Institut für Ernährungsmedizin

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Bedeutung von Tumorantigenen bei Hauttumorpatienten
(2008) Wiedemann, Nicole; Eichmüller, Stefan
Essential prerequisites for the development of specific immunotherapies and procedures for diagnosis and prognosis of tumor diseases are the knowledge and characterization of tumor antigens. Potential antigens for immunotherapeutic strategies and diagnosis tools should be tumor-specific. Moreover, indications for immune responses in patients e.g. antibody or T cell responses should be available. In this thesis, antibody responses of patients of cutaneous T cell lymphoma (CTCL), melanoma (MM) and controls were investigated using two different methods. In addition, the tumor antigen GAGE-7b was characterized using a rabbit polyclonal antibody. In order to test antibody frequencies of various tumor antigens in parallel, a serum antibody detection array (SADA) was established. Testing 42 tumor antigens, antibodies against 14 antigens were only detectable in patients but not in controls. Serum antibody frequencies of antigens GBP-5ta, GBP-5a, HD-MM48 and HD-MM-19 were significantly higher in MM patients compared to controls. The same was true for antigens HD-MM-48 and HD-CL-02 comparing CTCL patients and controls. In summary, antibody frequencies were relatively low ranging most frequently from 0% to 10% which limits the use of the respective antigens as diagnostic targets. An additional method to measure immunoreactivities of 13 cancer testis and tumor-associated antigens in different groups named multiplex serology was used. Antibodies against LAGE-1a were detected significantly more frequently in MM patients in comparison to controls. In addition, this higher antibody frequency in MM patients was stage dependent. For antigens MAGE-A3, GAGE-7b and se57-1 a higher antibody frequency in MM patients was measured likewise. Antibody titers of MM and CTCL patients rarely changed over time, thus seroconversions were seen only sporadically. Significantly higher reactivities could be identified for MAGE-A1 and A9 in CTCL patients of different stages compared to controls. In future, analyzing patients immunized with interferon-g, tumor or dendritic cells or immunotherapy targeting specific tumor antigens would be of high interest. For the first time, a comprehensively characterized rabbit polyclonal antibody against GAGE-7b was generated and used in Western Blot and immunohistology. In Western Blot analysis, 59% of all MM cell lines tested expressed GAGE-7b, whereas no protein was detected in both CTCL cell lines and control tissues except testis. This expression pattern was confirmed by immunocytology. Immunohistological tests confirmed that 53% of MM tissues are positive for GAGE-7b protein expression. Moreover, antibodies against GAGE-7b could be identified in 6% of MM and CTCL patients whereas controls had no detectable antibody responses. On the basis of the achieved results, the GAGE-7b antibody recognizes probably all GAGE family members. Future analysis using this antibody may permit the elucidation of functional aspects of GAGE expression in tumor diseases.
Benefits of fiber-enriched foods on satiety and parameters of human well-being in adults with and without cardiometabolic risk
(2023) Ehret, Janine; Brandl, Beate; Schweikert, Karsten; Rennekamp, Rachel; Ströbele-Benschop, Nanette; Skurk, Thomas; Hauner, Hans
Consumption of fiber-rich foods is linked to beneficial effects on chronic diseases and gut health, while implications towards improving satiety and parameters of well-being remain unclear. A randomized placebo-controlled intervention study was conducted to compare the effects of fiber-enriched foods to their non-enriched counterparts in adults over a 12-week period on selected clinical parameters—satiety, quality of life, body sensation, and life satisfaction—subjective health status, and importance of diet for well-being. Quality of life (QOL) differed significantly between intervention and control groups at baseline, throughout, and at the end of the study. No effects on satiety, satisfaction with life, or the importance of diet for well-being could be shown between groups. With higher fiber intake, body sensation ratings increased. A higher BMI was significantly associated with lower-body sensation, subjective health status and quality of life. Fiber-enriched foods do not seem to affect feeling of satiety or parameters of well-being. Larger samples and additional methods are necessary to fully explore the effect of increased fiber intake on patient-related outcomes in more detail.
