Publikationen

PUBMED (PMID: 40045464) - 2025 – Gut microbes

Autoren:
Schlicht K., Pape L., Rohmann N., Knappe C., Epe J., Geisler C., Pohlschneider D., Brodesser S., Kruse L., Rohlfing M.E., Hartmann K., Türk K., Marquardt J., Beckmann J., von Schönfels W., Beckmann A., Wietzke-Braun P., Schulte D.M., Hollstein T., Demetrowitsch T., Jensen-Kroll J., Brix F., Schreiber S., Franke A., Schwarz K., Waschina S., Laudes M. 

Abstract:

The interplay between bile acids (BAs) and metabolic diseases has gained importance in recent years, with a variety of studies investigating their relationship with diverging results. Therefore, in the present study we performed a detailed analysis of BA metabolism in 492 subjects with different metabolic phenotypes. Besides microbiomics and metabolomics this investigation included in silico analysis of community metabolism to examine metabolic interchange between different microbes as well as microbes and the human host. Our findings revealed distinct changes in the BA profiles of patients with diabetes and prediabetes, whereas obesity alone had no influence on circulating BAs. Impaired glycemic control led to increased circulating BAs, a shift toward more secondary BAs, and an increase in the ratio of glycine to taurine-conjugated BAs. Additional analyses revealed that the ratio of glycine to taurine conjugation demonstrated variations between the single BAs, cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), regardless of the metabolic status, with CA having a higher fraction of taurine conjugation. Furthermore, we found that microbiome alterations are associated with BAs, independent of diabetes or obesity. Analysis of microbial community metabolism revealed differential relative pathway abundance in relation to diabetes, particularly those related to membrane and polyamine synthesis. Increased bacterial cross-feeding of polyamines, galactose, and D-arabinose also coincided with an increase in BA. Notably, our serum metabolome analysis mirrored several of the previously in silico predicted exchanged metabolites, especially amino acid metabolism. Therefore, targeting BA metabolism may be a future approach for the treatment of metabolic diseases, especially prediabetes and type 2 diabetes.

PUBMED (PMID: 40022072) - 2025 – Cardiovasc Diabetol.

Autoren:
Rohmann N., Epe J., Geisler C., Schlicht K., Türk K., Hartmann K., Kruse L., Koppenhagen J., Kohestani A.Y., Adam T., Bang C., Franke A., Schulte D.M., Hollstein T., Laudes M. 

Abstract:

Background: The traditional binary classification of diabetes into Type 1 and Type 2 fails to capture the heterogeneity among diabetes patients. This study aims to identify and characterize diabetes subtypes within the German FoCus cohort, using the ANDIS cohort's classification framework, and to explore subtype-specific variations in metabolic markers, gut microbiota, lifestyle, social factors, and comorbidities.

Methods: We utilized data from 416 participants (208 with diabetes and 208 matched metabolically healthy controls) from the German FoCus cohort. Participants were classified into five subtypes: severe autoimmune diabetes (SAID)-like, severe insulin-deficient diabetes (SIDD)-like, severe insulin-resistant diabetes (SIRD)-like, mild obesity-related diabetes (MOD)-like, and mild age-related diabetes (MARD)-like. Comprehensive characterization included anthropometric measurements, dietary and physical activity questionnaires, blood biomarker analysis, and gut microbiota profiling.

Results: The subtype distribution in the FoCus cohort accounted to SAID-like: 2.84%, SIDD-like: 30.81%, SIRD-like: 32.23%, MOD-like: 17.54%, MARD-like: 16.59%. Of interest, inflammatory markers (C-reactive protein (CRP) and Interleukin-6 (IL-6)) and glucagon-like peptide-1 (GLP-1) levels were similarly elevated across all subtypes compared to controls, indicating common aspects in Type 2 diabetes molecular pathology despite different clinical phenotypes. While the gut microbiota and dietary patterns only showed minor differences, smoking status, sleep duration, physical activity and psychological aspects varied significantly between the subtypes. In addition, we observed a lower educational status especially for SIDD-like and SIRD-like groups, which should be considered in establishing future diabetes-related patient education programs. In respect to the development of cardio-metabolic comorbidities, we observe not only significant differences in the presence of the diseases but also for their age-of onset, highlighting the need for early preventive intervention strategies.

Conclusions: The study validates the ANDIS classification framework's applicability not only at the time point of manifestation but also in cohorts with pre-existing diabetes. While we did not find major differences regarding the classical metabolic, microbial and nutritional parameters, we identified several significant associations with lifestyle factors. Our findings underscore the importance of personalized, subtype-specific therapies not solely focusing on anthropometric and laboratory markers but comprehensively addressing the patient's own personality and situation of life.

PUBMED (PMID: 39449123) - 2024 – BMC Medicine

Autoren:
Rohmann, N., Geese, T., Nestel, S., Schlicht, K., Geisler, C., Türk, K., Brix, F., Jensen-Kroll, J., Demetrowitsch, T., Bang, C., Franke, A., Lieb, W., Schulte, D. M., Schwarz, K., Ruß, A. K., Sharma, A., Schreiber, S., Dempfle, A., & Laudes, M. 

Abstract:

Background: Biomedical and lifestyle factors in Western populations have significantly shifted in recent decades, influencing public health and contributing to the increasing prevalence of non-communicable diseases (NCDs) that share inflammation as common pathology.

Methods: We investigated the relationship between these factors and 11 NCDs in the cross-sectional FoCus cohort (n = 1220), using logistic regression models. Associations with age-at-disease-onset were specifically analyzed for type 2 diabetes (T2D, low-grade chronic inflammation) and inflammatory bowel disease (IBD, high-grade chronic inflammation) in disease-specific cohorts (FoCus-T2D, n = 514; IBD-KC, n = 1110). Important factors for disease risk were identified using Cox-PH-regression models and time-to-event analysis. We further explored the interaction between identified risk factors and gut microbiome composition using linear models.

Results: Lifestyle factors were clearly linked to disease phenotypes, particularly in T2D and IBD. Still, some factors affected only the age-at-onset, but not disease prevalence. High-quality nutrition significantly delayed onset for both IBD and T2D (IBD: HR = 0.81 [0.66; 0.98]; T2D: HR = 0.45 [0.28; 0.72]). Smoking accelerated T2D onset (HR = 1.82 [1.25; 2.65]) but delayed onset in ulcerative colitis (UC: HR = 0.47 [0.28; 0.79]). Higher microbiota diversity delayed IBD onset (Shannon: HR = 0.58 [0.49; 0.71]) but had no effect on T2D. The abundance of specific microbial genera was strongly associated with various biomedical and lifestyle factors in T2D and IBD. In unaffected controls, these effects were smaller or reversed, potentially indicating a greater susceptibility of the gut microbiome to negative influences in T2D and IBD.

Conclusions: The dual insights into age-at-disease-onset and gut microbiota composition in disease emphasize the role of certain biomedical and lifestyle factors, e.g., nutrition quality, in disease prevention and management. Understanding these relationships provides a foundation for developing targeted strategies to mitigate the impact of metabolic and inflammatory diseases through lifestyle modifications and gut health management.

PUBMED (PMID: 39237628) - 2024 – Nature medicine

Autoren:
Schreiber, S., Waetzig, G. H., Laudes, M., & Rosenstiel, P.

Abstract:

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PUBMED (PMID: 38952262) - 2024 - J Periodontal Res.

Autoren:
Fawzy El-Sayed, K., Mahlandt, E., Schlicht, K., Enthammer, K., Tölle, J., Wagner, J., Hartmann, K., Ebeling, P. R., Graetz, C., Laudes, M., Dörfer, C. E., & Schulte, D. M.

