Institut für Ernährungsmedizin

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Einfluss der mediterranen Ernährung auf das Fettsäuremuster von Erythrozytenmembranen sowie auf Darmmikrobiota- und Darmbarriere-assoziierte Biomarker : Mechanismen und klinische Anwendungen
(2022) Seethaler, Benjamin; Bischoff, Stephan C.
Dissertation from Benjamin Seethaler: "Effect of the Mediterranean diet on the fatty acid pattern of erythrocyte membranes and on gut microbiota- and gut barrier-associated biomarkers - mechanisms and clinical applications". In summary, the results of the PhD project offer new insights into the biomedical mechanisms of action and health effects of the Mediterranean diet. Of particular importance is the relationship we have shown between dietary fiber from the Mediterranean diet, its fermentation to short-chain fatty acids, and its beneficial influence on impaired intestinal barrier function. In the future, our studies may provide the basis for personalized nutritional therapy to improve impaired gut barrier function in high-risk breast cancer patients. Furthermore, we were able to establish LBP and zonulin as biomarkers to detect gut barrier function and to determine and assess gut barrier disorders. This method validation simplifies or enables the assessment of intestinal barrier function in clinical practice or clinical trials.
Einfluss verschiedener Getreidearten und Herstellungsverfahren auf den Gehalt immunogener Substanzen in Brot sowie in vivo auf die Verträglichkeit an der Maus und im Menschen
(2022) Zimmermann, Julia; Bischoff, Stephan C.
There are three medical conditions that are triggered by consumption of cereals. Celiac disease, wheat allergy and non-celiac wheat sensitivity (NCWS). While the underlying triggers and mechanisms of the first two entities have been extensively studied, there is still uncertainty in this regard for NCWS. Symptoms are nonspecific and diagnostic markers are lacking. Besides bacterial fermentable carbohydrates (FODMAPs), selected cereal proteins such as gluten or α-amylase trypsin inhibitors (ATIs) are in the focus of research as triggers. The aim of the present work was firstly to investigate the influence of the choice of cereal (common wheat, spelt, rye) and the production of bread (degree of milling and choice between yeast and sourdough) on the presence of potentially immunogenic proteins based on proteomic analysis. In a second step, the tolerability of selected breads should be investigated in a transgenic mouse model with intestinal inflammation and in a human study in patients with NCWS and subjective spelt tolerance. This was to narrow down possible triggers of NCWS and to investigate underlying mechanisms. Within the project, protein composition of bread and flour samples was analyzed based on a quantitative proteomics method (nano-UHPLC-ESI-MS based). In addition, a list of known and potentially immunogenic cereal proteins was generated based on Pfam annotation, which was used for the analysis of allergens in flour and bread. This showed that neither the absolute number nor the abundance of these allergenic proteins were dependent on the degree of milling of the flour or the fermentation process of the dough, which means that they are not selectively degraded during bread production. However, such proteins were identified in higher numbers and higher relative amounts in spelt and wheat samples compared to rye samples. Furthermore, different bread types from the proteome analysis were investigated in a mouse model with intestinal inflammation. This did not demonstrate better tolerability of rye bread compared to spelt and wheat bread. Instead, there was a trend for sourdough bread to have less negative effects on intestinal inflammation compared to yeast dough bread. It also turned out that inflammation was increased independently of gluten. No differences were found between wheat and spelt in either the proteomic analysis or the animal studies in this project. However, in a subgroup of NCWS patients, spelt bread is subjectively better tolerated than wheat bread, which could be due to both genetics and the different production of wheat and spelt bread. In order to verify the phenomenon and identify underlying mechanisms, if any, a clinical study was conducted in patients of this subgroup. The aim of the blinded study was to investigate whether spelt bread is actually better tolerated than wheat bread and whether the production process (16h dough or 1h dough + baking agent) has an influence. After each bread (4 days each + 3 days washout), gastrointestinal symptoms were assessed using the Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) questionnaire. Extraintestinal symptoms and various blood and stool parameters were also analyzed. It was found that spelt bread was not better tolerated compared to wheat bread after blinded consumption and that FODMAP-rich bread was not worse tolerated compared to FODMAP-poor bread.
