Institut für Ernährungsmedizin

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Predictors of cardiopulmonary fitness in cancer-affected and -unaffected women with a pathogenic germline variant in the genes BRCA1/2 (LIBRE-1)
(2022) Berling-Ernst, Anika; Yahiaoui-Doktor, Maryam; Kiechle, Marion; Engel, Christoph; Lammert, Jacqueline; Grill, Sabine; Dukatz, R.; Rhiem, Kerstin; Baumann, F. T.; Bischoff, Stephan C.; Erickson, N.; Schmidt, Thorsten; Niederberger, Uwe; Siniatchkin, M.; Halle, Martin; Berling-Ernst, A.; Department of Prevention and Sports Medicine, School of Medicine, University Hospital Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Yahiaoui-Doktor, M.; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany; Kiechle, M.; Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Engel, C.; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany; Lammert, J.; Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Grill, S.; Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Dukatz, R.; Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Rhiem, K.; Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University Hospital Cologne, Cologne, Nordrhein-Westfalen, Germany; Baumann, F. T.; Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University Hospital Cologne, Cologne, Nordrhein-Westfalen, Germany; Bischoff, S. C.; Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany; Erickson, N.; Comprehensive Cancer Center Ludwig Maximillian University (CCC LMU), University of Munich Clinic, Munich, Germany; Schmidt, T.; University Cancer Center Schleswig-Holstein (UCCSH), Kiel, Germany; Niederberger, U.; Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel, Germany; Siniatchkin, M.; Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel, Germany; Halle, M.; DZHK (German Centre for Cardiovascular Research), Munich, Germany
Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we wanted to identify predictors of CPF (represented by peak oxygen uptake: VO2peak) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO2peak reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33–46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35–50). The strongest predictor for reaching the reference VO2peak value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3–8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO2peak, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.
Consumption of yeast-fermented wheat and rye breads increases colitis and mortality in a mouse model of colitis
(2022) Zimmermann, Julia; De Fazio, Luigia; Kaden-Volynets, Valentina; Hitzmann, Bernd; Bischoff, Stephan C.; Zimmermann, Julia; Department of Nutritional Medicine/Prevention, University of Hohenheim, Stuttgart, Germany; De Fazio, Luigia; Department of Medical and Surgical Science (DIMEC), University of Bologna, Bologna, Italy; Kaden-Volynets, Valentina; Department of Nutritional Medicine/Prevention, University of Hohenheim, Stuttgart, Germany; Hitzmann, Bernd; Department of Process Analytics and Cereal Science, University of Hohenheim, Stuttgart, Germany; Bischoff, Stephan C.; Department of Nutritional Medicine/Prevention, University of Hohenheim, Stuttgart, Germany
Background: Cereals are known to trigger for wheat allergy, celiac disease and non-celiac wheat sensitivity (NCWS). Inflammatory processes and intestinal barrier impairment are suspected to be involved in NCWS, although the molecular triggers are unclear. Aims: We were interested if different bread types influence inflammatory processes and intestinal barrier function in a mouse model of inflammatory bowel disease. Methods: Epithelial caspase-8 gene knockout (Casp8 ΔIEC ) and control (Casp8 fl ) mice were randomized to eight groups, respectively. The groups received different diets for 28 days (gluten-free diet, gluten-rich diet 5 g%, or different types of bread at 50 g%). Breads varied regarding grain, milling and fermentation. All diets were isocaloric. Results: Regardless of the diet, Casp8 ΔIEC mice showed pronounced inflammation in colon compared to ileum, whereas Casp8 fl mice were hardly inflamed. Casp8 fl mice could tolerate all bread types. Especially yeast fermented rye and wheat bread from superfine flour but not pure gluten challenge increased colitis and mortality in Casp8 ΔIEC mice. Hepatic expression of lipopolysaccharide-binding protein and colonic expression of tumor necrosis factor-α genes were inversely related to survival. The bread diets, but not the gluten-rich diet, also decreased colonic tight junction expression to variable degrees, without clear association to survival and inflammation. Conclusions: Bread components, especially those from yeast-fermented breads from wheat and rye, increase colitis and mortality in Casp8 ΔIEC mice highly susceptible to intestinal inflammation, whereas control mice can tolerate all types of bread without inflammation. Yet unidentified bread components other than gluten seem to play the major role.