Characterization of the role of the NLR proteins NLRC5 and NLRP11 in the immune response
(2021) Kienes, Ioannis; Kufer, Thomas
Recognition of conserved molecular patterns by pattern recognition receptors (PRRs) is crucial for the initiation of an innate immune response. Within PRRs, the NOD-like receptor (NLR) family is, in humans, a group of 22 cytosolic proteins, which function as PRRs of the innate immune system and as regulators of adaptive immune responses. However, it has become evident, that several NLR proteins also function as regulators of innate immune responses. In this thesis the function of human NLR proteins NLRC5 and NLRP11 in immune responses was further characterized. The first part of this thesis was focused on the NOD-like receptor NLRC5. NLRC5 and major histocompatibility complex (MHC) class II transcriptional activator (CIITA) are the master regulators of MHC class I and II transcription, respectively. Both proteins can translocate into the nucleus, where they induce transcription of MHC class I and class II, respectively. As NLRC5 and CIITA do not possess intrinsic DNA binding capacities, they exert their function by binding to a common multiprotein complex, termed MHC enhanceosome and through recruitment of further transcriptional regulators. Although MHC enhanceosome components are, as known thus far, identical, NLRC5 and CIITA are specific for their respective transcriptional targets. In this work we employed several techniques to identify novel interaction partners of NLRC5 to understand the mechanisms behind this specificity. As the N-terminal domain death-domain like fold (DD) of NLRC5 has previously been shown to be involved in conferring specificity, we adapted a protocol for proximal ligation by fusion of the NLRC5 DD to biotin ligase from Aquifex aeolicus (BioID2) to unravel the interactome of this NLRC5 domain. By enrichment of biotinylated proteins through streptavidin-biotin precipitation and analysis of the proteins by LC-MS/MS, we aimed to identify novel putative interactors with functions in transcriptional regulation. Additionally, we used yeast 2 hybrid screening of the NLRC5 DD against a library of human CD4+ and CD8+ T cells for the identification of novel interaction partners. This led to the identification of the paired amphipathic helix protein Sin3A (Sin3A) and the negative elongation factor B (NELFB) as interactors of NLRC5 DD. Characterization of their role in transcriptional regulation of MHC class I revealed an inhibitory role of both proteins. However, as we also observed repression of CIITA-mediated MHC class II transcription, both proteins are likely not involved in determination of target specificity of NLRC5. Translocation of NLRC5 into the nucleus is essential for the induction of MHC class I transcription. It has however previously been shown, that forced nuclear localization of NLRC5 strongly diminishes its transcriptional activity. We therefore employed co-immunoprecipitation of differentially localized NLRC5 constructs to identify interaction partners which might be involved in post translational regulation of NLRC5. Further, to advance our understanding of the NLRC5 DD, we aimed to elucidate its crystal structure. For this, we established a protocol for large-scale recombinant expression and purification of the NLRC5 DD for subsequent crystallization of the recombinant protein. The second part of this thesis was focused on NLRP11. Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. NLRP11 has previously been shown to regulate type I IFN and other pro-inflammatory responses. To gain a deeper understanding of the underlying mechanism, we aimed to identify novel NLRP11 interactors, through which the inhibition is conferred. Here we generated cell lines stably expressing NLRP11-eGFP as novel tools to elucidate the functions of NLRP11. We identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11 by co immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKe-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the leucine-rich repeat (LRR) domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting, that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction, as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.
Editorial: Updates on RIG-I-like receptor-mediated innate immune responses
(2023) Kishore, Uday; Kufer, Thomas A.