Abstract:

Aims: Oxidized low-density lipoprotein (oxLDL) is an important player in the course of metabolic inflammatory diseases. oxLDL was identified in the gingival crevicular fluid, denoting possible associations between oxLDL-induced inflammation and periodontal disease. The current investigation compared for the first-time direct effects of oxLDL to a cytokine cocktail of IL-1ß/TNF-ɑ/INF-γ on gingival mesenchymal stem cells' (G-MSCs) attributes.

Methods: Human third passage G-MSCs, isolated from connective tissue biopsies (n = 5) and characterized, were stimulated in three groups over 7 days: control group, cytokine group (IL-1β[1 ng/mL], TNF-α[10 ng/mL], IFN-γ[100 ng/mL]), or oxLDL group (oxLDL [50 μg/mL]). Next Generation Sequencing and KEGG pathway enrichment analysis, stemness gene expression (NANOG/SOX2/OCT4A), cellular proliferation, colony-formation, multilinear potential, and altered intracellular pathways were investigated via histochemistry, next-generation sequencing, and RT-qPCR.

Results: G-MSCs exhibited all mesenchymal stem cells' characteristics. oxLDL group and cytokine group displayed no disparities in their stemness markers (p > .05). Next-generation-sequencing revealed altered expression of the TXNIP gene in response to oxLDL treatment compared with controls (p = .04). Following an initial boosting for up to 5 days by inflammatory stimuli, over 14 day, cellular counts [median count ×10-5 (Q25/Q75)] were utmost in control - [2.6607 (2.0804/4.5357)], followed by cytokine - [0.0433 (0.0026/1.4215)] and significantly lowered in the oxLDL group [0.0274 (0.0023/0.7290); p = .0047]. Osteogenic differentiation [median relative Ca2+ content(Q25/Q75)] was significantly lower in cytokine - [0.0066 (0.0052/0.0105)] compared to oxLDL - [0.0144 (0.0108/0.0216)] (p = .0133), with no differences notable for chondrogenic and adipogenic differentiation (p > .05).

Conclusions: Within the current investigation's limitations, in contrast to cytokine-mediated inflammation, G-MSCs appear to be minimally responsive to oxLDL-mediated metabolic inflammation, with little negative effect on their differentiation attributes and significantly reduced cellular proliferation.

PUBMED (PMID: 38665607) - 2024 – ACS Pharmacol Transl Sci.

Autoren:
Shearer, J., Shah, S., Shen-Tu, G., Schlicht, K., Laudes, M., & Mu, C.

Abstract:

Human gut microbiota are recognized as critical players in both metabolic disease and drug metabolism. However, medication-microbiota interactions in cardiometabolic diseases are not well understood. To gain a comprehensive understanding of how medication intake impacts the gut microbiota, we investigated the association of microbial structure with the use of single or multiple medications in a cohort of 134 middle-aged adults diagnosed with cardiometabolic disease, recruited from Alberta's Tomorrow Project. Predominant cardiometabolic prescription medication classes (12 total) were included in our analysis. Multivariate Association with Linear Model (MaAsLin2) was employed and results were corrected for age, BMI, sex, and diet to evaluate the relationship between microbial features and single- or multimedication use. Highly individualized microbiota profiles were observed across participants, and increasing medication use was negatively correlated with α-diversity. A total of 46 associations were identified between microbial composition and single medications, exemplified by the depletion of Akkermansia muciniphila by β-blockers and statins, and the enrichment of Escherichia/Shigella and depletion of Bacteroides xylanisolvens by metformin. Metagenomics prediction further indicated alterations in microbial functions associated with single medications such as the depletion of enzymes involved in energy metabolism encoded by Eggerthella lenta due to β-blocker use. Specific dual medication combinations also had profound impacts, including the depletion of Romboutsia and Butyriciocccus by statin plus metformin. Together, these results show reductions in bacterial diversity as well as species and microbial functional potential associated with both single- and multimedication use in cardiometabolic disease.

PUBMED (PMID: 38653010) - 2024 – Clinical Nutrition

Autoren:
Keweloh, B., Terenzi, D., Froehlich, E., Coricelli, C., Stürmer, P., Rohmann, N., Wietzke-Braun, P., Beckmann, A., Laudes, M., & Park, S. Q.

Abstract:

Background & aims: Risky decision making is shaped by individual psychological and metabolic state. Individuals with obesity show not only altered risk behavior, but also metabolic and psychological abnormalities. The aim of the present study was to investigate whether a substantial weight loss in individuals with severe obesity will 1) normalize their metabolic and psychological state and 2) will change their pattern of decision guidance.

Methods: We assessed the effect of glycated hemoglobin (HbA1c) and mood on risk behavior in individuals with obesity (n = 62, 41 women; BMI, 46.5 ± 4.8 kg/m2; age, 44.9 ± 14.7 years) before and after 10-weeks weight loss intervention.

Results: Results showed that this intervention reduced participants' risk behavior, which was significantly predicted by their changes in BMI. Before intervention, mood, but not HbA1c significantly predicted decisions. After the weight loss, mood no longer, but HbA1c significantly predicted decisions.

Conclusion: Our findings shed light on the psychological and metabolic mechanisms underlying altered risky decision making in severe obesity and can inform the development of strategies in the context of weight loss interventions.

PUBMED (PMID: 38908966) - 2024 – J Clin Lipidol.

Autoren:
Schumann, F., Kassner, U., Spira, D., Zimmermann, F. F., Bobbert, T., Steinhagen-Thiessen, E., & Hollstein, T.

Abstract:

Background: Elevated lipoprotein(a) (Lp(a)) is an established risk factor for cardiovascular disease (CVD). To date, the only approved treatment to lower Lp(a) is lipoprotein apheresis (LA). Previous studies have demonstrated that LA is effective in reducing cardiovascular (CV) risk in patients with elevated low-density lipoprotein cholesterol (LDL-C) and/or Lp(a). Here we report our long-term experience with LA and its effectiveness in reducing CVD events in patients with elevated Lp(a).

Methods: This retrospective open-label, single-center study included 25 individuals with Lp(a) elevation >60 mg/dL and LDL-C < 2.59 mmol/L who had indication for LA. The primary endpoint of this study was the incidence of any CV event (determined by medical records) after initiation of LA.

Results: Mean LA treatment duration was 7.1 years (min-max: 1-19 years). Median Lp(a) was reduced from 95.0 to 31.1 mg/dL after LA (-67.3%, p < 0.0001). Mean LDL-C was reduced from 1.85 to 0.76 mmol/L after LA (-58.9%, p < 0.0001). Prior to LA, 81 CV events occurred in total (0.87 events/patient/year). During LA, 49 CV events occurred in total (0.24 events/patient/year; -0.63, p = 0.001). Yearly major adverse cardiac event (MACE) rate was reduced from 0.34 to 0.006 (-0.33, p = 0.0002). Similar results were obtained when considering only individuals with baseline LDL-C below 1.42 mmol/L.

Conclusion: In this observational study of a heterogeneous CV high-risk cohort with elevated Lp(a), LA reduced Lp(a) levels and was paralleled by a decrease in CV events and MACE. We recommend LA for patients with high Lp(a) who still have CV events despite optimal lipid-lowering medication and lifestyle changes.

PUBMED (PMID: 36883605) - 2023 - European Journal of Endocrinology.

Autoren:
Sonnefeld, L., Rohmann, N., Geisler, C., Laudes, M.