Associations and patterns in lifestyle and body weight among university students over one year into the Covid-19 pandemic: A cluster analysis
(2025) Bschaden, Andreas; Ströbele-Benschop, Nanette
In March 2020, the first wave of SARS-CoV-2 infections led to far-reaching measures worldwide to slow the spread of the virus. University students were particularly affected by the COVID-19 pandemic due to the shift to distance learning. Research found an increase in body weight among a significant proportion of students, as well as unfavourable changes in food consumption and physical activity in the first months of the pandemic. The present study aimed to examine changes in food consumption, physical activity, and body weight more than one year into the COVID-19 pandemic. A cross-sectional online survey was conducted among students at a German university in July/August 2021 (n = 951). Changes in food consumption, physical activity, and self-reported body weight since the beginning of the pandemic were assessed in comparison to pre-pandemic levels. Weight gain was reported by 38 % of students, weight loss by 30 %. Changes in sweet and savoury snacks consumption were positively, and changes in sporting frequency and fruit consumption were negatively associated with weight change. A cluster analysis revealed five groups of student clusters, two of which were able to benefit from the changes in their daily lives with increased physical activity and vegetable consumption. Negative consequences, such as reduced physical activity or increased sweet and savoury snack consumption, were found in two groups. One group appeared to be unaffected. The study helps to understand how the pandemic affected students differently. A closer look is needed to identify the reasons for these varied consequences and to develop strategies to assist those who are struggling to better cope with such situations.
Mechanismen der diätinduzierten Störungen auf die Darmbarrierefunktion
(2024) Filipe Rosa, Louisa; Bischoff, Stephan C.
Störungen der Darmbarriere sind bei der Entstehung intestinaler und metabolischer Erkrankungen involviert. Dabei beeinflussen sowohl intrinsische als auch extrinsische Faktoren die Funktionalität der Darmbarriere. Obwohl dieser Zusammenhang generell akzeptiert ist, sind die zugrundeliegenden molekularen Mechanismen nicht hinreichend aufgeklärt. Darüber hinaus gibt es kaum Konzepte, wie eine dysfunktionale Darmbarriere diagnostisch genutzt oder therapeutisch behandelt werden könnte. Im Rahmen des vorliegenden Promotionsprojektes wurden deshalb die molekularen Effekte extrinsischer Nahrungsfaktoren sowie intrinsischer neuronaler und immunologischer Faktoren auf die Darmbarriere untersucht. Darüber hinaus wurde ein therapeutischer Ansatz bei diätinduzierter Darmbarrierestörung evaluiert sowie die Bedeutung der Darmbarrierefunktion für die Diagnostik von Nahrungsmittelunverträglichkeiten (NMUs) geprüft. Sowohl Mangelernährung als auch Überernährung wirken sich negativ auf die Darmbarriere aus. In Vorarbeiten wurden Darmbarrierestörungen im Tiermodell für Adipositas untersucht und gezeigt, dass Präbiotika und kurzkettige Fettsäuren präventiv wirksam sind. Im Rahmen des ersten Promotionsprojektes wurden die Auswirkungen eines Vitamin A (VA)- und Vitamin D (VD)-Mangels auf die Darmbarrierefunktion untersucht. Dazu wurden 36 C57BL/6J Mäuse für 12 Wochen entweder mit einer Kontrolldiät, einer Vitamin A-defizienten oder einer Vitamin D-defizienten Diät gefüttert und die Rolle verschiedener Signalwege in einem Organoid- Zellmodell evaluiert. Die Ergebnisse zeigen, dass sowohl ein VA- als auch ein VD-Mangel die immunologische Darmbarriere, insbesondere die antimikrobielle Peptidabwehr, im Ileum und Colon beeinträchtigten. Diese Veränderungen gingen mit Störungen des Wnt-Signalweges und vermehrten inflammatorischen