Effect of low ethanol concentrations on the production and stability of Interferon gamma
(2008) Sauter, Senja; Bode, Christiane
Alcohol is known to modulate the immune system in a complex manner. The effects of alcohol on immune responses vary with acute and chronic exposure as well as depending on the history of alcohol consumption and the blood level of alcohol. The presence or absence of alcohol can affect the cytokine cascade in complex ways. In the current study the immunmodulatory capability of an acute, moderate (1 ?) to high amount (3 ?) of alcohol was tested on isolated Peripheral Blood Mononuclear Cells production of several proinflammatory and antiinflammatory cytokines after incubation for 12 to 72 hours. The most affected cytokine in our model system of isolated human PBMC treated with two different ethanol concentrations was IFN-γ. Its concentration decreased in a highly significant manner in PHA- as well as in LPS-stimulated PBMC when treated with 66 mM ethanol and in a significant manner in PHA-activated PBMC when treated with 22 mM ethanol. The fact that ethanol negatively affects IFN-γ production is supported by several in vivo and in vitro studies by Wagner et al., 1992, Chen et al., 1993, Laso et al., 1997 Waltenbaugh et al., 1998, Starkenburg et al., 2001, Szabo et al., 2001, Dokur et al., 2003. The reduced IFN-γ level observed might be a key factor in explaining comprised immunity seen after chronic alcohol abuse, since together with IL-12, IFN-γ is crucial for the innate and adaptive immune response to viral and bacterial infection (Vicente-Gutierrez et al., 1991, Windle et al., 1993, Szabo 1997, Szabo et al., 1999). As seen in isolated human Peripheral Blood Mononuclear Cells IFN-γ production by IL-12 stimulated NK-92 cells is significantly reduced in the presence of ethanol. However, this decrease did not correlate with decreased phosphorylation and nuclear translocation of STAT4, a central regulator of IFN-γ gene expression. These results indicated that acute alcohol treatment in vitro did not affect intracellular pathways leading to IFN-γ gene expression. These findings paralleled results indicating that the amount of mRNA for IFN-γ synthesis in NK-92 cells is not affected by the applied ethanol concentrations as well. Additionally it was shown within the current work, that the reduced IFN-γ production by NK-92 cells in the presence of ethanol might not be explained by an intracellular accumulation of the IFN-γ protein. The inhibitory action of ethanol on IFN-γ may rather be caused by posttranslational modification once IFN-γ is released by NK-92 cells, since the addition of recombinant human IFN-γ to the cell culture supernatants of ethanol-treated cells led to a decline in the amount of IFN-γ concentration. We therefore hypothesized that ethanol may cause the release of either an IFN-γ-binding or IFN-γ-degrading protein. An increase in soluble IFN-γ receptor as a result of ethanol treatment was not observed. But the addition of mixture of 5 commercially available protease inhibitors counteracted the effect of ethanol treatment, giving us a first hint of IFN-γ-modulatory mechanism, where IFN-γ released by NK-92 cells may be disintegrated by a protease released as consequence of ethanol incubation. To our best knowledge we are the first to demonstrate a posttranslational modification of IFN-γ as a consequence of ethanol incubation. In summary, the present results support the inhibitory role of ethanol on IFN-γ, but are too preliminary to explain the underlying immunmodulatory effect.
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.
Effekte der Proteinzufuhr während einer Gewichtsabnahme auf fettfreie Masse, Ruheenergieumsatz und physische Funktion bei übergewichtigen postmenopausalen Frauen - eine randomisierte, kontrollierte Studie
(2020) Englert, Isabell; Kohlenberg-Müller, Kathrin
Aim Weight loss in old age increases the risk of sarcopenia caused by the age-related reduction of fat-free mass (FFM). Due to the strong correlation between FFM and resting energy expenditure (REE), the maintenance of this must also be considered. In addition, the physical function (PF) must be maintained. The objective was to investigate the impact of protein intake on changes in fat-free mass (FFM), resting energy expenditure (REE), and physical function (PF) during weight loss. Methods 54 postmenopausal women (BMI 30.9 ± 3.4 kg/m²; 59 ± 7 years of age) were randomized into two groups with 0.8 g (K) or 1.5 g protein/kg body weight/d (P) energy-restricted diets (- 750 kcal of individual energy requirements) for 12 weeks, followed by six months weight maintenance with ad libitum food intake. The protein dose was evenly distributed to two liquid and one solid meal. The shakes of the P