Abstract:

Obesity and its comorbidities are long-standing, challenging global health problems. Lack of exercise, overnutrition, and especially the consumption of fat-rich foods are some of the most important factors leading to an increase in prevalence in modern society. The pathophysiology of obesity as a metabolic inflammatory disease has moved into focus since new therapeutic approaches are required. The hypothalamus, a brain area responsible for energy homeostasis, has recently received special attention in this regard. Hypothalamic inflammation was identified to be associated with diet-induced obesity and new evidence suggests that it may be, beyond that, a pathological mechanism of the disease. This inflammation impairs the local signaling of insulin and leptin leading to dysfunction of the regulation of energy balance and thus, weight gain. After a high-fat diet consumption, activation of inflammatory mediators such as the nuclear factor κB or c-Jun N-terminal kinase pathway can be observed, accompanied by elevated secretion of pro-inflammatory interleukins and cytokines. Brain resident glia cells, especially microglia and astrocytes, initiate this release in response to the flux of fatty acids. The gliosis occurs rapidly before the actual weight gain. Dysregulated hypothalamic circuits change the interaction between neuronal and non-neuronal cells, contributing to the establishment of inflammatory processes. Several studies have reported reactive gliosis in obese humans. Although there is evidence for a causative role of hypothalamic inflammation in the obesity development, data on underlying molecular pathways in humans are limited. This review discusses the current state of knowledge on the relationship between hypothalamic inflammation and obesity in humans.

PUBMED (PMID: 36646062) - 2023 - Neuroendocrinology.

Autoren:
Seoudy, A. K., Schlicht, K., Kulle, A., Demetrowitsch, T., Beckmann, A., Geisler, C., Türk, K., Rohmann, N., Hartmann, K., Brandes, J., Schulte, D. M., Schreiber, S., Schwarz, K., Holterhus, P. M., Laudes, M.

Abstract:

Introduction: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response.

Methods: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 μg/L) and a pathological (11-deoxycortisol <70 μg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics.

Results: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 μg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%).

Conclusion: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

PUBMED (PMID: 36715653) - 2023 - J Clin Endocrinol Metab.

Autoren:
Hollstein, T., Piaggi, P.

Abstract:

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PUBMED (PMID: 37330047) - 2023 - Journal of Advanced Research

Autoren:
Rohmann, N., Stürmer, P., Geisler, C., Schlicht, K., Knappe, C., Hartmann, K., Türk, K., Hollstein, T., Beckmann, A., Seoudy, A. K., Becker, U., Wietzke-Braun, P., Settgast, U., Tran, F., Rosenstiel, P., Beckmann, J. H., von Schönfels, W., Seifert, S., Heyckendorf, J., Franke, A., Schreiber, S., Schulte, D. M., Laudes, M.

Abstract:

Introduction: Clara cell 16-kDa protein (CC16) is an anti-inflammatory, immunomodulatory secreted pulmonary protein with reduced serum concentrations in obesity according to recent data.

Objective: Studies focused solely on bodyweight, which does not properly reflect obesity-associated implications of the metabolic and reno-cardio-vascular system. The purpose of this study was therefore to examine CC16 in a broad physiological context considering cardio-metabolic comorbidities of primary pulmonary diseases.

Methods: CC16 was quantified in serum samples in a subset of the FoCus (N = 497) and two weight loss intervention cohorts (N = 99) using ELISA. Correlation and general linear regression analyses were applied to assess CC16 effects of lifestyle, gut microbiota, disease occurrence and treatment strategies. Importance and intercorrelation of determinants were validated using random forest algorithms.

Results: CC16 A38G gene mutation, smoking and low microbial diversity significantly decreased CC16. Pre-menopausal female displayed lower CC16 compared to post-menopausal female and male participants. Biological age and uricosuric medications increased CC16 (all p < 0.01). Adjusted linear regression revealed CC16 lowering effects of high waist-to-hip ratio (est. -11.19 [-19.4; -2.97], p = 7.99 × 10-3), severe obesity (est. -2.58 [-4.33; -0.82], p = 4.14 × 10-3) and hypertension (est. -4.31 [-7.5; -1.12], p = 8.48 × 10-3). ACEi/ARB medication (p = 2.5 × 10-2) and chronic heart failure (est. 4.69 [1.37; 8.02], p = 5.91 × 10-3) presented increasing effects on CC16. Mild associations of CC16 were observed with blood pressure, HOMA-IR and NT-proBNP, but not manifest hyperlipidemia, type 2 diabetes, diet quality and dietary weight loss intervention.

Conclusion: A role of metabolic and cardiovascular abnormalities in the regulation of CC16 and its modifiability by behavioral and pharmacological interventions is indicated. Alterations by ACEi/ARB and uricosurics could point towards regulatory axes comprising the renin-angiotensin-aldosterone system and purine metabolism. Findings altogether strengthen the importance of interactions among metabolism, heart and lungs.

PUBMED (PMID: 37364592) - 2023 - Exp Clin Endocrinol Diabetes

Autoren:
Reinke, L. M., Seoudy, A. K., Gärtner, F., Rohmann, N., Schulte, D. M., Schreiber, S., Jansen, O., & Laudes, M.

Abstract:

The syndrome of inappropriate ADH-secretion (SIADH) is a common cause of low sodium levels with diverse aetiology. Here, we report a case of a 41 years old male patient diagnosed with SIADH and a good response to Tolvaptan therapy. Of interest, as a potential unique cause, magnetic resonance imaging revealed a micronodular structure in the posterior pituitary, while no other common cause of SIADH could be identified. Hence, to the best of our knowledge, this is the first case of a Tolvaptan-responsive SIADH associated with a pituitary micronodular structure.

PUBMED (PMID: 37887323) - 2023 - Cells

Autoren:
Tölle, J., Koch, A., Schlicht, K., Finger, D., Kaehler, W., Höppner, M., Graetz, C., Dörfer, C., Schulte, D. M., & Fawzy El-Sayed, K.

Abstract:

The present study explores for the first time the effect of hyperbaric oxygen (HBO) on gingival mesenchymal stem cells' (G-MSCs) gene expression profile, intracellular pathway activation, pluripotency, and differentiation potential under an experimental inflammatory setup. G-MSCs were isolated from five healthy individuals (n = 5) and characterized. Single (24 h) or double (72 h) HBO stimulation (100% O2, 3 bar, 90 min) was performed under experimental inflammatory [IL-1β (1 ng/mL)/TNF-α (10 ng/mL)/IFN-γ (100 ng/mL)] and non-inflammatory micro-environment. Next Generation Sequencing and KEGG pathway enrichment analysis, G-MSCs' pluripotency gene expression, Wnt-/β-catenin pathway activation, proliferation, colony formation, and differentiation were investigated. G-MSCs demonstrated all mesenchymal stem/progenitor cells' characteristics. The beneficial effect of a single HBO stimulation was evident, with anti-inflammatory effects and induction of differentiation (TLL1, ID3, BHLHE40), proliferation/cell survival (BMF, ID3, TXNIP, PDK4, ABL2), migration (ABL2) and osteogenic differentiation (p < 0.05). A second HBO stimulation at 72 h had a detrimental effect, significantly increasing the inflammation-induced cellular stress and ROS accumulation through HMOX1, BHLHE40, and ARL4C amplification and pathway enrichment (p < 0.05). Results outline a positive short-term single HBO anti-inflammatory, regenerative, and differentiation stimulatory effect on G-MSCs. A second (72 h) stimulation is detrimental to the same properties. The current results could open new perspectives in the clinical application of short-termed HBO induction in G-MSCs-mediated periodontal reparative/regenerative mechanisms.