Prozessen im Colon einher. Zudem regulierten VA und VD die Expression antimikrobieller Peptide durch den Jak/STAT5-Signalweg. Die Ergebnisse zeigen, dass VA und VD die Darmbarrierefunktion beeinflussen und dass bei Mangelernährung der Vitaminstatus überprüft und gegebenenfalls korrigiert werden sollte. Im zweiten Promotionsprojekt wurde die Darmbarrierefunktion in einem Tiermodell für Adipositas untersucht. Insbesondere wurde die Rolle des intestinalen serotonergen Systems nach Barrierestörung durch eine Western-Style Diät (WSD) sowie die Darm-Leber-Achse analysiert. Dazu wurden 32 Mäuse, welche einen knock-out im Gen für den Serotonin- Wiederaufnahme-Transporter (SERT) aufweisen (SERT-/-) sowie 32 Wildtyp Mäuse (SERT+/+) für 12 Wochen entweder mit einer Kontrolldiät oder einer WSD mit oder ohne 30 %-iger Fruktoselösung (F) gefüttert. Die Ergebnisse zeigen, dass Veränderungen des intestinalen serotonergen Systems die Gen- und Proteinexpression von Tight Junctions (TJ) reduzierten, was mit einer erhöhten Dünndarmpermeabilität einherging. SERT-/- Mäuse wiesen eine Abnahme der Mukusproduktion sowie der antimikrobiellen Peptidabwehr auf. Dadurch kam es zu einer vermehrten bakteriellen Translokation und einer Zunahme von Leberentzündung und -steatose. Somit spielt das serotonerge System bei der Entwicklung von Darmbarrierestörungen, bakterieller Translokation sowie metabolischen Erkrankungen eine Rolle. Im dritten Promotionsprojekt wurden neue Therapieansätze zur Behandlung von Darmbarrierestörungen untersucht. Konkret wurde geprüft, ob antimikrobielle Peptide diätinduzierte Störungen der Darmbarriere sowie metabolische Folgeerkrankungen reduzieren. Dazu erhielten 84 C57BL/6J Mäuse für 18 Wochen entweder eine Kontrolldiät oder eine WSD±F. Ab der 13. Versuchswoche wurden die Mäuse zusätzlich entweder mit HD51-9, hBD2 oder einem Kontrollpeptid behandelt. Zudem wurden potenzielle Signalwege anhand des Organoid-Zellmodells evaluiert. Die Ergebnisse zeigen, dass eine 6-wöchige Defensinbehandlung mit HD51-9 oder hBD2 den Grad der Lebersteatose sowie die Glukosetoleranz bei WSDF-gefütterten Mäusen verbesserte, die Expression ilealer TJ-Proteine erhöhte und die Darmpermeabilität reduzierte. Des Weiteren resultierte die therapeutische Intervention in einer Zunahme der intestinalen antimikrobiellen Peptidabwehr, wobei der Wnt-, TLR/Myd88-, p38 MAPK sowie der Jak/STAT-Signalweg in diese Defensinvermittelten Effekte involviert waren. Defensin-Peptide sind somit ein neuer, vielversprechender Therapieansatz für die Behandlung einer dysfunktionalen Darmbarriere. Im vierten Promotionsprojekt wurde untersucht, ob die Darmbarriere, das enterische Nervensystem (ENS) sowie das mukosale Immunsystem bei der Pathologie von Nicht- Zöliakie-Weizensensitivität (NCWS) involviert sind. Dazu wurden 142 Patienten rekrutiert und anhand einer Allergiediagnostik als betroffen (n = 94) oder nicht betroffen (n = 48) klassifiziert. Zudem wurden mittels einer oralen, doppelblinden, placebokontrollierten Weizenprovokation (DBPCFC) 15 Patienten mit NCWS sowie 19 Kontrollen identifiziert. Anschließend wurden 78 Patienten im Rahmen einer konfokalen Laserendoskopie (CLE) duodenal mit Nahrungsmittelallergenen provoziert. Die Untersuchungen von Gewebeproben mittels RNA-Sequenzierung sowie histologischer und immunhistochemischer Färbungen zeigen, dass Patienten mit NCWS eine Veränderung der Mastzellzahl, eine vermehrte Aktivierung des ENS und möglicherweise Veränderungen des Defensinsystems der Darmbarriere aufwiesen. Im Rahmen der Promotionsprojekte konnten Mechanismen, die diätinduzierten Darmbarrierestörungen zugrunde liegen, beschrieben und ein neuer Therapieansatz aufgezeigt werden. Die Daten unterstreichen die Bedeutung der Darmbarriere für die Pathophysiologie, Diagnostik und Therapie ernährungsassoziierter Erkrankungen.
