identified amplified monoallelic regions may include oncogenes activated by allele-specific-amplification (i.e. Cyclin D1). However, at present, the majority of the monoallelic regions located in the present study have not yet been associated with known tumor suppressor genes and oncogenes. Further studies are warranted to identify relevant genes in the respective regions and to further verify the results presented here.

[The role of the diet in the prevention of gastrointestinal tumors]. / Ernährungstipps zur Prävention gastrointestinaler Tumoren. Obst und Gemüse sind die Favoriten.

Second only to cardiovascular diseases, malignant tumors are the most common fatal disease, with malignant neoplasms in the gastrointestinal tract playing an important role. Underlying the most numerous of these malignancies is a complex interaction between genetic and environmental factors. The data relating to the role of environmental factors (for the most part dietary factors) in the development of gastrointestinal tumors derive mainly from, epidemiological research. The current evidence is "convincin" with regard to complex lifestyle patterns, but at most "plausible" when the chemically defined individual substances are considered. Summarizing the potential protective value of dietary factors reveals that the risk of contracting the majority of the gastrointestinal tumors can be reduced by increasing the intake of fruit and vegetables. An additional protective effect is associated with a balanced diet, physical activity, preservation of normal weight, avoidance of smoking, and moderation in the amount of alcohol consumed.

[Phlegmonous gastritis in a 44-year-old woman on immunosuppressive therapy]. / Phlegmonöse Gastritis bei einer 44-jährigen Patientin unter immunsuppressiver Therapie.

HISTORY AND ADMISSION FINDINGS: A 44-year-old woman was on long-term immunosuppressive therapy with leflunomide and adalimumab for rheumatoid arthritis. She was admitted to the emergency room with diffuse abdominal pain of sudden onset. On physical examination she had rebound tenderness in all four abdominal quadrants. INVESTIGATIONS: The white blood cell count was 3300/l, C-reactive protein 25 mg/dl and serum lactate 10 mmol/l. Abdominal computed tomography revealed a diffusely thickened gastric wall and ascites. At explorative laparotomy 1000 ml of a cloudy peritoneal fluid were aspirated and found to be negative for bacteria. But a culture of a mesenterial smear grew streptococci group A. Intra-operative endoscopy showed extensive hemorrhagic gastritis. Because there was no perforation or transmural necrosis gastric resection was not performed. DIAGNOSIS, TREATMENT AND COURSE: Diffuse thickening of the gastric wall, extended mucosal necrosis and the peritoneal finding of streptococci in an immunocompromised patient suggested the diagnosis of phlegmonous gastritis. On treatment with antibiotics and proton pump inhibitor the patient made a slow recovery over the following eight weeks. Nine months after the event an asymptomatic antral stricture was noticed at follow-up gastroscopy. CONCLUSION: Phlegmonous gastritis is a rare but life-threatening complication in immunosuppressed patients.

[The abdominal compartment syndrome - widely unknown in gastroenterology]. / Das abdominelle Compartmentsyndrom - ein in der Gastroenterologie weitgehend unbekanntes Krankheitsbild.

A sustained increase in intra-abdominal pressure may derange cardiovascular haemodynamics, respiratory and renal functions and finally lead to multi-organ failure. It is primarily seen in surgical intensive care units and is most frequently associated with small and large bowel surgery, vascular surgery, and abdominal trauma. An expert panel has defined elevated intra-abdominal pressure > 20 mmHg in conjunction with newly occurring organ dysfunction as "abdominal compartment syndrome" (ACS). This entity is not well recognised in gastroenterology, although ACS may occur as a complication of endoscopic perforation resulting in tension pneumoperitoneum. With the propagation of laparoscopic procedures it may be appropriate to emphasise the importance of intra-abdominal pressure monitoring in order to avoid this potentially lethal complication.

Effect of isomalt consumption on faecal microflora and colonic metabolism in healthy volunteers.

Due to its low digestibility in the small intestine, a major fraction of the polyol isomalt reaches the colon. However, little is known about effects on the intestinal microflora. During two 4-week periods in a double-blind, placebo-controlled, cross-over design, nineteen healthy volunteers consumed a controlled basal diet enriched with either 30 g isomalt or 30 g sucrose daily. Stools were collected at the end of each test phase and various microbiological and luminal markers were analysed. Fermentation characteristics of isomalt were also investigated in vitro. Microbiological analyses of faecal samples indicated a shift of the gut flora towards an increase of bifidobacteria following consumption of the isomalt diet compared with the sucrose diet (P<0.05). During the isomalt phase, the activity of bacterial beta-glucosidase decreased (P<0.05) whereas beta-glucuronidase, sulfatase, nitroreductase and urease remained unchanged. Faecal polyamines were not different between test periods with the exception of cadaverine, which showed a trend towards a lower concentration following isomalt (P=0.055). Faecal SCFA, lactate, bile acids, neutral sterols, N, NH3, phenol and p-cresol were not affected by isomalt consumption. In vitro, isomalt was metabolized in several bifidobacteria strains and yielded high butyrate concentrations. Isomalt, which is used widely as a low-glycaemic and low-energy sweetener, has to be considered a prebiotic carbohydrate that might contribute to a healthy luminal environment of the colonic mucosa.