PUBMED (PMID: 36311771) - 2022 - Frontiers in Immunology.

Autoren:
Rohmann, N., Stürmer, P., Geisler, C., Schlicht, K., Hartmann, K., Türk, K., Hollstein, T., Tran, F., Rosenstiel, P., Franke, A., Heyckendorf, J., Schreiber, S., Schulte, D. M., Laudes, M.

Abstract:

Background: Clara cell 16 kDa protein (CC16) is a secretory protein primarily expressed in epithelial cells in the lungs. Previous studies show that CC16 exerts anti-inflammatory and immune-modulatory properties in both acute and chronic pulmonary diseases. However, despite the evidence of CC16's high biomarker potential, evaluation of its role in infectious diseases is yet very limited.

Methods: Serum CC16 concentrations were measured by ELISA and assessed in two different types of severe infections. Using a case-control study design, patients treated for either severe SARS-CoV-2 or severe non-pulmonary sepsis infection were compared to age- and sex-matched healthy human subjects.

Results: Serum CC16 was significantly increased in both types of infection (SARS-CoV-2: 96.22 ± 129.01 ng/ml vs. healthy controls: 14.05 ± 7.48 ng/ml, p = 0.022; sepsis: 35.37 ± 28.10 ng/ml vs. healthy controls: 15.25 ± 7.51 ng/ml, p = 0.032) but there were no distinct differences between infections with and without pulmonary focus (p = 0.089). Furthermore, CC16 serum levels were positively correlated to disease duration and inversely to the platelet count in severe SARS-CoV-2 infection.

Conclusions: Increased CC16 serum levels in both SARS-CoV-2 and sepsis reinforce the high potential as a biomarker for epithelial cell damage and bronchoalveolar-blood barrier leakage in pulmonary as well as non-pulmonary infectious diseases.

PUBMED (PMID: 36245062) - 2022 - Eur J Epidemiol.

Autoren:
Geisler, C., Schlicht, K., Knappe, C., Rohmann, N., Hartmann, K., Türk, K., Settgast, U., Schulte, D. M., Demetrowitsch, T., Jensen-Kroll, J., Pisarevskaja, A., Brix, F., Gruber, B., Rimbach, G., Döring, F., Rosenstiel, P., Franke, A., Schreiber, S., Henning, C., Lieb, W., Nöthlings, U., Schwarz, K., Laudes, M.

Abstract:

The Food Chain Plus (FoCus) cohort was launched in 2011 for population-based research related to metabolic inflammation. To characterize this novel pathology in a comprehensive manner, data collection included multiple omics layers such as phenomics, microbiomics, metabolomics, genomics, and metagenomics as well as nutrition profiling, taste perception phenotyping and social network analysis. The cohort was set-up to represent a Northern German population of the Kiel region. Two-step recruitment included the randomised enrolment of participants via residents' registration offices and via the Obesity Outpatient Centre of the University Medical Center Schleswig-Holstein (UKSH). Hence, both a population- and metabolic inflammation- based cohort was created. In total, 1795 individuals were analysed at baseline. Baseline data collection took place between 2011 and 2014, including 63% females and 37% males with an age range of 18-83 years. The median age of all participants was 52.0 years [IQR: 42.5; 63.0 years] and the median baseline BMI in the study population was 27.7 kg/m2 [IQR: 23.7; 35.9 kg/m2]. In the baseline cohort, 14.1% of participants had type 2 diabetes mellitus, which was more prevalent in the subjects of the metabolic inflammation group (MIG; 31.8%). Follow-up for the assessment of disease progression, as well as the onset of new diseases with changes in subject's phenotype, diet or lifestyle factors is planned every 5 years. The first follow-up period was finished in 2020 and included 820 subjects.

PUBMED (PMID: 36142858) - 2022 - International Journal of Molecular Science

Autoren:
Torres, G. G., Dose, J., Hasenbein, T. P., Nygaard, M., Krause-Kyora, B., Mengel-From, J., Christensen, K., Andersen-Ranberg, K., Kolbe, D., Lieb, W., Laudes, M., Görg, S., Schreiber, S., Franke, A., Caliebe, A., Kuhlenbäumer, G., Nebel, A.

Abstract:

Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer's disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson's disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10-35; AD = 0.59, p = 3.16 × 10-25; AF = 0.57, p = 1.07 × 10-16; CAD = 0.56, p = 1.88 × 10-12; CRC = 0.52, p = 5.85 × 10-3; PD = 0.52, p = 1.91 × 10-3; T2D = 0.51, p = 2.61 × 10-3). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10-15). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40/APOE/APOC1 gene region (AUC (incl. TOMM40/APOE/APOC1) = 0.56, p = 1.45 × 10-5, seven variants; AUC (excl. TOMM40/APOE/APOC1) = 0.55, p = 9.85 × 10-3, 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40/APOE/APOC1 as a longevity hub.

PUBMED (PMID: 36056109) - 2022 - Scientific Reports

Autoren:
Brandes, J., Zobel, I., Rohmann, N., Schlicht, K., Geisler, C., Hartmann, K., Türk, K., von Schönfels, W., Beckmann, J., Tran, F., Laudes, M.

Abstract:

Obesity and type 2 diabetes (T2D) show an increased risk for a severe COVID-19 disease. Treatment with DPP4 inhibitor (DPP4i) results in reduced mortality and better clinical outcome. Here, we aimed to identify potential mechanisms for the observed DPP4i effect in COVID-19. Comparing T2D subjects with and without DPP4i treatment, we identified a significant increase of the anti-inflammatory adipokine sFRP5 in relation to DPP4 inhibition. sFRP5 is a specific antagonist to Wnt5a, a glycopeptide secreted by adipose tissue macrophages acting pro-inflammatory in various diseases. We therefore examined sFRP5 levels in patients hospitalised for severe COVID-19 and found significant lower levels compared to healthy controls. Since sFRP5 might consequently be a molecular link for the beneficial effects of DPP4i in COVID-19, we further aimed to identify the exact source of sFRP5 in adipose tissue on cellular level. We therefore isolated pre-adipocytes, mature adipocytes and macrophages from adipose tissue biopsies and performed western-blotting. Results showed a sFRP5 expression specifically in mature adipocytes of subcutaneous and omental adipose tissue. In summary, our data suggest that DPP4i increase serum levels of anti-inflammatory sFRP5 which might be beneficial in COVID-19, reflecting a state of sFRP5 deficiency.

PUBMED (PMID: 36038634) - 2022 - Nature Genetics

Autoren:
Sazonovs, A., Stevens, C. R., Venkataraman, G. R., Yuan, K., Avila, B., Abreu, M. T., Ahmad, T., Allez, M., Ananthakrishnan, A. N., Atzmon, G., Baras, A., Barrett, J. C., Barzilai, N., Beaugerie, L., Beecham, A., Bernstein, C. N., Bitton, A., Bokemeyer, B., Chan, A., Chung, D., …, Laudes, M., …, Daly, M. J.

Abstract:

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

PUBMED (PMID: 35754497) - 2022 - Frontiers in Pharmacology

Autoren:
Schulte, D. M., Waetzig, G. H., Schuett, H., Marx, M., Schulte, B., Garbers, C., Lokau, J., Vlacil, A. K., Schulz, J., Seoudy, A. K., Schieffer, B., Rosenstiel, P., Seeger, M., Laudes, M., Rose-John, S., Lützen, U., Grote, K., Schreiber, S.