The gut microbiota predicts and time-restricted feeding delays experimental colitis
(2025) Ruple, Hannah K.; Haasis, Eva; Bettenburg, Anna; Maier, Carina; Fritz, Carolin; Schüle, Laura; Löcker, Sarah; Soltow, Yvonne; Schintgen, Lynn; Schmidt, Nina S.; Schneider, Celine; Lorentz, Alex; Fricke, W. Florian
The etiology of inflammatory bowel disease (IBD) remains unclear, treatment options unsatisfactory and disease development difficult to predict for individual patients. Dysbiosis of the gastrointestinal microbiota and disruption of the biological clock have been implicated and studied as diagnostic and therapeutic targets. Here, we examine the relationship of IBD to biological clock and gut microbiota by using the IL-10 deficient (IL-10-/-) mouse model for microbiota-dependent spontaneous colitis in combination with altered (4 h/4 h) light/dark cycles to disrupt and time-restricted feeding (TRF) to restore circadian rhythmicity. We show that while altered light/dark cycles disrupted the intestinal clock in wild type (WT) mice, IL-10-/- mice were characterized by altered microbiota composition, impaired intestinal clock, and microbiota rhythmicity irrespective of external clock disruption, which had no consistent colitis-promoting effect on IL-10-/- mice. TRF delayed colitis onset reduced the expression of inflammatory markers and increased the expression of clock genes in the intestine, and increased gut microbiota rhythmicity in IL-10-/- mice. Compositional changes and reduced rhythmicity of the fecal microbiota preceded colitis and could predict colitis symptoms for individual IL-10-/- mice across different experiments. Our findings provide perspectives for new diagnostic and TRF-based, therapeutic applications in IBD that should be further explored.
Effect of the Mediterranean diet on the faecal long-chain fatty acid composition and intestinal barrier integrity: An exploratory analysis of the randomised controlled LIBRE trial
(2024) Seethaler, Benjamin; Basrai, Maryam; Neyrinck, Audrey M.; Vetter, Walter; Delzenne, Nathalie M.; Kiechle, Marion; Bischoff, Stephan C.
We recently showed that adherence to the Mediterranean diet increased the proportion of plasma n-3 PUFA, which was associated with an improved intestinal barrier integrity. In the present exploratory analysis, we assessed faecal fatty acids in the same cohort, aiming to investigate possible associations with intestinal barrier integrity. Women from the Lifestyle Intervention Study in Women with Hereditary Breast and Ovarian Cancer (LIBRE) randomised controlled trial, characterised by an impaired intestinal barrier integrity, followed either a Mediterranean diet (intervention group, n 33) or a standard diet (control group, n 35). At baseline (BL), month 3 (V1) and month 12 (V2), plasma lipopolysaccharide-binding protein, faecal zonulin and faecal fatty acids were measured. In the intervention group, faecal proportions of palmitoleic acid (16:1, n-7) and arachidonic acid (20:4, n-6) decreased, while the proportion of linoleic acid (18:2, n-6) and α linoleic acid (18:3, n-3) increased (BL-V1 and BL-V2, all P < 0·08). In the control group, faecal proportions of palmitic acid and arachidic acid increased, while the proportion of linoleic acid decreased (BL-V1, all P < 0·05). The decrease in the proportion of palmitoleic acid correlated with the decrease in plasma lipopolysaccharide-binding protein (ΔV1-BL r = 0·72, P < 0·001; ΔV2-BL r = 0·39, P < 0·05) and correlated inversely with adherence to the Mediterranean diet (Mediterranean diet score; ΔV1-BL r = –0·42, P = 0·03; ΔV2-BL r = -0·53, P = 0·005) in the intervention group. Our data show that adherence to the Mediterranean diet induces distinct changes in the faecal fatty acid composition. Furthermore, our data indicate that the faecal proportion of palmitoleic acid, but not faecal n-3 PUFA, is associated with intestinal barrier integrity in the intervention group.
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.
Bacterial subversion of NLR-mediated immune responses
(2022) Kienes, Ioannis; Johnston, Ella L.; Bitto, Natalie J.; Kaparakis-Liaskos, Maria; Kufer, Thomas A.
