Institut für Ernährungsmedizin

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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.
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.
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.; Stroebele‐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.
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.
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.
Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers
(2021) Grill, Sabine; Yahiaoui-Doktor, Maryam; Basrai, Maryam; Struck, Joachim; Schulte, Janin; Berling-Ernst, Anika; Engel, Christoph; Ullrich, Mirjam; Lammert, Jacqueline; Bischoff, Stephan C.; Schmidt, Thorsten; Niederberger, Uwe; Chronas, Dimitrios; Rhiem, Kerstin; Schmutzler, Rita; Halle, Martin; Kiechle, Marion
Background: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)—involved in tumorigenesis and obesity-related diseases—are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC. Methods: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors. Results: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = − 0.435; CI − 0.653 to − 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061–0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: − 37.9, p = 0.097/0.080) in multivariate analysis. Conclusion: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.
Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: Results of the lifestyle intervention pilot study LIBRE-1
(2021) Neirich, Leonie; Yahiaoui-Doktor, Maryam; Lammert, Jacqueline; Basrai, Maryam; Seethaler, Benjamin; Berling-Ernst, Anika; Ramser, Juliane; Quante, Anne S.; Schmidt, Thorsten; Niederberger, Uwe; Rhiem, Kerstin; Schmutzler, Rita; Engel, Christoph; Bischoff, Stephan C.; Halle, Martin; Kiechle, Marion; Grill, Sabine
Purpose: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. Methods: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. Results: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = − 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). Conclusion: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.
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.
NLRC5-CIITA fusion protein as an effective inducer of MHC-I expression and antitumor immunity
(2023) Santharam, Madanraj Appiya; Shukla, Akhil; Levesque, Dominique; Kufer, Thomas A.; Boisvert, François-Michel; Ramanathan, Sheela; Ilangumaran, Subburaj
Aggressive tumors evade cytotoxic T lymphocytes by suppressing MHC class-I (MHC-I) expression that also compromises tumor responsiveness to immunotherapy. MHC-I defects strongly correlate to defective expression of NLRC5, the transcriptional activator of MHC-I and antigen processing genes. In poorly immunogenic B16 melanoma cells, restoring NLRC5 expression induces MHC-I and elicits antitumor immunity, raising the possibility of using NLRC5 for tumor immunotherapy. As the clinical application of NLRC5 is constrained by its large size, we examined whether a smaller NLRC5-CIITA fusion protein, dubbed NLRC5-superactivator (NLRC5-SA) as it retains the ability to induce MHC-I, could be used for tumor growth control. We show that stable NLRC5-SA expression in mouse and human cancer cells upregulates MHC-I expression. B16 melanoma and EL4 lymphoma tumors expressing NLRC5-SA are controlled as efficiently as those expressing full-length NLRC5 (NLRC5-FL). Comparison of MHC-I-associated peptides (MAPs) eluted from EL4 cells expressing NLRC5-FL or NLRC5-SA and analyzed by mass spectrometry revealed that both NLRC5 constructs expanded the MAP repertoire, which showed considerable overlap but also included a substantial proportion of distinct peptides. Thus, we propose that NLRC5-SA, with its ability to increase tumor immunogenicity and promote tumor growth control, could overcome the limitations of NLRC5-FL for translational immunotherapy applications.
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.
NOD-like receptors - emerging links to obesity and associated morbidities
(2023) Bauer, Sarah; Hezinger, Lucy; Rexhepi, Fjolla; Ramanathan, Sheela; Kufer, Thomas A.
Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases.

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