Gut microbiota patterns predicting long-term weight loss success in individuals with obesity undergoing nonsurgical therapy
(2022) Bischoff, Stephan C.; Nguyen, Nguyen K.; Seethaler, Benjamin; Beisner, Julia; Kügler, Philipp; Stefan, Thorsten
The long-term success of nonsurgical weight reduction programs is variable; thus, predictors of outcome are of major interest. We hypothesized that the intestinal microbiota known to be linked with diet and obesity contain such predictive elements. Methods: Metagenome analysis by shotgun sequencing of stool DNA was performed in a cohort of 15 adults with obesity (mean body mass index 43.1 kg/m2) who underwent a one-year multidisciplinary weight loss program and another year of follow-up. Eight individuals were persistently successful (mean relative weight loss 18.2%), and seven individuals were not successful (0.2%). The relationship between relative abundancies of bacterial genera/species and changes in relative weight loss or body mass index was studied using three different statistical modeling methods. Results: When combining the predictor variables selected by the applied statistical modeling, we identified seven bacterial genera and eight bacterial species as candidates for predicting success of weight loss. By classification of relative weight-loss predictions for each patient using 2–5 term models, 13 or 14 out of 15 individuals were predicted correctly. Conclusions: Our data strongly suggest that gut microbiota patterns allow individual prediction of long-term weight loss success. Prediction accuracy seems to be high but needs confirmation by larger prospective trials.
High-resolution proteomics reveals differences in the proteome of spelt and bread wheat flour representing targets for research on wheat sensitivities
(2020) Afzal, Muhammad; Pfannstiel, Jens; Zimmermann, Julia; Bischoff, Stephan C.; Würschum, Tobias; Longin, C. Friedrich H.
Wheat consumption can trigger celiac disease, allergic reactions and non-celiac wheat sensitivity (NCWS) in humans. Some people with NCWS symptoms claim a better tolerability of spelt compared to bread wheat products. We therefore investigated potential differences in the proteomes of spelt and bread wheat flour using nano LC–ESI–MS/MS on a set of 15 representative varieties for each of the two species. Based on the bread wheat reference, we detected 3,050 proteins in total and for most of them the expression was mainly affected by the environment. By contrast, 274 and 409 proteins in spelt and bread wheat, respectively, had a heritability ≥ 0.4 highlighting the potential to influence their expression level by varietal choice. We found 84 and 193 unique proteins for spelt and bread wheat, respectively, and 396 joint proteins, which expression differed significantly (p ≤ 0.05) when comparing both species. Thus, about one third of proteins differed significantly between spelt and bread wheat. Of them, we identified 81 proteins with high heritability, which therefore might be interesting candidates for future research on wheat hypersensitivities.
How does dietary intake relate to dispositional optimism and health-related quality of life in germline BRCA1/2 mutation carriers?
(2023) Esser, Anne; Neirich, Leonie; Grill, Sabine; Bischoff, Stephan C.; Halle, Martin; Siniatchkin, Michael; Yahiaoui-Doktor, Maryam; Kiechle, Marion; Lammert, Jacqueline
Background: The Mediterranean diet (MD) is an anti-inflammatory diet linked to improved health-related quality of life (HRQoL). Germline (g)BRCA1/2 mutation carriers have an increased risk of developing breast cancer and are often exposed to severe cancer treatments, thus the improvement of HRQoL is important. Little is known about the associations between dietary intake and HRQoL in this population. Methods: We included 312 gBRCA1/2 mutation carriers from an ongoing prospective randomized controlled lifestyle intervention trial. Baseline data from the EPIC food frequency questionnaire was used to calculate the dietary inflammatory index (DII), and adherence to MD was captured by the 14-item PREDIMED questionnaire. HRQoL was measured by the EORTC QLQ-C30 and LOT-R questionnaires. The presence of metabolic syndrome (MetS) was determined using anthropometric measurements, blood samples and vital parameters. Linear and logistic regression models were performed to assess the possible impact of diet and metabolic syndrome on HRQoL. Results: Women with a prior history of cancer (59.6%) reported lower DIIs than women without it (p = 0.011). A greater adherence to MD was associated with lower DII scores (p < 0.001) and reduced odds for metabolic syndrome (MetS) (p = 0.024). Women with a more optimistic outlook on life reported greater adherence to MD (p < 0.001), whereas a more pessimistic outlook on life increased the odds for MetS (OR = 1.15; p = 0.023). Conclusions: This is the first study in gBRCA1/2 mutation carriers that has linked MD, DII, and MetS to HRQoL. The long-term clinical implications of these findings are yet to be determined.