Members of the mammalian Nod-like receptor (NLR) protein family are important intracellular sensors for bacteria. Bacteria have evolved under the pressure of detection by host immune sensing systems, leading to adaptive subversion strategies to dampen immune responses for their benefits. These include modification of microbe-associated molecular patterns (MAMPs), interception of innate immune pathways by secreted effector proteins and sophisticated instruction of anti-inflammatory adaptive immune responses. Here, we summarise our current understanding of subversion strategies used by bacterial pathogens to manipulate NLR-mediated responses, focusing on the well-studied members NOD1/2, and the inflammasome forming NLRs NLRC4, and NLRP3. We discuss how bacterial pathogens and their products activate these NLRs to promote inflammation and disease and the range of mechanisms used by bacterial pathogens to evade detection by NLRs and to block or dampen NLR activation to ultimately interfere with the generation of host immunity. Moreover, we discuss how bacteria utilise NLRs to facilitate immunotolerance and persistence in the host and outline how various mechanisms used to attenuate innate immune responses towards bacterial pathogens can also aid the host by reducing immunopathologies. Finally, we describe the therapeutic potential of harnessing immune subversion strategies used by bacteria to treat chronic inflammatory conditions.
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.
Detection of bacterial membrane vesicles by NOD-like receptors
(1996) Johnston, Ella L.; Heras, Begoña; Kufer, Thomas A.; Kaparakis-Liaskos, Maria
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 NLRs in the regulation of type I interferon signaling, host defense and tolerance to inflammation
(2021) Kienes, Ioannis; Weidl, Tanja; Mirza, Nora; Chamaillard, Mathias; Kufer, Thomas A.
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
Serotonin receptor 5-HT2A regulates TrkB receptor function in heteroreceptor complexes
(2022) Ilchibaeva, Tatiana; Tsybko, Anton; Zeug, Andre; Müller, Franziska E.; Guseva, Daria; Bischoff, Stephan C.; Ponimaskin, Evgeni; Naumenko, Vladimir
Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A–TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.
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.
Resveratrol attenuates mast cell mediated allergic reactions: Potential for use as a nutraceutical in allergic diseases?
(2022) Civelek, Mehtap; Bilotta, Sabrina; Lorentz, Axel
Allergic diseases are one of the most common health disorders affecting about 30% of the world population. Mast cells (MCs) are key effector cells of allergic reactions by releasing proinflammatory mediators including histamine, lipid mediators, and cytokines/chemokines. Natural substances like secondary plant substances such as resveratrol (RESV), which can contribute to prevention and treatment of diseases, are becoming increasingly interesting for use as nutraceuticals. In this review, the anti‐inflammatory effects of RESV on MC‐mediated allergic reactions in vitro and in vivo models are summarized. The studies indicate that RESV inhibits MC degranulation, synthesis of arachidonic acid metabolites, expression of cytokines and chemokines as well as activation of signal molecules involved in proinflammatory mechanisms. Also, beneficial impacts by this polyphenol are reported in randomized controlled trials with allergic rhinitis patients. Although it cannot yet be concluded that RESV can be used successfully in allergy patients in general, there are many results that indicate a possible role for RESV for use as an anti‐inflammatory nutraceutical. However, strategies to favorably influence the poor bioavailability of RESV would be helpful.
Potential modulation of inflammation by probiotic and omega-3 supplementation in elderly with chronic low-grade inflammation - a randomized, placebo-controlled trial
(2022) Tingö, Lina; Hutchinson, Ashley N.; Bergh, Cecilia; Stiefvatter, Lena; Schweinlin, Anna; Jensen, Morten G.; Krüger, Kirsten; Bischoff, Stephan C.; Brummer, Robert J.
Probiotic and omega-3 supplements have been shown to reduce inflammation, and dual supplementation may have synergistic health effects. We investigated if the novel combination of a multi-strain probiotic (containing B. lactis Bi-07, L. paracasei Lpc-37, L. acidophilus NCFM, and B. lactis Bl-04) alongside omega-3 supplements reduces low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) in elderly participants in a proof-of-concept, randomized, placebo-controlled, parallel study (NCT04126330). In this case, 76 community-dwelling elderly participants (median: 71.0 years; IQR: 68.0–73.8) underwent an intervention with the dual supplement (n = 37) or placebo (n = 39) for eight weeks. In addition to hs-CRP, cytokine levels and intestinal permeability were also assessed at baseline and after the eight-week intervention. No significant difference was seen for hs-CRP between the dual supplement group and placebo. However, interestingly, supplementation did result in significant increases in the level of the anti-inflammatory marker IL-10. In addition, dual supplementation increased levels of valeric acid, further suggesting the potential of the supplements in reducing inflammation and conferring health benefits. Together, the results suggest that probiotic and omega-3 dual supplementation exerts modest effects on inflammation and may have potential use as a non-pharmacological treatment for low-grade inflammation in the elderly.
