Institut für Ernährungsmedizin

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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.
Flavor-boosting of Phaeodactylum tricornutum by fermentation with edible mushrooms
(2024) Rigling, Marina; Liang, Jiaqi; Entenmann, Isa; Frick, Konstantin; Schmid-Staiger, Ulrike; Xiang, Can; Kopp, Lena; Bischoff, Stephan C.; Zhang, Yanyan
Microalgae are a promising and sustainable source of nutritious food, especially for use in alternatives to fish and seafood. Among them, Phaeodactylum tricornutum (PT) stands out for its potential to revolutionize future diets with its rich nutrient profile and eco-friendly cultivation methods. However, its typically fishy and “brackish water” off-odor has been a significant deterrent. Using 13 basidiomycetes as starter cultures, the dynamic changes in the aroma were studied. To better understand the aroma development during fermentation, odor-active compounds were identified using headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry–olfactometry. By submerged fermentation lasting 39 and 51 hours with Pleurotus citrinopileatus (PCI) and Pleurotus eryngii (PER), respectively, the unpalatable odor of PT was transformed into savory and seafood-like aromas, while retaining most of the valuable carotenoids (fucoxanthin and β-carotene were retained at 75 % and 90 %) and fatty acids (eicosapentaenoic acid and docosahexaenoic acid were preserved at 80 % of their initial concentrations). Throughout the fermentation process, key odorants responsible for the algae's initial green, grassy, and unpleasant odor were reduced, while compounds responsible for savory and seafood-like fragrances increased. A series of sulfur compounds, such as dimethyl disulfide, were found to be major contributors to the post-fermentation aroma.
Immunomodulatory effects of resveratrol on human intestinal mast cell signaling in vitro and mast cell associated enteritis and colitis in mice
(2023) Bilotta, Sabrina; Lorentz, Axel
By releasing their pre-stored or de novo synthesized mediators, mast cells (MC) are important immunoregulatory cells responsible for a variety of inflammatory reactions. Although known to be major effector cells in immunoglobuline (Ig) E dependent allergic reactions, MC have been widely shown to play a role in various inflammations of the gut. Diseases of the gastrointestinal tract (GIT) are widespread and multicausal. Those affected suffer from the sometimes severe symptoms and may experience restrictions on their daily life. Even if conventional medication is applied routinely, aim of the past and current research is to establish supportive and/or alternative medication that is based on natural substances. These may be on the basis of small natural components like resveratrol, a stilbene mostly found in grapes. Numerous positive properties are attributed to resveratrol. These are anti-inflammatory, anti-cancerogenic, anti-oxidative, as well as neuroprotective effects. The use of substances of natural origin as so-called nutraceuticals can help to increase the acceptance of medication by those affected, but also to reduce and overcome the side effects associated with conventional treatment. Effects of resveratrol were examined on the reactivity of MC isolated from patients’ tissue undergoing bowel resection. The results of this work show that resveratrol exhibited potent inhibitory effects on high affinity IgE receptor mediated activation of MC, strongly inhibiting not only MC degranulation, but also gene expression of the pro-inflammatory cytokines C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 and tumor necrosis factor (TNF-) α. Ultimately, the intracellular signaling cascade triggered during MC activation via IgE receptor leads to mediator release. Following IgE receptor mediated activation, phosphorylation of signaling molecules like extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3, occurs. ERK1/2 was found to be responsible for phosphorylation of mitochondrial STAT3, which contributes significantly to MC degranulation. Treatment with resveratrol was able to inhibit the phosphorylation of STAT3 by more than 50 % and that of ERK1/2 by almost 100 %. Furthermore, the experiments performed succeeded in isolating the mitochondrial fraction from relatively low human intestinal MC (hiMC) numbers. Also, in this fraction we could detect phosphorylation of STAT3 and ERK1/2 after MC activation, which was reduced after treatment with resveratrol. Having shown the strong inhibitory effects in vitro, we set out to examine immunomodulatory effects of resveratrol in vivo. Presence and activity of MC are closely related to intestinal inflammations in consequence of food allergy (FA) and inflammatory bowel disease (IBD). In mice, FA can be studied using the ovalbumin (OVA)-induced allergic enteritis model and colitis can be studied using the IL-10 knockout (-/-) mice, which develop a spontaneous form of chronic colitis. We could show that the oral application of resveratrol inhibited the increase of MC numbers in the colon and duodenum of affected animals in both experimental settings. Less pronounced but still visible effects of resveratrol administration were observed in the colon with regard to epithelial damage, cell infiltration and reduction of goblet cell numbers. In all cases, based on a scoring system, the damage decreased to the level of the corresponding controls receiving no additive and in which no allergic enteritis was induced or nor colitis developed. Overall, allergic enteritis resulted in a weaker symptomatology, and IL-10-/- animals showed a delayed appearance of the typical symptoms. The results of this thesis show a strong inhibitory effect of resveratrol on hiMC. This could be detected for mediator release as well as on gene expression levels and in the phosphorylation of the signaling molecules ERK1/2 and STAT3, which we could also identify in the mitochondria of hiMC. We observed positive influences on MC-associated parameters in the OVA enteritis and IL-10-/- colitis mouse models. With regard to its use as nutraceutical, resveratrol could therefore come more of a focus in the future.