group were additionally enriched with pure whey protein. Four seminars were held to provide information on the course of the study and in particular on healthy nutrition. At the beginning and at the end of the study, the subjects kept a 7-day nutrition protocol. FFM (by bioelectrical impedance analysis), REE (by indirect calorimetry), PF (strength, endurance, and balance by short physical performance battery test (SPPB), 400 m walking speed and handgrip strength by hand dynamometer), blood parameters (lipid and carbohydrate profile, urea, vitamin D, calcium, magnesium, liver and kidney values from serum) and blood pressure were measured at baseline, after weight loss, and after follow up. The evaluation was primarily based on an intention to treat analysis with correlation and regression analysis, paired and unpaired t-tests, whereby the significance level was set ≤ at 0.05. The values given are continuous mean values ± standard deviation. Results 46 women completed the weight loss intervention and 29 were followed up after weight maintenance. Weight loss was -4.6 ± 3.6 kg (P) and -5.2 ± 3.4 kg (K) (both p < 0.001) and weight regain during follow up was 1.3 ± 2.8 kg (P, p = 0.028) and 0.4 ± 2.5 kg (K) (p = 0.392) with no differences between protein groups. Similar losses in FFM (-0.9 ± 1.1 kg (P) vs. -1.0 ± 1.3 kg (K)) and REE (-206 ± 136 kcal/d (P) vs. -239 ± 134 kcal/d (K), both p < 0.001) were observed in both groups. At follow-up, no changes in FFM were detected in both groups whereas in the NP group the REE increased again (138 ± 296, p = 0.02). The main determinants of the FFM loss were the energy deficit and the speed of weight loss. In the NP group, SPPB score improved with weight loss (0.6 ± 0.8, p < 0.001) and handgrip strength decreased (-1.7 ± 3.4 kg, p < 0.001) whereas no changes were observed in the HP group. The blood profile improved, especially regarding the carbohydrate profile, due to weight loss, and blood pressure. Conclusion A high protein weight loss diet without exercise had no impact on preserving FFM and REE but may help maintain muscle strength in postmenopausal women. As the handgrip strength can be a sensitive parameter for incipient sarcopenia even before the muscle mass decreases noticeably, it can be concluded that an increased protein intake during weight loss can counteract the risk of sarcopenia. Energy deficit and speed of weight loss should be considered as confounders in future studies. In addition, further strategies must be pursued to maintain FFM in weight loss in old age.
Einfluss der IgG-Subklassen sowie der immunmodulatorischen Aminosäuren Arginin und Glutamin auf die Aktivierung menschlicher Darmmastzellen
(2011) Lechowski, Sandra; Lorentz, Axel
Mast cells are key effector cells in allergic diseases, like food allergy. Activation of mast cells occurs mainly by crosslinking of immunoglobulin E (IgE) receptor FcεRI. The role of allergen specific immunoglobulin G (IgG) subclasses IgG1, IgG2, IgG3, and IgG4 in activation of intestinal mast cells is not yet fully clarified. On the one hand, mast cells can be activated via IgG1 and by the mechanisms of ?IgG-supercrosslinking?. On the other hand, IgG1 and IgG4 are up regulated during immunotherapy and might be able to attenuate allergic reactions. In this work, we investigated the effect of IgG subclasses on IgE dependent and IgE-independent mediator release of human intestinal mast cells. Mast cells, isolated and purified from human intestinal tissue, were cultured with their growth factor stem cell factor (SCF) in combination with interferon γ (IFN-γ) or with interleukin 4 (IL-4). IFN-γ is known to up regulate expression of the activating IgG receptor FcγRI on mast cells, derived from peripheral blood. IL-4 is known to enhance IgE triggered mediator release from human intestinal mast cells. Expression of FcγRI, FcγRII, FcγRIII and FcεRI was analysed by flow cytometry. IgG subclasses should be isolated from human sera by affinity chromatography. However, the required purity of at least 95 % for each subclass could not be achieved. Thus, intestinal mast cells were stimulated with human myeloma IgG1-4 and their specific anti-IgG1-4 antibodies in combination with IgE/anti-IgE and the release of inflammatory mediators was measured. We could show that human intestinal mast cells cultured with IFN-γ express FcγRI, while FcγRII and FcγRIII were only weakly expressed. Mast cells cultured with IL-4 do not express FcγR. IgG subclasses themselves did not activate intestinal mast cells neither in culture with IFN-γ, nor cultured with IL-4. In combination with IgE/anti-IgE, the IgG subclasses IgG1/anti IgG1, IgG2/anti IgG2 and IgG4/anti IgG4 tended to decrease the release of pre-stored β-hexosaminidase and de novo synthesized