Die Mikroalge Phaeodactylum tricornutum : Bioverfügbarkeit, Sicherheit und potenzieller gesundheitlicher Nutzen für die humane Ernährung
(2023) Kopp, Lena Janine; Bischoff, Stephan C.
The dissertation by Lena Kopp investigated the suitability of the microalga Phaeodactylum tricornutum (PT) for human nutrition. PT contains essential nutrients such as the long-chain omega-3 fatty acid eicosapentaenoic acid (EPA), which is otherwise found mainly in fish. In addition, PT contains a high content of other nutrients such as proteins, carotenoids (in particular fucoxanthin), vitamins and β-glucans, which have nutritive and therapeutic potential. Clinical and animal studies have shown that the PT biomass ingestion is safe and has potential health effects, such as anti-inflammatory and prebiotic effects. The results suggest that PT can be used as a food for human nutrition with possible health-promoting effects.
No difference in tolerance between wheat and spelt bread in patients with suspected non-celiac wheat sensitivity
(2022) Zimmermann, Julia; Longin, Friedrich H.; Schweinlin, Anna; Basrai, Maryam; Bischoff, Stephan C.
Individuals with suspected non-celiac wheat sensitivity (NCWS) often report better tolerance of spelt (Triticum aestivum ssp. spelta) compared to wheat (Triticum aestivum ssp. aestivum) bakery products. This experience has neither been validated nor explained on a molecular level. Therefore, we performed blinded wheat and spelt bread challenge in this patient group. Twenty-four adults with a history of NCWS but suspected spelt tolerance were challenged in a single-blinded crossover design over six weeks with six different study breads each at 300 g per day for 4 days followed by a washout phase of 3 days. Study breads comprised spelt and wheat breads made either after a traditional (T) or a current (C) recipe, resulting in four bread types plus a gluten-free bread with 1.5% added oligosaccharides (+FODMAP) and a gluten-free bread with 5% added wheat gluten (+Gluten). The main outcome parameter was the Irritable Bowel Syndrome—Severity Scoring System, which was higher than self-estimated by the participants after spelt bread consumption (p = 0.002 for T; p = 0.028 for C) and lower for wheat bread (p = 0.052 for T; p = 0.007 for C), resulting in no difference between wheat and spelt bread tolerance. The +FODMAP bread was better tolerated than both T breads (p = 0.003 for spelt; p = 0.068 for wheat) and equally well tolerated as both C breads and +Gluten breads after normalization to the washout scores. Neither signs of inflammation nor markers for intestinal barrier integrity were influenced. Our data do not confirm, on an objective basis, the differences in expected symptoms resulting from wheat and spelt products, suggesting a strong nocebo effect for wheat and a placebo effect for spelt.
Oral intake of the microalgae Nannochloropsis oceanica, Chlorella vulgaris, or Phaeodactylum tricornutum improves metabolic conditions in hypercaloric-fed mice
(2024) Kopp, Lena; Seethaler, Benjamin; Neumann, Ulrike; Bischoff, Stephan C.
Diet-induced metabolic load is associated with excess body weight and liver steatosis. Here, selected microalgae, known to contain bioactive nutrients, were studied for beneficial metabolic effects in a mouse model of liver steatosis. Adult mice (8 per group) were fed either a Western-style diet (WSD) or a control diet +/ 15 % of the microalgae Chlorella vulgaris (CV), Nannochloropsis oceanica (NO), or Phaeodactylum tricornutum (PT) for 12 weeks. We evaluated liver fat content and liver damage, as well as fecal microbiota and lipopolysaccharide (LPS) translocation. NO supplementation to a WSD reduced the grade of liver steatosis (from 17 % to 4.7 %, p < 0.002), the liver damage score (p < 0.001), and LPS translocation (p < 0.001). PT had similar effects on liver damage score (p < 0.001) and LPS translocation (p < 0.001). CV supplementation reduced LPS translocation (p < 0.001). In conclusion, dietary supplementation of microalgae may be a novel sustainable approach to combat metabolic loads.