Inflammation and nutrition: friend or foe?
(2023) Stumpf, Franziska; Keller, Bettina; Gressies, Carla; Schuetz, Philipp
The importance of the interplay between inflammation and nutrition has generated much interest in recent times. Inflammation has been identified as a key driver for disease-related malnutrition, leading to anorexia, reduced food intake, muscle catabolism, and insulin resistance, which are stimulating a catabolic state. Interesting recent data suggest that inflammation also modulates the response to nutritional treatment. Studies have demonstrated that patients with high inflammation show no response to nutritional interventions, while patients with lower levels of inflammation do. This may explain the contradictory results of nutritional trials to date. Several studies of heterogeneous patient populations, or in the critically ill or advanced cancer patients, have not found significant benefits on clinical outcome. Vice versa, several dietary patterns and nutrients with pro- or anti-inflammatory properties have been identified, demonstrating that nutrition influences inflammation. Within this review, we summarize and discuss recent advances in both the role of inflammation in malnutrition and the effect of nutrition on inflammation.
Resveratrol is a natural inhibitor of human intestinal mast cell activation and phosphorylation of mitochondrial ERK1/2 and STAT3
(2021) Bilotta, Sabrina; Paruchuru, Lakshmi Bhargavi; Feilhauer, Katharina; Köninger, Jörg; Lorentz, Axel
Mast cells play a critical role as main effector cells in allergic and other inflammatory diseases. Usage of anti-inflammatory nutraceuticals could be of interest for affected patients. Resveratrol, a natural polyphenol found in red grapes, is known for its positive properties. Here, we analyzed the effects of resveratrol on FcεRI-mediated activation of mature human mast cells isolated from intestinal tissue (hiMC). Resveratrol inhibited degranulation and expression of cytokines and chemokines such as CXCL8, CCL2, CCL3, CCL4, and TNF-α in a dose-dependent manner. Further, resveratrol inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3. ERK1/2 is known to be involved in cytokine expression of hiMC and to directly interact with STAT3. Mitochondrial STAT3 is phosphorylated by ERK1/2 and contributes to mast cell degranulation. We were able to isolate mitochondrial fractions from small hiMC numbers and could show that activation of mitochondrial STAT3 and ERK1/2 in hiMC was also inhibited by resveratrol. Our results indicate that resveratrol inhibits hiMC activation by inhibiting the phosphorylation of mitochondrial and nuclear ERK1/2 and STAT3, and it could be considered as an anti-inflammatory nutraceutical in the treatment of mast cell-associated diseases.