leukotriene C4 (LTC4) but the reduction was not significant. To conclude, IFN-γ induced in human intestinal mast cells the expression of FcγRI, but this did not result in stimulation of the cells by IgG. Thus, human intestinal mast cells do not respond or only to a small extend to IgG subclasses and differ from mast cells derived from peripheral blood which could be activated via IgG1. The second part of the work examines the effect of the immunomodulatory amino acids arginine and glutamine on IgE-dependent activation of human intestinal mast cells. Background was the measured anti-inflammatory effect of combined pharmacological doses of both amino acids on intestinal biopsies from patients with Crohn?s disease. Beside allergic diseases, mast cells play a role in chronic intestinal inflammation. Therefore, they could be involved in the described effect. Human intestinal mast cells were incubated over night with combined physiological doses or pharmacological doses of arginine (0.1 mmol/L or 2 mmol/l) and glutamine (0.6 mmol/l or 10 mmol/l). Mast cells were stimulated with IgE/anti-IgE and release of β-hexosaminidase and LTC4, induction of cytokines and activation of signaling molecules was analysed. In human intestinal mast cells, cultured in SCF and IL-4, combined pharmacological concentrations of arginine and glutamine led to decreased release of LTC4 about 40 ± 22 % and to reduced induction of cytokines like CCL2 (monocyte chemotactic protein 1), CCL4 (macrophage inflammatory protein 1 beta), CXCL8 (IL-8), and TNF (tumor growth factor alpha) about an average of 58 ± 35 % compared to physiological doses of arginine and glutamine. The anti-inflammatory effects of arginine and glutamine were associated with decreased activation levels of MAP kinases like ERK1/2, p38, JNK pan und MEK1/2 about 38 ± 17 % as well as serine/threonine kinase Akt about 23 ± 20 %. Therewith, arginine and glutamine reduce activation levels of signaling molecules known to be involved in IgE dependent mast cell cytokine expression. Here, the results show that arginine and glutamine exert anti-inflammatory effects on human intestinal mast cells in vitro. Further investigations are necessary to monitor these findings in vivo prior to use arginine and glutamine as immunomodulatory agents in inflammatory and allergic diseases.
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.
Ernährung von sozial benachteiligten Menschen am Beispiel von Tafelkunden : Betrachtung des Ernährungs- und Gesundheitsverhaltens, der Verbreitung von Ernährungsarmut und des Obst- und Gemüsekonsums
(2018) Depa, Julia; Ströbele-Benschop, Nanette
In industrialized countries the distribution of mortality of morbidity follows a social gradient. Hence, among people with a lower socioeconomic status (SES) the nutritional quality is poor and low fruit and vegetable consumption occur more frequently compared to people with a higher SES. A particularly vulnerable group are socially disadvantaged people such as food bank users. Food insecurity (FI) is also more common in this population group. Food banks exist worldwide and distribute donated groceries (e.g. from food retailers) to socially disadvantaged people. In Germany, 1.5 million users are supported by over 900 food banks providing mainly fresh fruits and vegetables (FV). In Germany, little is known about the diet of food bank users. The following research questions were developed for this thesis: 1. Are there differences in health and nutrition status among people using food banks in different types of cities and can differences in these variables be found when comparing food bank users with the as low SES defined German population (chapter 2, first publication)? 2. How widespread is FI among food bank users and which socio-demographic, food bank-related and health variables are associated with FI (chapter 3, second publication)? 3. Are there differences in FV intake between male food bank users and male eligible non-food bank users and can FV intake among this study population be increased by an intervention providing weekly free and personally selected FV (14 portions/ per week) for four weeks (chapter 4, third publication)? For the publications of this thesis data of food bank users regarding socio-demographic, health- and nutrition-related variables were collected in different cities. The questions were taken from the questionnaire of the national study DEGS (German Health Interview and Examination Survey for Adults) and GEDA (German Health Update) and from the FIES (Food Insecurity and Experience Scale). Additionally, questionnaires were adapted to the study population. In all publications cross-sectional study designs were used. Except in the third publication for the second part of the research