Abstract:

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr -/-) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr -/- mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.

PUBMED (PMID: 35684151) - 2022 - Nutrients

Autoren:
Rohmann, N., Munthe, L., Schlicht, K., Geisler, C., Demetrowitsch, T. J., Bang, C., Jensen-Kroll, J., Türk, K., Bacher, P., Franke, A., Schwarz, K., Schulte, D. M., Laudes, M.

Abstract:

Background: Alongside metabolic diseases (esp. obesity), allergic disorders are becoming increasingly prevalent. Since both obesity and allergies are highly impacted by environmental determinants, with this study we assessed the potential link between metabolic implications and two distinct types of allergies.

Methods: Using cross-sectional data from the German FoCus cohort, n = 385 allergy cases, either hay fever (=type I allergy, n = 183) or contact allergy (=type IV allergy, n = 202) were compared to age- and sex-matched healthy control subjects (1:1 ratio, in total n = 770) regarding their metabolic phenotype, diet, physical activity, sleep, gut microbial composition, and serum metabolite profile using suitable BMI-adjusted models.

Results: Obesity and metabolic alterations were found significantly more prevalent in subjects with allergies. In fact, this relation was more pronounced in contact allergy than hay fever. Subsequent BMI-adjusted analysis reveals particular importance of co-occurring hyperlipidaemia for both allergy types. For contact allergy, we revealed a strong association to the dietary intake of poly-unsaturated fatty acids, particularly α-linolenic acid, as well as the enrichment of the corresponding metabolic pathway. For hay fever, there were no major associations to the diet but to a lower physical activity level, shorter duration of sleep, and an altered gut microbial composition. Finally, genetic predisposition for hyperlipidaemia was associated to both contact allergy and hay fever.

Conclusions: Reflected by higher allergy prevalence, our findings indicate an impaired immune response in obesity and hyperlipidaemia, which is differentially regulated in type I and type IV allergies by an unfavourable lifestyle constellation and subsequent microbial and metabolic dysfunctions.

PUBMED (PMID: 35565905) - 2022 - Nutrients

Autoren:
Mewes, L., Knappe, C., Graetz, C., Wagner, J., Demetrowitsch, T. J., Jensen-Kroll, J., Mohamed Fawzy El-Sayed, K., Schwarz, K., Dörfer, C. E., Schreiber, S., Laudes, M., & Schulte, D. M.

Abstract:

Vitamins and omega-3 fatty acids (Ω3FA) modulate periodontitis-associated inflammatory processes. The aim of the current investigation was to evaluate associations of oral nutrient intake and corresponding serum metabolites with clinical severity of human periodontitis. Within the Food Chain Plus cohort, 373 periodontitis patients-245 without (POL) and 128 with tooth loss (PWL)-were matched to 373 controls based on sex, smoking habit, age and body mass index in a nested case-control design. The amount of oral intake of vitamins and Ω3FAs was assessed from nutritional data using a Food Frequency Questionnaire. Oral intake and circulatory bioavailability of vitamins and Ω3FA serum metabolomics were compared, using ultra-high-resolution mass spectrometry. Periodontitis patients exhibited a significantly higher oral intake of vitamin C and Ω3FA Docosapentaenoic acid (p < 0.05) compared to controls. Nutritional intake of vitamin C was higher in PWL, while the intake of Docosapentaenoic acid was increased in POL (p < 0.05) compared to controls. In accordance, serum levels of Docosapentaenoic acid were also increased in POL (p < 0.01) compared to controls. Vitamin C and the Ω3FA Docosapentaenoic acid might play a role in the pathophysiology of human periodontitis. Further studies on individualized nutritional intake and periodontitis progression and therapy are necessary.

PUBMED (PMID: 35565847) - 2022 - Nutrients

Autoren:
Agamennone, V., Abuja, P. M., Basic, M., De Angelis, M., Gessner, A., Keijser, B., Larsen, M., Pinart, M., Nimptsch, K., Pujos-Guillot, E., Schlicht, K., Sharon, I., Untersmayr, E., Laudes, M., Pischon, T., Bouwman, J., & On Behalf Of The Consortium

Abstract:

Studies indicate that the intestinal microbiota influences general metabolic processes in humans, thereby modulating the risk of chronic diseases such as type 2 diabetes, allergy, cardiovascular disease, and colorectal cancer (CRC). Dietary factors are also directly related to chronic disease risk, and they affect the composition and function of the gut microbiota. Still, detailed knowledge on the relation between diet, the microbiota, and chronic disease risk is limited. The overarching aim of the HDHL-INTIMIC (INtesTInal MICrobiomics) knowledge platform is to foster studies on the microbiota, nutrition, and health by assembling available knowledge of the microbiota and of the other aspects (e.g., food science and metabolomics) that are relevant in the context of microbiome research. The goal is to make this information findable, accessible, interoperable, and reusable (FAIR) to the scientific community, and to share information with the various stakeholders. Through these efforts a network of transnational and multidisciplinary collaboration has emerged, which has contributed to further develop and increase the impact of microbiome research in human health. The roles of microbiota in early infancy, during ageing, and in subclinical and clinically manifested disease are identified as urgent areas of research in this knowledge platform.

PUBMED (PMID: 35435797) - 2022 - Gut Microbes

Autoren:
Henneke, L., Schlicht, K., Andreani, N.A., Hollstein, T., Demetrowitsch, T., Knappe, C., Hartmann, K., Jensen-Kroll, J., Rohmann, N., Pohlschneider, D., Geisler, C., Schulte, D.M., Settgast, U., Türk, K., Zimmermann, J., Kaleta, C., Baines, J.F., Shearer, J., Shah, S., Shen-Tu, G., Schwarz, K., Franke, A., Schreiber, S., Laudes, M.

Abstract:

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/β diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development.

PUBMED (PMID: 34943818) - 2021 - Cells

Autoren:
Fawzy El-Sayed, K. M., Bittner, A., Schlicht, K., Mekhemar, M., Enthammer, K., Höppner, M., Es-Souni, M., Schulz, J., Laudes, M., Graetz, C., Dörfer, C. E., Schulte, D. M.

Abstract:

The present study explored the effects of ascorbic-acid (AA)/retinol and timed inflammation on the stemness, the regenerative potential, and the transcriptomics profile of gingival mesenchymal stem/progenitor cells' (G-MSCs). STRO-1 (mesenchymal stem cell marker) immuno-magnetically sorted G-MSCs were cultured in basic medium (control group), in basic medium with IL-1β (1 ng/mL), TNF-α (10 ng/mL) and IFN-γ (100 ng/mL, inflammatory-medium), in basic medium with AA (250 µmol/L) and retinol (20 µmol/L) (AA/retinol group) or in inflammatory medium with AA/retinol (inflammatory/AA/retinol group; n = 5/group). The intracellular levels of phosphorylated and total β-Catenin at 1 h, the expression of stemness genes over 7 days, the number of colony-forming units (CFUs) as well as the cellular proliferation aptitude over 14 days, and the G-MSCs' multilineage differentiation potential were assessed. Next-generation sequencing was undertaken to elaborate on up-/downregulated genes and altered intracellular pathways. G-MSCs demonstrated all mesenchymal stem/progenitor cells characteristics. Controlled inflammation with AA/retinol significantly elevated NANOG (p < 0.05). The AA/retinol-mediated reduction in intracellular phosphorylated β-Catenin was restored through the effect of controlled inflammation (p < 0.05). Cellular proliferation was highest in the AA/retinol group (p < 0.05). AA/retinol counteracted the inflammation-mediated reduction in G-MSCs' clonogenic ability and CFUs. Amplified chondrogenic differentiation was observed in the inflammatory/AA/retinol group. At 1 and 3 days, the differentially expressed genes were associated with development, proliferation, and migration (FOS, EGR1, SGK1, CXCL5, SIPA1L2, TFPI2, KRATP1-5), survival (EGR1, SGK1, TMEM132A), differentiation and mineral absorption (FOS, EGR1, MT1E, KRTAP1-5, ASNS, PSAT1), inflammation and MHC-II antigen processing (PER1, CTSS, CD74) and intracellular pathway activation (FKBP5, ZNF404). Less as well as more genes were activated the longer the G-MSCs remained in the inflammatory medium or AA/retinol, respectively. Combined, current results point at possibly interesting interactions between controlled inflammation or AA/retinol affecting stemness, proliferation, and differentiation attributes of G-MSCs.