Role of plasminogen activator inhibitor (PAI-1) in the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD)
(2012) Kanuri, Giridhar; Bischoff, Stephan C.
Non-alcoholic fatty liver disease (NAFLD), a liver disease frequently associated with obesity, type 2 diabetes and dyslipidemia has become a worldwide health problem during the last decades. Results of recent studies suggest that a diet rich in fructose may also be a risk factor for the development of NAFLD. Results of our own group but also other group suggest that TNFα and PAI-1 may be involved in the development of NAFLD in rodents but also humans. Therefore, the aim of the present study was to investigate the role TNFα and PAI-1 in the onset of fructose-induced NAFLD in a mouse model as well as in human NAFLD patients. The specific aims were 1) Are TNFR1-/- mice protected from fructose-induced NAFLD? If yes, what are the molecular mechanisms involved? TNFR1 -/- and wild-type mice were either fed 30% fructose solution or tap water. Chronic fructose feeding caused a significant ~5-fold increase in triglyceride accumulation and neutrophil infiltration in livers of wild-type mice and an ~8-fold increase in plasma alanine aminotransferase (ALT) levels in comparison to control mice. Similar effects of fructose feeding were not found in TNFR 1-/- mice. Indeed, the protective effect of the tumor necrosis factor receptor 1 (TNFR1) deletion against the onset of fructose-induced steatosis was associated with decreased sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FAS) and plasminogen activator inhibitor 1 (PAI-1) expression in the liver. Furthermore, the protective effect was also associated with protection against alterations markers of insulin signaling cascade (e.g. adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) levels). However, markers of hepatic lipid peroxidation, inducible nitric oxide synthase (iNOS) protein and adenosine triphosphate (ATP) levels were similar between wild-type and TNFR1 -/- mice fed fructose. Taken together, these data suggest that TNFα plays a casual role in the onset of fructose-induced liver damage as well as insulin resistance in mice through signaling cascades downstream of TNFR1. 2) Are PAI-1-/- mice protected from fructose-induced NAFLD? And if so, what are the molecular mechanisms involved? To address if PAI-1 is also a critical factor in the onset of fructose-induced NAFLD, PAI-1-/- and wild-type mice were either fed a fructose solution or tap water. Chronic fructose feeding in wild-type mice caused a marked increase in hepatic triglycerides, PAI-1 expression and plasma ALT levels in comparison to water controls. A similar effect of fructose feeding was not found in PAI-1-/- mice. PAI-1-/- mice fed fructose were protected from hepatic steatosis despite similar portal endotoxin levels, alterations of markers of insulin resistance and hepatic TNFα protein levels between fructose fed groups. The protective effect of the loss of PAI-1 against the onset of fructose-induced steatosis was associated with a significant increase in phospho-cMet, phospho Akt, expression of apolipoprotein B (ApoB) and activity of microsomal triglyceride transfer protein (MTTP) in livers of PAI-1-/- mice in comparison to fructose fed wild-type mice. Moreover, in PAI-1-/- mice expression of CD1d and markers of CD1d-reactive iNKT cells were markedly higher than in wild-type mice; however, expression of markers of activation of CD1d-reactive iNKT cells (e.g. interleukin 15 (IL-15) and interferon γ (INFγ)) were only found to be increased in livers of fructose fed PAI-1-/- mice. Taken together, these data suggest that PAI-1 plays a causal role in mediating the early phase of fructose-induced liver damage in mice through signalling cascades down-stream of Kupffer cells and TNFα. 3) Are molecular mechanisms identified in mouse studies also relevant to human situation? To determine if the alterations found in livers of animals with NAFLD are also relevant in humans with NAFLD, markers of lipid peroxidation, insulin signaling and number of iNKT cells were determined in 6 controls and 11 NAFLD patients.4-hydroxynonenal (4-HNE) protein adducts levels were significantly higher in livers of NAFLD patients whereas expression of insulin receptor substrate (IRS-1) was reduced by ~80 % in comparison to controls. PAI-1 protein levels primarily found in hepatocytes was significantly higher in NAFLD patients; however, hepatic CD1d and MTTP mRNA expression did not differ between groups. Hepatic c-Met and BCL-2l mRNA expressions were significantly lower in NAFLD patients in comparison to controls and number of CD3ζ positive cells was higher. In contrast, expression of iNKT cell markers (e.g. IL-4 and IL-15) was significantly lower in livers of patients with NAFLD when compared with controls.Taken together, the present study suggests that the molecular mechanism involved in the progression of NAFLD is similar in both rodents and humans. Furthermore, TNFα and PAI-1 may be considered as therapeutic targets for NAFLD.