Effects of isomalt consumption on gastrointestinal and metabolic parameters in healthy volunteers.

The polyol isomalt (Palatinit) is a well established sugar replacer. The impact of regular isomalt consumption on metabolism and parameters of gut function in nineteen healthy volunteers was examined in a randomised, double-blind, cross-over trial with two 4-week test periods. Volunteers received 30 g isomalt or 30 g sucrose daily as part of a controlled diet. In addition to clinical standard diagnostics, biomarkers and parameters currently discussed as risk factors for CHD, diabetes or obesity were analysed. Urine and stool Ca and phosphate excretions were measured. In addition, mean transit time, defecation frequency, stool consistency and weight were determined. Consumption of test products was affirmed by the urinary excretion of mannitol. Blood lipids were comparable in both phases, especially in volunteers with hyperlipidaemia, apart from lower apo A-1 (P=0.03) for all subjects. Remnant-like particles, oxidised LDL, NEFA, fructosamine and leptin were comparable and not influenced by isomalt. Ca and phosphate homeostasis was not affected. Stool frequency was moderately increased in the isomalt phase (P=0.006) without changes in stool consistency and stool water. This suggests that isomalt is well tolerated and that consumption of isomalt does not impair metabolic function or induce hypercalciuria. In addition, the study data indicate that isomalt could be useful in improving bowel function.

Antiproliferative effect of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on colonic epithelium of patients with adenomatous polyps in vitro.

We have consistently shown that the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a superior cancer chemopreventive agent and less toxic than selenite or certain naturally-occurring selenoamino acids. To elucidate the effects of p-XSC on human colonic mucosa, biopsies from endoscopically normal sigmoid colon of 30 patients with adenomatous polyps were incubated with p-XSC at concentrations of 1, 2 and 5 micromol/l dissolved in dimethylsulphoxide (DMSO). Biopsies incubated with DMSO or pure culture medium served as a control. Proliferating cells were labelled by bromodeoxyuridine immunohistochemistry and the labelling index (LI) was computed. Upper crypt labelling index (LI of crypt compartments 4+5) and Phih value, which are both discriminators of the expansion of the proliferative zone, were significantly lower after incubation with 1 and 5 micromol/l p-XSC, respectively (LI 4+5: 0.8 and 1.0; Phih value: 2.1 and 2.4), as compared with DMSO (LI 4+5: 3.6 and 4.5; Phih value: 7.0 and 8.3) or culture medium (LI 4+5: 3.3 and 4.5; Phih value: 7.2 and 8.1) (P<0.005 and P<0.05 by Friedman's block test). A trend towards lower levels of LI 4+5 (P=0.059) and Phih value (P=0.075) were seen after 2 micromol/l p-XSC incubation compared with DMSO. Since hyperproliferation of colonic crypt cells with expansion of the proliferative zone is regarded as a biomarker of increased cancer risk, the antiproliferative effects of p-XSC especially on upper crypt LI and Phih value may indicate a possible protective effect of this organoselenium compound in the prevention of human colon cancer development.

Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways.

BACKGROUND AND AIMS: Short chain fatty acids (SCFA) exert profound effects on the colonic mucosa. In particular, SCFA modulate mucosal immune functions. The antimicrobial cathelicidin LL-37 is expressed by colon epithelial cells. In the present study the effect of SCFA on LL-37 expression was investigated. METHODS: LL-37 expression in vivo was assessed by immunohistochemistry. Real time quantitative reverse transcription-polymerase chain reaction was employed to determine LL-37 expression in colonocytes in vitro after treatment with various cytokines, SCFA, or flavone. LL-37 levels were correlated to cell differentiation which was determined by alkaline phosphatase (AP) activity. In addition, intracellular signalling pathways such as MEK-ERK (mitogen/extracellular signal protein kinase (MEK)/extracellular signal regulated protein kinase (ERK)) and p38/mitogen activated protein (MAP) kinase were explored. RESULTS: In vivo, LL-37 expression in healthy mucosa was restricted to differentiated epithelial cells in human colon and ileum. In colonocytes, increased LL-37 expression associated with cell differentiation was detected in vitro following treatment with butyrate, isobutyrate, propionate, and trichostatin A. Flavone induced LL-37 transcription but did not affect AP activity while cytokines had no effect. To dissect pathways mediating differentiation and LL-37 expression, specific inhibitors were applied. Inhibition of the protein kinase MEK enhanced butyrate induced AP activity while LL-37 expression in colon epithelial cells was blocked. In contrast, inhibition of p38/MAP kinase blocked cell differentiation without inhibiting LL-37 expression. CONCLUSIONS: Expression of the cathelicidin LL-37 in colonocytes and cellular differentiation are separately modulated by SCFA via distinct signalling pathways. These data may provide a rationale for dietary modulation of mucosal defence mechanisms.