PUBMED (PMID: 34836121) - 2021 - Nutrients

Autoren:
Laudes, M., Geisler, C., Rohmann, N., Bouwman, J., Pischon, T., Schlicht, K.

Abstract:

Within the last two decades tremendous efforts in biomedicine have been undertaken to understand the interplay of commensal bacteria living in and on our human body with our own human physiology. It became clear that (1) a high diversity especially of the microbial communities in the gut are important to preserve health and that (2) certain bacteria via nutrition-microbe-host metabolic axes are beneficially affecting various functions of the host, including metabolic control, energy balance and immune function. While a large set of evidence indicate a special role for small chain fatty acids (SCFA) in that context, recently also metabolites of amino acids (e.g., tryptophan and arginine) moved into scientific attention. Of interest, microbiome alterations are not only important in nutrition associated diseases like obesity and diabetes, but also in many chronic inflammatory, oncological and neurological abnormalities. From a clinician's point of view, it should be mentioned, that the microbiome is not only interesting to develop novel therapies, but also as a modifiable factor to improve efficiency of modern pharmaceutics, e.g., immune-therapeutics in oncology. However, so far, most data rely on animal experiments or human association studies, whereas controlled clinical intervention studies are spare. Hence, the translation of the knowledge of the last decades into clinical routine will be the challenge of microbiome based biomedical research for the next years. This review aims to provide examples for future clinical applications in various entities and to suggest bacterial species and/or microbial effector molecules as potential targets for intervention studies.

PUBMED (PMID: 34835999) - 2021 - Nutrients

Autoren:
Geisler, C., Pankoke, J., Schlicht, K., Knappe, C., Rohmann, N., Hartmann, K., Settgast, U., Türk, K., Seoudy, A. K., Franke, A., Schreiber, S., Schulte, D. M., Laudes, M.

Abstract:

Background: The incidence of neurological diseases is increasing throughout the world. The aim of the present study was to identify nutrition and microbiome factors related to structural and functional neurological abnormalities to optimize future preventive strategies.

Methods: Two hundred thirty-eight patients suffering from (1) structural (neurodegeneration) or (2) functional (epilepsy) neurological abnormalities or (3) chronic pain (migraine) and 612 healthy control subjects were analyzed by validated 12-month food frequency questionnaire (FFQ) and 16S rRNA microbiome sequencing (from stool samples). A binomial logistic regression model was applied for risk calculation and functional pathway analysis to show which functional pathway could discriminate cases and healthy controls.

Results: Detailed analysis of more than 60 macro- and micronutrients revealed no distinct significant difference between cases and controls, whereas BMI, insulin resistance and metabolic inflammation in addition to alcohol consumption were major drivers of an overall neurological disease risk. The gut microbiome analysis showed decreased alpha diversity (Shannon index: p = 9.1× 10-7) and species richness (p = 1.2 × 10-8) in the case group as well as significant differences in beta diversity between cases and controls (Bray-Curtis: p = 9.99 × 10-4; Jaccard: p = 9.99 × 10-4). The Shannon index showed a beneficial effect (OR = 0.59 (95%-CI (0.40, 0.87); p = 8 × 10-3). Cases were clearly discriminated from healthy controls by environmental information processing, signal transduction, two component system and membrane transport as significantly different functional pathways.

Conclusions: In conclusion, our data indicate that an overall healthy lifestyle, in contrast to supplementation of single micro- or macronutrients, is most likely to reduce overall neurological abnormality risk and that the gut microbiome is an interesting target to develop novel preventive strategies.

PUBMED (PMID: 34515658) - 2021 - Endocrinol Diabetes Metab Case Rep.

Autoren:
Melzer, F., Geisler, C., Schulte, D. M., Laudes, M.

Abstract:

Summary: Familial partial lipodystrophy (FPLD) syndromes are rare heterogeneous disorders especially in women characterized by selective loss of adipose tissue, reduced leptin levels and severe metabolic abnormalities. Here we report a 34-year-old female with a novel heterozygotic c.485 thymine>guanine (T>G) missense variant (p.phenylalanine162cysteine; (Phe162Cys)) in exon 4 of the peroxisome proliferator-activated receptor gamma (PPARG) gene, developing a non-ketotic diabetes and severe hypertriglyceridemia with triglyceride concentrations >50 mmol/L. In this case, a particular interesting feature in comparison to other known PPARG mutations in FPLD is that while glycaemic control could be achieved through standard anti-diabetic medication, hypertriglyceridemia did neither respond to fibrate nor to omega-3-fatty acid therapy. This might suggest a lipid metabolism driven phenotype of the novel PPARG c.485T>G missense variant. Notably, recombinant leptin replacement therapy (metreleptin (Myalepta®)) was initiated showing a rapid and profound effect on triglyceride levels as well as on liver function tests and satiety feeling. Unfortunately, severe allergic skin reactions developed at the side of injection which could be covered by anti-histaminc treatment. We conclude that the heterozygous PPARG c.485T>G variant is a yet undescribed molecular basis underlying FPLD with difficulties predominantly to control hypertriglyceridemia and that recombinant leptin therapy may be effective in affected subjects.

Learning points: Heterozygous c.485T>G variant in PPARG is most likely a cause for FPLD in humans. This variant results in a special metabolic phenotype with a predominant dysregulation of triglyceride metabolism not responding to standard lipid lowering therapy. Recombinant leptin therapy is effective in rapidly improving hypertriglyceridemia.

PUBMED (PMID: 33980890) - 2021 - Scientific Reports

Autoren:
Hollstein, T., Schlicht, K., Krause, L., Hagen, S., Rohmann, N., Schulte, D. M., Türk, K., Beckmann, A., Ahrens, M., Franke, A., Schreiber, S., Becker, T., Beckmann, J., Laudes, M.

Abstract:

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

PUBMED (PMID: 33531116) - 2021 - Deutsches Ärzteblatt int.

Autoren:
Seoudy, A. K., Schulte, D. M., Hollstein, T., Böhm, R., Cascorbi, I., Laudes, M.

Abstract:

Background: Gliflozins are effective drugs for the treatment of type 2 diabetes. They inhibit sodium glucose cotransporter 2 in the proximal renal tubule, leading to increased glucose excretion. On the basis of findings from relevant studies, gliflozins are also increasingly used in clinical practice to treat congestive heart failure and renal failure.

Methods: This review is based on pertinent publications retrieved from a selective literature search in PubMed and GoogleScholar.