Serotonin reuptake transporter deficiency promotes liver steatosis and impairs intestinal barrier function in obese mice fed a Western‐style diet
(2023) Rosa, Louisa Filipe; Haasis, Eva; Knauss, Annkathrin; Guseva, Daria; Bischoff, Stephan C.
Background: Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western-style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high-fat and high-sugar diets. Methods: 6–8 weeks old male serotonin reuptake transporter knockout mice (SERT−/−) and wild-type controls (SERT+/+) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. Key Results: SERT−/− mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT−/− mice exhibited reduced energy (−21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT−/− mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO-1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. Conclusion and Inferences: Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.
Study protocol to investigate the efficacy of confocal laser endomicroscopy-based selective single-elimination diet over standard fivefold elimination diet in patients with endomicroscopically proven food intolerance: app-assisted, monocentric, double-blind, randomised and controlled trial in Germany
(2023) Heßler, Nicole; Kordowski, Anna; Sasse, Jill; Ahlemann, Greta; Schulz, Franziska; Schröder, Torsten; Exner, Anna; Jablonski, Lennart; Jappe, Uta; Bischoff, Stephan C.; Grzegorzek, Marcin; König, Inke R; Sina, Christian
Introduction: Imprecise nutritional recommendations due to a lack of diagnostic test accuracy are a frequent problem for individuals with adverse reactions to foods but no precise diagnosis. Consequently, patients follow very broad and strict elimination diets to avoid uncontrolled symptoms such as diarrhoea and abdominal pain. Dietary limitations and the uncertainty of developing gastrointestinal symptoms after the inadvertent ingestion of food have been demonstrated to reduce the quality of life (QoL) of affected individuals and subsequently might increase the risk of malnutrition and intestinal dysbiosis. This trial aims to investigate the effects of a tailored diet based on the confocal laser endoscopy (CLE) examination result to limit the side effects of unspecific and broad elimination diets and to increase the patient’s QoL. Methods and analysis: The study is designed as a prospective, double-blind, monocentric, randomised and controlled trial conducted at the University Hospital of Schleswig-Holstein, Campus Lübeck, Germany. One hundred seventy-two patients with non-IgE-related food allergies and positive CLE results will be randomised to either a tailored diet or a standard fivefold elimination diet. The primary endpoints are the difference between the end and the start of the intervention in health-related QoL and the sum score of the severity of symptoms after 12 weeks. Key secondary endpoints are changes in the severity of symptoms, further QoL measurements, self-assessed state of health and number of days with a pathologically altered stool. Microbiome diversity and metabolome of stool, urine and blood will also be investigated. Safety endpoints are body composition, body mass index and adverse events. Ethics and dissemination: The study protocol was accepted by the ethical committee of the University of Lübeck (AZ: 22-111) on 4 May2022. Results of the study will be published in peer-reviewed journals and presented at scientific meetings. Trial registration number: German Clinical Trials Register (DRKS00029323).
Untersuchungen zur Rolle des intestinalen serotonergen Systems in der Entstehung von Adipositas und der nahrungsinduzierten nicht-alkoholbedingten Fettlebererkrankung im Mausmodell
(2011) Haub, Synia; Bischoff, Stephan C.