questions an intervention study using a longitudinal design was conducted. The first publication shows that food bank users from the three examined cities (Berlin n=94, Ludwigsburg n=64, Fulda n=114) are not a homogenous group. Food bank users assess their self-rated health mostly worse than people from the low SES German population (proportion self-rated health as moderate, bad or very bad: men 67.4% vs. 43.5%, women 68.8% vs. 36.7%). Additionally, they consume less fruit daily (proportion of daily fruit consumption: men 39.8% vs. 43.5%, women 56.2% vs. 62.4%). The second publication reveals with 70.2% a high rate of FI among food bank users (Stuttgart n=510, Karlsruhe n=186, Berlin n=337). Especially age (r τ = -0.224, p<0.000) and smoking (V=0.219, p<0.000) are strongly associated with FI. The third publication clarifies that male food banks users (n=24) from Stuttgart did not differ in consumed FV amount (2.2 portions/day vs. 1.8 portions/day) and variety (17 types/month vs. 14.4 types/month) compared to non-food bank users (n=28). Besides, the weekly provision of free fruit and vegetables for four weeks (14 portions/ month) increases the consumed fruit and vegetable amount (difference-IG 1.1 portions/day vs. difference-CG -0.2 portions/day) and variety (difference-IG 2.6 types/month vs. difference-CG -1.2 types/month) among the intervention group (n=25) compared to the control group (n=27). It is important to note the high amount of smokers among food bank users both in the first (46.9%) and the third publication (66.7%). The reported results correspond to research from abroad. Results of the publications are limited by unbalanced standardization and representation procedures (first and second publication) and the cross-sectional design (first and second publication and first research question of the third publication). It can be concluded that food banks are a suitable option to target socially disadvantaged people and to explore their nutrition and health behavior as well as a suitable option to provide intervention opportunities. The extent of health inequality is probably underestimated. FI is widespread among food bank users and smoking as poverty factor among food bank users should be further examined. The free provision of fruit and vegetables seems to be an appropriate possibility to increase the consumption and variety of fruit and vegetables among socially disadvantaged people.
Geschlechtsspezifische Unterschiede in der Entstehung von alkoholbedingten Lebererkrankungen
(2010) Wagnerberger, Sabine; Bode, Christiane
Women are assumed to have a higher susceptibility to alcohol-induced liver disease (ALD) than men. Gender-related differences in food preference were described in previous studies for several populations. As certain micronutrients are reported to take influence on the development of ALD in animal experiments, the hypothesis of the present retrospective cross-sectional study was that gender-dependent (micro-) nutrient intake in patients with ALD may cause the higher susceptibility of women to this disease. In 210 patients (male: 158, female: 52) with different stages of ALD (ALD1: mild stage of liver damage; ALD2: moderately severe changes of the liver with signs of hepatic inflammation; ALD3: severely impaired liver function) and in 336 controls (male: 208, female: 128), nutrient intake was determined by a computer-guided diet history and related to the severity of ALD in dependence on the sex of the patients. No significant differences between males and females with ALD were calculated for the intake (per kg body/day) of protein, carbohydrates, fat, and the intake (per kg body/day) of most micronutrients. In females with ALD, higher intake was found for vitamin C (ALD3), calcium (ALD2), iron (ALD1 and ALD2), and zinc (ALD1), but the consumption of none of these micronutrients seems to contribute to a higher susceptibility to ALD in females. In the present study, a higher activity of ?liver-specific? enzymes and a higher DeRitis quotient was measured in female patients with ALD despite equal or lower amounts of consumed alcohol. This may indicate a higher susceptibility to the development of ALD in women. However, the data of calculated daily macro- and micronutrient intake do not suggest any explicit influence of gender-specific nutrition in the development of ALD. In a chronic setting of alcohol intake, women and female rodents are more susceptible to alcohol-induced liver disease than men and male mice. Starting from this background, the purpose of the present study was to determine if female mice are also more susceptible to acute alcohol-induced steatosis than male mice and to investigate whether this is due to alterations in hepatic lipid export. Male and female