Results: Cardiovascular safety studies revealed early on that gliflozins can lower the hospitalization rate of patients suffering from congestive heart failure with a reduced leftventricular ejection fraction (HFrEF). They also showed favorable effects on multiple renal endpoints. In recent years, studies such as DAPA-HF and CREDENCE have further documented the benefit of gliflozins in the treatment of congestive heart failure and renal failure in patients with type 2 diabetes, and gliflozins have accordingly been incorporated into the pertinent guidelines. In the recently published EMPEROR-Reduced trial, empagliflozin was found to significantly lower the frequency of a combined cardiovascular endpoint in patients with HFrEF (19.4 % versus 24.7%; hazard ratio [HR] 0.75; 95% confidence interval [0.65; 0.86]; number needed to treat [NNT] 19, p <0.001). In the DAPA-CKD trial, which was also recently published, dapagliflozin was found to significantly lower the frequency of a combined renal endpoint (9.2% versus 14.5%; HR 0.61 [0.51; 0.72]; NNT 19; p <0.001).

Conclusion: On the basis of findings from specific studies, gliflozins will henceforth be a major class of drug for the treatment of HFrEF and renal failure, independently of the presence of type 2 diabetes.

PUBMED (PMID: 33462485) - 2021 - Nature Genetics

Autoren:
Kurilshikov, A., Medina-Gomez, C., Bacigalupe, R., Radjabzadeh, D., Wang, J., Demirkan, A., Le Roy, C. I., Raygoza Garay, J. A., Finnicum, C. T., Liu, X., Zhernakova, D. V., Bonder, M. J., Hansen, T. H., Frost, F., Rühlemann, M. C., Turpin, W., Moon, J. Y., Kim, H. N., Lüll, K., Barkan, E., … Laudes, M., …, Zhernakova, A.

Abstract:

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

PUBMED (PMID: 33462482) - 2021 - Nature Genetics

Autoren:
Rühlemann, M. C., Hermes, B. M., Bang, C., Doms, S., Moitinho-Silva, L., Thingholm, L. B., Frost, F., Degenhardt, F., Wittig, M., Kässens, J., Weiss, F. U., Peters, A., Neuhaus, K., Völker, U., Völzke, H., Homuth, G., Weiss, S., Grallert, H., Laudes, M., Lieb, W., … Franke, A.

Abstract:

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory1,2, neurologic3 and neoplastic diseases4. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain5-11. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition11. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.

PUBMED (PMID: 32600859) - 2021 - Clinical Nutrition

Autoren:
Fangmann, D., Geisler, C., Schlicht, K., Hartmann, K., Köpke, J., Tiede, A., Settgast, U., Türk, K., Schulte, D.M., Altmann, K., Clawin-Rädecker, I., Lorenzen, P.C., Schreiber, S., Schwarz, K., Laudes, M.

Abstract:

Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies.

PUBMED (PMID: 33084870) - 2021 - J Clin Endocrinol Metab

Autoren:
Rohmann, N., Schlicht, K., Geisler, C., Hollstein, T., Knappe, C., Krause, L., Hagen, S., Beckmann, A., Seoudy, A. K., Wietzke-Braun, P., Hartmann, K., Schulte, D., Türk, K., Beckmann, J., von Schönfels, W., Hägele, F. A., Bosy-Westphal, A., Franke, A., Schreiber, S., Laudes, M.

Abstract:

Context: Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings.

Objectives: We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases.

Design: sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis.

Results: sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight.

Conclusions: Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.

PUBMED (PMID: 32958905) - 2020 - Int J Obes

Autoren:
Schlicht, K., Rohmann, N., Geisler, C., Hollstein, T., Knappe, C., Hartmann, K., Schwarz, J., Tran, F., Schunk, D., Junker, R., Bahmer, T., Rosenstiel, P., Schulte, D., Türk, K., Franke, A., Schreiber, S., Laudes, M.

Abstract:

Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. For several years DPP-4 inhibitors in addition to GLP-1 analogues are of major importance in the clinical management of obesity and type 2 diabetes. DPP-4 is also known as CD26 and represents a membrane bound protease on the surface of several eukaryotic cell types. Of interest, DPP-4, like ACE2, has been shown to serve as a binding partner for corona-like viruses to enter host immune cells. Since metabolic diseases are major risk factors for the present COVID-19 pandemic, we examined circulating soluble DPP-4 serum concentrations in patients suffering from severe COVID-19 infection and in healthy human subjects in a case control design. In this analysis sDPP-4 levels were significantly lower in COVID-19 patients compared to controls (242.70 ± 202.12 ng/mL versus 497.70 ± 188.13 ng/mL, p = 0.02). We also examined sDPP-4 serum concentrations in patients suffering from sepsis not due to corona-like viruses. In these subjects, sDPP-4 levels were not different compared to healthy case controls (p = 0.14), which might suggest the decrease of sDPP-4 to be specific for corona-like virus infections. Currently, most data point towards membrane bound ACE2 in contrast to DPP-4 as the major binding partner for COVID-19 internalization into host immune cells. However, the finding that the circulating soluble form of DPP-4 is reduced in hospitalized patients might suggest a regulatory role for both, ACE and DPP-4, in COVID-19 infections, especially since obesity and type 2 diabetes are major risk factor for a severe course of the disease.

PUBMED (PMID: 32879473) - 2020 - Nature Metabolism

Autoren:
Hollstein T, Schulte DM, Schulz J, Glück A, Ziegler AG, Bonifacio E, Wendorff M, Franke A, Schreiber S, Bornstein SR, Laudes M.

Abstract:

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l-1, blood glucose concentration of 30.6 mmol l-1 (552 mg dl-1) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic β-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on β-cells.

PUBMED (PMID: 32197072) - 2020 - Cell Metabolism

Autoren:
van Dam, E., van Leeuwen, L.A.G., Dos Santos, E., James, J., Best, L., Lennicke, C., Vincent, A.J., Marinos, G., Foley, A., Buricova, M., Mokochinski, J.B., Kramer, H.B., Lieb, W., Laudes, M., Franke, A., Kaleta, C., Cochemé, H.M.

Abstract:

High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.

PUBMED (PMID: 31411693) - 2019 - Journal of Clinical Endocrinology and Metabolism

Autoren:
van Dam, E., van Leeuwen, L.A.G., Dos Santos, E., James, J., Best, L., Lennicke, C., Vincent, A.J., Marinos, G., Foley, A., Buricova, M., Mokochinski, J.B., Kramer, H.B., Lieb, W., Laudes, M., Franke, A., Kaleta, C., Cochemé, H.M.

Abstract:

Context: Immunoassay interference has been most often found with prolactin measurement. However, only few data exist on immunoassay interference for other hormones.

Case description: A 36-year-old woman with obesity (body mass index, 31 kg/m2) had regularly attended our endocrine unit for type 2 diabetes therapy. When she was included as a control subject in a study for obesity management, detailed laboratory testing was performed, including PTH. In the absence of clinical symptoms, she presented with normal calcium, phosphate, and vitamin D levels. However, the PTH levels were >5000 ng/L. These results were obtained using the Roche Elecsys electrochemiluminescence assay. Repeated measurements with this assay (mouse antibody) led to the same findings. However, using an Euroimmun assay (goat antibody), the exact PTH values were measured at 18.0 ng/L. After pretreatment with a heterophilic antibody blocking reagent, the results of the Roche assay had decreased to a normal level. This phenomenon was explained by the detection of human anti-mouse antibodies in the proband's serum.

Conclusions: In cases of prolactin immunoassay interference, endogenous antibodies will bind to the hormone in vivo, resulting in complexes of a high molecular weight that are less efficiently cleared by the kidneys and, thus, accumulate in the blood. In contrast, the PTH values >5000 ng/L detected in our subject most likely had resulted from the specific interference of the human anti-mouse antibodies present in the proband's serum with the assay antibody, resulting in artificial stimulation of the Roche assay detection system ex vivo.