Butyrate and aspirin in combination have an enhanced effect on apoptosis in human colorectal cancer cells.

Laboratory and epidemiological studies suggest that butyrate, a metabolic product of microbial fermentation of dietary fibre, and aspirin, a non-steroidal antiphlogistic drug, both reduce the risk of developing colon cancer. Notably, few data exist on potential interactions of these two substances. In this study, the effects of a butyrate-aspirin combination on human colon cancer cells were compared with treatment with aspirin or butyrate alone. Both substances decreased proliferation and induced differentiation and apoptosis. Butyrate reduced mutant p53 expression, whereas aspirin did not affect p53 expression. Butyrate-induced apoptosis correlated with an increase in Bak expression and a decrease in the expression of Bcl-XL. Aspirin had no effect on the investigated apoptosis-controlling factors. The antiproliferative and pro-apoptotic effects of the butyrate-aspirin combination were markedly enhanced. The combination resulted in a stronger decrease in the expression of PCNA and cdk2. Our data suggest that the anticarcinogenic effect of aspirin might effectively be augmented by combination with the short-chain fatty acid butyrate.

Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis.

BACKGROUND: In ulcerative colitis (UC) the activation (i.e. nuclear translocation) of nuclear factor kappa B (NF-kappaB) is an important step in the regulation of cytokines secreted by lamina propria macrophages. Clinical trials suggest anti-inflammatory effects of locally administered butyrate in UC. The potential effects of butyrate on NF-kappaB activation in lamina propria macrophages of UC patients were investigated. METHODS: Eleven patients with distal UC were treated for up to 8 weeks with butyrate at 100 mM (n = 6) or placebo (n = 5) enemas. At entry and after 4 and 8 weeks, clinical status was noted and intestinal inflammation was graded endoscopically and histologically. Double-staining with antibodies against NF-kappaB (p65) and CD68 was employed to detect NF-kappaB and macrophages, respectively. RESULTS: In untreated patients, nuclear translocation of NF-kappaB was detectable in virtually all macrophages. Butyrate treatment for 4 and 8 weeks resulted in a significant reduction in the number of macrophages being positive for nuclear translocated NF-kappaB. In addition, butyrate significantly reduced both the number of neutrophils in crypt and surface epithelia and of the lamina propria lymphocytes/plasma cells. These findings correlated with a significant decrease in the Disease Activity Index (DAI). CONCLUSIONS: The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF-kappaB translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF-kappaB activation in these macrophages.

Spectral karyotype analysis of colon cancer cell lines of the tumor suppressor and mutator pathway.

BACKGROUND AND AIMS: Microsatellite instability (MSI) is characterized by the size variation of microsatellites in tumor DNA as compared to matching normal DNA due to defects in the mismatch repair system. To examine the chromosomal differences in microsatellite-stable (MSS) and -unstable (MSI) tumors in detail, we analyzed MSS (Caco-2, Colo-205, SW948) and MSI (HCT-15, HCT-116, LoVo) cell lines by spectral karyotyping (SKY). METHODS: SKY is a sensitive method to detect chromosome aberrations by visualizing each chromosome in a different color. Metaphases were hybridized with a SKY probe mixture. Images were visualized with the SpectraCube system and analyzed with the SKYview imaging software. RESULTS: The average number of chromosomes was 49 in LoVo, 45 in HCT-116, 46 in HCT-15, 71 in Colo-205, 89 in Caco-2 and 66 in SW-948. Three aberrant chromosomes were detected in LoVo, three in HCT-116, two in HCT-15, seventeen in Colo-205, fourteen in Caco-2 and nine in SW948. CONCLUSION: The karyotypes of MSS colon cancer cells displayed complex numerical and structural aberrations. In contrast the chromosomes of MSI colon cancer cells were mostly unaltered but displayed a few isolated numerical and structural aberrations. We speculate that these isolated aberrations may be specifically involved in the pathogenesis of MSI tumors.

Butyrate inhibits interleukin-1-mediated nuclear factor-kappa B activation in human epithelial cells.

Nuclear factor-kappa B (NF-kappaB) is a critical transcription factor for the inducible expression of multiple genes involved in inflammation. NF-kappaB is sequestered in the cytoplasm by inhibitory IkappaB proteins. Extracellular stimuli, notably interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) activate NF-kappaB nuclear translocation via IkappaB phosphorylation and degradation. Since previous reports suggest that the short chain fatty acid butyrate has antiinflammatory properties, the effects of butyrate on NF-kappaB nuclear translocation in human epithelial cells (HeLa229) were tested. In cells pretreated with butyrate, a time- and dose-dependent inhibition of IL-1beta-mediated NF-kappaB nuclear translocation was observed. However, IkappaB alpha phosphorylation and degradation occurred rapidly in both butyrate pretreated and nonpretreated cells, respectively. These data indicate that inhibition of IL-1beta-induced NF-kappaB activation by butyrate does not require an intact IkappaB alpha protein.