C57/Bl6-mice received one single dose of ethanol (6 g/kg) or isocaloric maltose-dextrin solution (control) intragastrically. Hepatic triglycerides, lipid accumulation, mRNA expression of microsomal triglyceride transfer protein (MTP) and apolipoprotein (Apo) B, as well as MTP activity were measured 12, 24, and 48 h after alcohol intake. In both genders, acute alcohol ingestion markedly increased hepatic lipid and triglyceride levels; however, total lipid accumulation was ~2-fold higher and more persistent in livers of female than in male mice. Fourty-eight h after ethanol treatment hepatic triglyceride concentrations in male and female ethanol-treated mice were similar to those of controls. MTP activity was significantly increased only in male mice 12 h after ethanol ingestion; whereas expression of MTP mRNA was significantly reduced in female alcohol-treated animals compared to controls at this timepoint. Expression of ApoB was also reduced only in livers of female mice after 12 h; however, differences did not reach level of significance. The results of the present study suggest that the markedly more pronounced and more prolonged susceptibility to acute alcohol-induced liver steatosis of female mice results at least partly from a gender-specific regulation of hepatic lipid export. In our experiments, the selective estrogen recepor modulator (SERM) toremifen did not protect against alcohol-induced hepatic lipid accumulation. The liver plays an important role not only in the metabolism of ethanol but also in the immune system. Lymphatic NK cells are present at an unusually high frequency among liver-resident lymphocytes (30-50 %). By producing the pro-inflammatoric and anti-fibrotic cytokine IFN-g NK cells are involved in the development of liver diseases. Results of studies of our own working group indicate a decrease of IL-12-induced IFN-g production in NK-92 cells after treatment with ethanol for 6 h. The aim of the present study was to investigate whether male (testosterone) or female (estrogen, progesterone, FSH, LH) sex hormones influence the ethanol-induced immunosuppression in NK-92 cells. Therefore, NK-92 cells were incubated with different sex hormones for 19 h and were subsequently treated with ethanol (1-3 ?) and sex hormones for 18 h. Concentrations of IFN-g were determined by ELISA. According to previous studies ethanol treatment resulted in a significant decrease of released IFN-g in comparison to NK-92 cells that were not incubated with ethanol. However, treatment with male and female sex hormones did not affect IFN-g release in NK-92 cells. The results of the present study suggest that solely ethanol treatment but not incubation with sex hormones has an immun modulating effect on NK-92 cells.
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.
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.
Metabolic chamber studies on energy- and macronutrient metabolism : impact of meal skipping and energy flux
(2018) Nas, Alessa; Bosy-Westphal, Anja
The classical concept of body weight regulation attributes the development of obesity to a chronically positive energy balance. There is, however, evidence indicating that beyond this basic concept, the effectiveness of body weight regulation is affected by the circadian regulation of metabolism and the level of energy flux (EF, level of energy balance). Meal skipping affects circadian regulation and might therefore also affect the regulation of body weight. In addition, an asymmetric regulation of body weight is hypothesized with improved effectiveness when EF is high (active lifestyle) and less effectiveness at a low EF (sedentary lifestyle). Metabolic chambers offer the opportunity to acquire short-term parameters of energy and macronutrient balance that precede long-term weight gain and therefore, can help to understand the impact of nutrition and physical activity interventions on body weight regulation. This thesis presents the implementation of a metabolic chamber system (Chapter II) and investigates the acute impact of meal skipping (Chapter III) and energy flux (Chapter IV) on energy and macronutrient metabolism by performing two well-controlled, cross-over intervention studies using metabolic chambers. The implementation of the metabolic chambers revealed, that thorough considerations must be made in terms of the metabolic chamber environment (room ventilation and position of analyzer unit), the additional devices (e.g. air conditioner) used as well as the study protocol, in order to obtain good data quality. The study on meal skipping includes 17 healthy participants who underwent 3 isocaloric 24-h interventions (55%, 30%, and 15% carbohydrate, fat and protein, respectively): a breakfast skipping day (BSD) and a dinner skipping