PUBMED (PMID: 31474368) - 2019 - Cell

Autoren:
Pryor, R., Norvaisas, P., Marinos, G., Best, L., Thingholm, L. B., Quintaneiro, L., De Haes, W., Esser, D., Waschina, S., Lujan, C., Smith, R. L., Scott, T., Martinez-Martinez, D., Woodward, O., Bryson, K., Laudes, M., Lieb, W., Houtkooper, R. H., Franke, A., Temmerman, L., Bjedov, I., Cochemé, H. M., Kaleta, C., Cabreiro, F.

Abstract:

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies.

PUBMED (PMID: 31399369) - 2019 - Cell Host Microbe

Autoren:
Thingholm, L. B., Rühlemann, M. C., Koch, M., Fuqua, B., Laucke, G., Boehm, R., Bang, C., Franzosa, E. A., Hübenthal, M., Rahnavard, A., Frost, F., Lloyd-Price, J., Schirmer, M., Lusis, A.J., Vulpe, C.D., Lerch, M. M., Homuth, G., Kacprowski, T., Schmidt, C.O., Nöthlings, U., Karlsen, T.H., Lieb, W., Laudes, M., Franke, A., Huttenhower, C.

Abstract:

Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies.

PUBMED (PMID: 30137542) - 2018 - Journal of Clinical Endocrinology and Metabolism

Autoren:
Relling, I., Akcay, G., Fangmann, D., Knappe, C., Schulte, D.M., Hartmann, K., Müller, N., Türk, K., Dempfle, A., Franke, A., Schreiber, S., Laudes, M.

Abstract:

Context: Common nutrition-associated diseases like obesity and type 2 diabetes are linked to chronic low-grade inflammation. The secreted glycopeptide wingless-type mouse mammary tumor virus integration site family member 5a (wnt5a) has been implicated in metabolic inflammation in rodent models, suggesting a potential treatment target. Data on the role of wnt5a in human physiology have yielded conflicting results.

Objective: Serum concentrations of wnt5a were measured in a cross-sectional cohort of 896 people to gain deeper insights into wnt5a physiology.

Design: Serum concentrations of wnt5a were measured by ELISA and related to several phenotyping and genotyping data. In vitro experiments were performed in THP-1 macrophages to examine potential molecular mechanisms.

Results: Wnt5a levels were significantly positively correlated to IL-6 and triglyceride levels. In subjects with diabetes, wnt5a levels were elevated and significantly correlated with fasting plasma glucose concentrations. Although wnt5a levels were not influenced by common single-nucleotide polymorphisms in the human wnt5a gene, environmental factors significantly altered wnt5a concentrations, as follows: (1) wnt5a levels were reduced in subjects with high nutritional load of the long-chain eicosatetraenoic acid independent of the total caloric intake and overall composition of the macronutrients, and (2) wnt5a levels were lower in humans with a high gut microbiome α diversity. In vitro experiments revealed that stimulation of the IL-6 receptor or the long-chain fatty acid receptor GPR40 directly affected wnt5a expression in human macrophages.

Conclusion: Our data suggest that wnt5a is important in linking inflammation to metabolism. The nutrition and the microbiome might be interesting targets to prevent and/or treat wnt5a-mediated metabolic inflammation.

PUBMED (PMID: 29212824) - 2018 - Diabetes Care

Autoren:
Fangmann, D., Theismann, E.M., Türk, K., Schulte, D.M., Relling, I., Hartmann, K., Keppler, J.K., Knipp, J.R., Rehman, A., Heinsen, F.A., Franke, A., Lenk, L., Freitag-Wolf, S., Appel, E., Gorb, S., Brenner, C., Seegert, D., Waetzig, G.H., Rosenstiel, P., Schreiber, S., Schwarz, K., Laudes, M.

Abstract:

Objective: Gut microbiota represent a potential novel target for future prediabetes and type 2 diabetes therapies. In that respect, niacin has been shown to beneficially affect the host-microbiome interaction in rodent models.

Research design and methods: We characterized more than 500 human subjects with different metabolic phenotypes regarding their niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and their gut microbiome. In addition, NA and NAM delayed-release microcapsules were engineered and examined in vitro and in vivo in two human intervention studies (bioavailability study and proof-of-concept/safety study).

Results: We found a reduced α-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.

Conclusion: Targeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes.

PUBMED (PMID: 28576837) - 2017 - Diabetes

Autoren:
Kreutzer, C., Peters, S., Schulte, D.M., Fangmann, D., Türk, K., Wolf, S., van Eimeren, T., Ahrens, M., Beckmann, J., Schafmeyer, C., Kerby, T., Rohr, A., Riedel, C., Heinsen, F.A., Degenhardt, F., Franke, A., Rosenstiel, P., Henning, C., Freitag-Wolf, S., Dempfle, A., Jansen, O., Schreiber, S., Laudes, M.

Abstract:

Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors.

PUBMED (PMID: 27723756) - 2016 - Nature Genetics

Autoren:
Wang, J., Thingholm, L. B., Skiecevičienė, J., Rausch, P., Kummen, M., Hov, J. R., Degenhardt, F., Heinsen, F. A., Rühlemann, M. C. , Szymczak, S. , Holm, K., Esko, T. , Sun, J. , Pricop-Jeckstadt, M. , Al-Dury, S. , Bohov, P. , Bethune, J., Sommer, F., Ellinghaus, D., Berge, R. K. , Hübenthal, M. , Koch, M. , Schwarz, K., Rimbach, G., Hüppe, P., Pan, W. H., Sheibani-Tezerji, R., Häsler, R., Rosenstiel, P., D’Amato, M., Cloppenborg-Schmidt, K., Künzel, S. , Laudes, M., Marschall, H. U. , Lieb, W. , Nöthlings, U. , Karlsen, T. H. , Baines, J. F., Franke., A.

Abstract:

Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.

PUBMED (PMID: 25713100) - 2015 - Journal of Lipid Research

Autoren:
Müller, N., Schulte, D.M., Türk, K., Freitag-Wolf, S., Hampe, J., Rose-John, S., Zeuner, R., Schröder, J. O., Gouni-Berthold, I., Berthold, H., Krone, W., Schreiber, S., Laudes, M.

Abstract:

Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at -46 to -40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.

PUBMED (PMID: 20032469) - 2010 - Journal of Biological Chemistry

Autoren:
Bilkovski, R., Oberhauser, F., Droste, A., Schulte, D. M., Gomolka, M., Udelhoven M., Hettich M., Roth, B., Heidenreich, A., Gutschow, C., Krone, W., Laudes, M.

Abstract:

Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.

PUBMED (PMID: 14988272) - 2004 - Diabetes

Autoren:
Laudes, M., Barroso, I., Luan, J., Soos, M.A., Yeo, G., Meirhaeghe, A., Logie, L., Vidal-Puig, A., Schafer, A., Wareham, N.J., O´Rahilly.

Abstract:

The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to transactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio = 1.42 [1.11–1.82], P = 0.005) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly higher levels of total and LDL cholesterol (P < 0.05) compared with wild-type individuals. In summary, we have conducted the first study of the SREBP-1c gene as a candidate for human insulin resistance. Although the rare mutations identified were functionally silent in the assays used, we obtained some evidence, which requires conformation in other populations, that a common variant in the SREBP-1c gene might influence diabetes risk and plasma cholesterol level.