Role of homovanillic acid esters in the regulation of skin inflammatory pathways and their effect on tight junction protein expression
(2025) Cervantes Recalde, Maria Fernanda; Bogensperger, Elena Zoe; Hans, Joachim; Stuhlmann, Dominik; Somoza, Veronika; Lieder, Barbara
In the context of epidermal inflammation, the inflammatory response not only involves the release of inflammatory cytokines like interleukin 8 (IL-8), but also modulation of tight junction protein expression levels. Previous studies showed that the tight junction protein claudin 1 (CLDN1) is upregulated during tumor necrosis factor α (TNFα)-induced inflammation by capsaicin in keratinocytes in a transient receptor potential channel vanilloid 1 (TRPV1)-dependent manner. However, the caveat with TRPV1 ligands is the undesired pain response elicited by the activation of neuronal TRPV1 channels. In this study, we hypothesized that also less or non-pungent homovanillic acid esters as structural analogs of capsaicin target CLDN1 upregulation during inflammation. Methods: We aimed to identify beneficial structural characteristics by selecting homovanillic acid esters with different aliphatic tail structures and screening them for CLDN1 upregulation at early stages of TNFα-induced inflammation in basal keratinocytes. Results: CLDN1 expression was upregulated independently of TRPV1 by compounds with a tail of 5 or 6 C-atoms, regardless of the presence of ramifications and double bonds with a maximum fold change of 2.05 ± 0.22 against control. The induction of CLDN1 expression was accompanied by increased expression of the differentiation marker involucrin (IVL). Discussion: The results suggest that the homovanillic ester-induced CLDN1 upregulation is a result of increased differentiation of the basal keratinocytes towards the keratinocyte morphology present in the stratum granulosum (SG), where tight junctions are formed. In conclusion, homovanillic acid esters with a 5 or 6 C-atom long aliphatic chain induced CLDN1 expression, thereby stimulating keratinocyte differentiation, independent from TRPV1 activation.
Saccharomyces boulardii CNCM I-745 supernatant improves markers of gut barrier function and inflammatory response in small intestinal organoids
(2025) Filipe Rosa, Louisa; Gonda, Steffen; Roese, Nadine; Bischoff, Stephan C.; Lachowicz-Wiśniewska, Sabina
Objectives: Saccharomyces boulardii CNCM I-745, a probiotic yeast, is effectively used for the treatment of acute diarrhea as well as for the prevention and treatment of traveller‘s diarrhea and diarrhea under tube feeding. The underlying mechanisms are not fully elucidated. Both antitoxic and regulatory effects on the intestinal barrier, mediated either by the yeast or yeast-derived substrates, have been discussed. Methods: To examine the effects of Saccharomyces boulardii released substrates (S.b.S) on gastrointestinal (GI) barrier function, a murine small intestinal organoid cell model under stress was used. Stress was induced by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GFRed). Stressed organoids were treated with S.b.S (200 µg/mL), and markers of GI barrier and inflammatory response were assessed. Results: GFRed-induced stress was characterized by disturbances in selected tight junction (TJ) (p < 0.05), adherent junction (AJ) (p < 0.001), and mucin (Muc) formation (p < 0.01), measured by gene expressions, whereby additional S.b.S treatment was found to reverse these effects by increasing Muc2 (from 0.22 to 0.97-fold change, p < 0.05), Occludin (Ocln) (from 0.37 to 3.5-fold change, p < 0.0001), and Claudin (Cldn)7 expression (from 0.13 ± 0.066-fold change, p < 0.05) and by decreasing Muc1, Cldn2, Cldn5, and junctional adhesion molecule A (JAM-A) expression (all p < 0.01). Further, S.b.S normalized expression of nucleotide binding oligomerization domain (Nod)2- (from 44.5 to 0.51, p < 0.0001) and matrix metalloproteinase (Mmp)7-dependent activation (from 28.3 to 0.02875 ± 0.0044 ** p < 0.01) of antimicrobial peptide defense and reduced the expression of several inflammatory markers, such as myeloid differentiation primary response 88 (Myd88) (p < 0.01), tumor necrosis factor α (Tnfα) (p < 0.01), interleukin (IL)-6 (p < 0.01), and IL-1β (p < 0.001). Conclusions: Our data provide new insights into the molecular mechanisms by which Saccharomyces boulardii CNCM I-745-derived secretome attenuates inflammatory responses and restores GI barrier function in small intestinal organoids.

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