day (DSD) separated by a conventional 3-meal-structure day (control). Energy and macronutrient balance were measured and postprandial glucose and insulin concentrations, as well as 24-h glycemia and 24-h insulin secretion (C-peptide), were analyzed. When compared with the 3-meal control, 24-h energy expenditure was higher on DSD (DSD: +69 kcal/d; p < 0.05), but not on BSD. Whereas, fat oxidation increased on the BSD only (+13 g/d; p < 0.01). Spontaneous physical activity, 24-h glycemia, and 24-h insulin secretion did not differ between intervention days. The postprandial homeostasis model assessment index (+54%) and glucose concentrations after lunch (+46%) were, however, higher on the BSD than on the DSD (both p < 0.05). When compared with 3 meals/d, dinner skipping increased energy expenditure. In contrast, higher postprandial insulin concentrations and increased fat oxidation with breakfast skipping show the development of metabolic inflexibility in response to prolonged fasting that may in the long-term lead to impaired glucose homeostasis. The study on energy flux includes 16 healthy participants who underwent three 24-h interventions with different levels of EF: (i) low EF, physical activity level (PAL) = 1.3 – 1.4 (ii) medium EF, PAL = 1.5 – 1.6 and (iii) high EF, PAL = 1.7 – 1.8 each at energy balance (EB), caloric restriction (CR), and overfeeding (OF) (100%, 75% and 125% of individual energy requirement with 50% carbohydrate, 35% fat, 15% protein). Different levels of EF were accomplished by walking (4 km/h) on a treadmill (0, 165 and 330 min). Sleeping energy expenditure (SEE), 24-h macronutrient oxidation and relative macronutrient balance (oxidation relative to intake) were determined. During EB and OF, 24-h fat oxidation increased with higher EF. This resulted in a higher relative fat balance at medium EF (EB: +17%, OF: +14%) and high EF (EB: +23%, OF: +17%) compared to low EF (all p < 0.05). SEE during EB and OF was higher at medium (EB: +5 kcal/3h and OF: +12 kcal/3h) and high (EB: +7 kcal/3h and OF: +18 kcal/3h) EF compared to low EF (all, p < 0.05). In contrast, during CR 24-h fat oxidation was only higher at high EF compared to low EF and neither relative fat balance nor SEE differed between the EF levels. A higher EF might have beneficial effects on body weight regulation during short-term overfeeding and energy balance because it increased SEE and improved relative fat balance. However, during short-term caloric restriction, a higher EF had no impact on the regulation of energy or fat balance. Therefore, a high EF especially can attenuate the adverse effects of short-term overfeeding. Altogether, this thesis emphasizes the importance of physical activity in daily life and suggests that the adverse metabolic outcome of breakfast skipping (caused by a positive energy balance after lunch with a preceding prolonged fasting period) might be attenuated by a high EF.
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.
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.
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.
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.
NOD1 cooperates with HAX‐1 to promote cell migration in a RIPK2‐ and NF‐ĸB‐independent manner
(2023) Hezinger, Lucy; Bauer, Sarah; Ellwanger, Kornelia; Piotrowsky, Alban; Biber, Felix; Venturelli, Sascha; Kufer, Thomas A.
The human Nod-like receptor protein NOD1 is a well-described pattern-recognition receptor (PRR) with diverse functions. NOD1 associates with F-actin and its protein levels are upregulated in metastatic cancer cells. A hallmark of cancer cells is their ability to migrate, which involves actin remodelling. Using chemotaxis and wound healing assays, we show that NOD1 expression correlated with the migration rate and chemotactic index in the cervical carcinoma cell line HeLa. The effect of NOD1 in cell migration was independent of the downstream kinase RIPK2 and NF-ĸB activity. Additionally, NOD1 negatively regulated the phosphorylation status of cofilin, which inhibits actin turnover. Co-immunoprecipitation assays identified HCLS1-associated protein X-1 (HAX-1) as a previously unknown interaction partner of NOD1. Silencing of HAX-1 expression reduced the migration behaviour to similar levels as NOD1 knockdown, and simultaneous knockdown of NOD1 and HAX-1 showed no additive effect, suggesting that both proteins act in the same pathway. In conclusion, our data revealed an important role of the PRR NOD1 in regulating cell migration as well as chemotaxis in human cervical cancer cells and identified HAX-1 as a protein that interacts with NOD1 and is involved in this signalling pathway.
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.

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