The worldwide prevalence of overweight and obesity has increased dramatically throughout the last decades. The causes of obesity are numerous and complex and the understanding of the mechanism(s) involved in the disease process are still limited. The same is true for the development of NAFLD, a liver disease for which a strong association with overweight and obesity has repeatedly been shown. High dietary fat intake has long been thought to be the major cause of obesity and NAFLD. However, other factors like carbohydrate intake may also contribute. Alterations at the level of the intestinal tract have also been discussed to be associated with the development of NAFLD and obesity. The enteric nervous system (ENS) might be of particular importance in this context, regulating the fundamental intestinal functions like peristalsis, secretion and permeability through its main neurotransmitter serotonin (5-HT) and different 5-HT receptors. The termination of the 5-HT action is mediated by the 5-HT selective reuptake transporter (SERT), located on epithelial cells. Based on this background the aim of the present work was to investigate the role of the intestinal serotonergic system and herein particularly of SERT and 5-HT3R in the onset of sugar-induced overweight and NAFLD as well as in the progression of NAFLD in mouse models.
Vitamin A- and D-deficient diets disrupt intestinal antimicrobial peptide defense involving Wnt and STAT5 signaling pathways in mice
(2023) Filipe Rosa, Louisa; Petersen, Patricia P.; Görtz, Lisa F.; Stolzer, Iris; Kaden-Volynets, Valentina; Günther, Claudia; Bischoff, Stephan C.
Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (p < 0.01) and decreased crypt depth in the colon (p < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (p < 0.05/p < 0.0001 for VAd/VDd) and lysozyme protein levels (p < 0.001/p < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (p < 0.05/p < 0.05) and total cryptdins (p < 0.001/p < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (p < 0.0001/p < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.
Wechselwirkungen zwischen humanen Darmmastzellen und humanen Darmfibroblasten
(2008) Montier, Yves; Bischoff, Stephan C.
Fibroblasts (FB) play a central role in the pathogenesis of fibrosis since they are the major source of extracellular matrix proteins. However, the regulation of extracellular matrix production in fibroblasts, the mechanisms that lead to loss of control of extracellular matrix homeostasis during chronic inflammation and the role of human intestinal mast cells are still not fully understood. Mast cells are key effector cells in allergic reactions but also involved in host defense and tissue remodeling processes such as wound healing, angiogenesis, and fibrogenesis. The group pf Prof. Bischoff has shown previously that human intestinal fibroblasts suppress apoptosis in human intestinal MC independent of the known human mast cell growth factors stem cell factor interleukin-3, interleukin-4, and nerve growth factor.In this work I could show that the effects of fibroblasts on mast cells are mediated by interleukin-6. The molecular crosstalk between human mast cells and human fibroblasts, both isolated and purified from intestinal tissue was analyzed. Mast cells survival in the presence of fibroblasts could be blocked using an anti-interleukin-6 antibody. Mast cells incubated with interleukin-6 survived for up to 3 weeks. Intestinal fibroblasts produced interleukin-6 upon direct stimulation by mast cells in co-culture or by mast cell mediators such as tumor necrosis factor alpha, interleukin-1 beta, tryptase or histamine. Moreover, fibroblasts stimulated by mast cell mediators produce the antifibrotic enzyme matrix metalloproteinase-1. Matrix metalloproteinase-1 should be considered as multifunctional molecule since it participates not only in the turnover of collagen fibrils in the extracellular space but also in the cleavage of a number of non-matrix substrates and cell surface molecules suggesting a role in the regulation of cellular behaviour. Noteworthy, fibroblasts co-cultured with mast cells or treated with matrix metalloproteinase-1 lost confluence. Matrix metalloproteinase-1 expression in fibroblasts triggered by mast cells was dependent on the MEK/ERK cascade as shown by inhibitor experiments. In conclusion, this study show that mast cells mediators stimulate fibroblasts to produce interleukin-6, and, vice versa, fibroblasts derived interleukin-6 supports mast cells survival. Furthermore, mast cell mediators induce expression of matrix metalloproteinase-1 in fibroblasts, a key enzyme in fibrolysis, which in turn leads to lost of confluence of cultured fibroblasts. Taken together the results of my work suggest that mast cells accumulating at sites of fibrosis rather limite than promote fibrogenesis.

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