Outcomes addressed in randomized controlled lifestyle intervention trials in community‐dwelling older people with (sarcopenic) obesity - an evidence map
(2022) Galicia Ernst, Isabel; Torbahn, Gabriel; Schwingshackl, Lukas; Knüttel, Helge; Kob, Robert; Kemmler, Wolfgang; Sieber, Cornel C.; Batsis, John A.; Villareal, Dennis T.; Ströbele-Benschop, Nanette; Visser, Marjolein; Volkert, Dorothee; Kiesswetter, Eva; Schoene, Daniel
Obesity and sarcopenic obesity (SO) are characterized by excess body fat with or without low muscle mass affecting bio‐psycho‐social health, functioning, and subsequently quality of life in older adults. We mapped outcomes addressed in randomized controlled trials (RCTs) on lifestyle interventions in community‐dwelling older people with (sarcopenic) obesity. Systematic searches in Medline, Embase, Cochrane Central, CINAHL, PsycInfo, Web of Science were conducted. Two reviewers independently performed screening and extracted data on outcomes, outcome domains, assessment methods, units, and measurement time. A bubble chart and heat maps were generated to visually display results. Fifty‐four RCTs (7 in SO) reporting 464 outcomes in the outcome domains: physical function (n = 42), body composition/anthropometry (n = 120), biomarkers (n = 190), physiological (n = 30), psychological (n = 47), quality of life (n = 14), pain (n = 4), sleep (n = 2), medications (n = 3), and risk of adverse health events (n = 5) were included. Heterogeneity in terms of outcome definition, assessment methods, measurement units, and measurement times was found. Psychological and quality of life domains were investigated in a minority of studies. There is almost no information beyond 52 weeks. This evidence map is the first step of a harmonization process to improve comparability of RCTs in older people with (sarcopenic) obesity and facilitate the derivation of evidence‐based clinical decisions.
Potentially beneficial effects on healthy aging by supplementation of the EPA-rich microalgae phaeodactylum tricornutum or its supernatant - a randomized controlled pilot trial in elderly individuals
(2022) Stiefvatter, Lena; Frick, Konstantin; Lehnert, Katja; Vetter, Walter; Montoya-Arroyo, Alexander; Frank, Jan; Schmid-Staiger, Ulrike; Bischoff, Stephan C.
Dietary supplements that promote healthy aging are mostly warranted in an aging society. Because of age-related risks, anti-inflammatory and anti-oxidative agents such as microalgae are potential candidates for intervention. In a randomized controlled trial, we tested Phaeodactylum tricornutum (PT), a microalgae rich in eicosapentaenoic acid (EPA), carotenoids, vitamins, and β-glucans, cultured in bioreactors. In this pilot trial, 19 healthy elderly received supplements for two weeks based on either the whole PT (A), the β-1,3-glucan-rich PT supernatant (SupB), the combination thereof (A+SupB), or a Comparator product (Comp). The primary outcome variable plasma interleukin-6 was reduced after treatment with A+SupB compared to the Comp group (p = 0.04). The mobility parameters 5 s sit-to-stand test (p = 0.04 in the A group) and by trend gait speed (p = 0.08 in the A+SupB diet) were improved compared to Comp. No treatment effects were observed for fatty acids, compared to Comp but omega-6 to -3 fatty acid ratio (p = 0.006) and arachidonic acid/EPA ratio (p = 0.006) were reduced within group A+SupB. Further, the SupB study product reduced faecal zonulin (p = 0.03) compared to the Comp. The data revealed an anti-inflammatory and potentially anti-oxidative effect of particular PT preparations, suggesting that they might be suitable for effects in healthy elderly.
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.
Editorial: Updates on RIG-I-like receptor-mediated innate immune responses
(2023) Kishore, Uday; Kufer, Thomas A.

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