Metabolic and lifestyle factors accelerate disease onset and alter gut microbiome in inflammatory non-communicable diseases.

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.

MRI signs of intracranial hypertension in morbidly obese and normal-weight individuals.

PURPOSE: Idiopathic intracranial hypertension (IIH) is associated with intracranial abnormalities, although not obligatory, which can be detected with cranial MRI. Obesity is an important risk factor for IIH and a pathogenetic link is suspected but the extent to which these MRI signs are already related to obesity has not yet been examined. We investigated whether IIH-MRI signs are present more often in obese individuals with a BMI > 30 kg/m² than in individuals of normal weight. MATERIALS AND METHODS: Brain MRI of 32 obese and 53 normal-weight participants from the Food-Chain-Plus cohort were analyzed for three main signs of IIH: (I) stenosis of the transverse sinus, (II) increased width of the optic nerve sheath, and (III) reduction of pituitary height. In addition, a scoring system for the MRI signs was applied. Furthermore, tortuosity of the optic nerve and flattening of the posterior globe were considered as additional MRI signs. RESULTS: Obese participants had a significantly higher MRI score (p < 0.001) than those in the normal-weight cohort, with significant differences in quantitative measurements of cerebral venous sinus stenosis (p < 0.001), widening of the optic nerve sheath (p < 0.05), and flattening of the pituitary gland (p < 0.05) also always being observed more frequently and in a more pronounced manner in the obese group. Furthermore, our findings correlated significantly with BMI and proportionately with hip and waist circumference. CONCLUSION: Obese individuals show a significantly higher prevalence of cerebral MRI signs related to IIH. This supports the hypothesis that obesity is a risk factor for possible intracranial hypertension and reinforces the suspicion that obesity is involved in the pathomechanism of IIH. KEY POINTS: · Obesity is associated with changes such as those seen in IIH.. · BMI, weight, and body measurements correlate with the expression of MRI signs of IIH.. · To prevent IIH symptoms in obesity, the pathomechanism must be further clarified..

Effects of lifestyle and associated diseases on serum CC16 suggest complex interactions among metabolism, heart and lungs.

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.

Differential Diagnosis in Hypophysitis: First Report on a Spindle Cell Rhabdomyosarcoma of the Pituitary Gland.

Pituitary gland metastases are very rare. Most patients with pituitary gland metastases are asymptomatic; therefore, most cases of this disease are diagnosed during autopsies. Moreover, the four most common primary tumors that metastasize to the pituitary gland are breast, lung, thyroid, and renal carcinomas. We present a very rare case of pituitary metastasis of spindle cell rhabdomyosarcoma (RMS). Our patient presented with headache, visual disorder, panhypopituitarism, and diabetes insipidus. Due to tumor expansion, resection was not possible, so diagnosis was confirmed by biopsy, and chemotherapy and irradiation were administered. Our patient showed widespread spindle cell RMS, which harbors a mutation of myogenic differentiation 1 (MYOD1) and is associated with a poor prognosis. Even high-risk patients can show a remission after chemotherapy and irradiation. In the cases with indistinct lesions in the sella region, pituitary metastasis should always be considered.

Brief Research Report: Serum clara cell 16 kDa protein levels are increased in patients hospitalized for severe SARS-CoV-2 or sepsis infection.

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.

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score.

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.

HDHL-INTIMIC: A European Knowledge Platform on Food, Diet, Intestinal Microbiomics, and Human Health.

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.

Vitamin C and Omega-3 Fatty Acid Intake Is Associated with Human Periodontitis-A Nested Case-Control Study.

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 patients­245 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.

A dietary carbohydrate - gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes.

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/ß 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.

Ascorbic Acid/Retinol and/or Inflammatory Stimuli's Effect on Proliferation/Differentiation Properties and Transcriptomics of Gingival Stem/Progenitor Cells.

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-1ß (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 ß-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 ß-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.

Microbiota in Health and Disease-Potential Clinical Applications.

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.

Rapid response to leptin therapy in a FPLD patient with a novel PPARG missense variant.

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.

Effect of various weight loss interventions on serum NT-proBNP concentration in severe obese subjects without clinical manifest heart failure.

Obesity is associated with a "natriuretic handicap" indicated by reduced N-terminal fragment of proBNP (NT-proBNP) concentration. While gastric bypass surgery improves the natriuretic handicap, it is presently unclear if sleeve gastrectomy exhibits similar effects. We examined NT-proBNP serum concentration in n = 72 obese participants without heart failure before and 6 months after sleeve gastrectomy (n = 28), gastric bypass surgery (n = 19), and 3-month 800 kcal/day very-low calorie diet (n = 25). A significant weight loss was observed in all intervention groups. Within 6 months, NT-proBNP concentration tended to increase by a median of 44.3 pg/mL in the sleeve gastrectomy group (p = 0.07), while it remained unchanged in the other groups (all p ≥ 0.50). To gain insights into potential effectors, we additionally analyzed NT-proBNP serum concentration in n = 387 individuals with different metabolic phenotypes. Here, higher NT-proBNP levels were associated with lower nutritional fat and protein but not with carbohydrate intake. Of interest, NT-proBNP serum concentrations were inversely correlated with fasting glucose concentration in euglycemic individuals but not in individuals with prediabetes or type 2 diabetes. In conclusion, sleeve gastrectomy tended to increase NT-proBNP levels in obese individuals and might improve the obesity-associated "natriuretic handicap". Thereby, nutritional fat and protein intake and the individual glucose homeostasis might be metabolic determinants of NT-proBNP serum concentration.

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

OBJECTIVE: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. DESIGN: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. RESULTS: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. CONCLUSION: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Frailty in patients undergoing transcatheter aortic valve replacement: prognostic value of the Geriatric Nutritional Risk Index.

BACKGROUND: Malnutrition is a hallmark of frailty, is common among elderly patients, and is a predictor of poor outcomes in patients with severe symptomatic aortic stenosis (AS). The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established screening tool to predict the risk of morbidity and mortality in elderly patients. In this study, we evaluated whether GNRI may be used in the risk stratification and management of patients undergoing transcatheter aortic valve replacement (TAVR). METHODS: Patients with symptomatic severe AS (n = 953) who underwent transfemoral TAVR at the University Hospital Schleswig-Holstein Kiel, Germany, between 2010 and 2019 (development cohort) were divided into two groups: normal GNRI ≥ 98 (no nutrition-related risk; n = 618) versus low GNRI < 98 (at nutrition-related risk; n = 335). The results were validated in an independent (validation) cohort from another high-volume TAVR centre (n = 977). RESULTS: The low-GNRI group had a higher proportion of female patients (59.1% vs. 52.1%), higher median age (82.9 vs. 81.8 years), prevalence of atrial fibrillation (50.4% vs. 40.0%), median logistic EuroSCORE (17.5% vs. 15.0%) and impaired left ventricular function (<35%: 10.7% vs. 6.8%), lower median estimated glomerular filtration rate (50 vs. 57 mL/min/1.73 m2 ) and median albumin level (3.5 vs. 4.0 g/dL) compared with the normal-GNRI group. Among peri-procedural complications, Acute Kidney Injury Network (AKIN) Stage 3 was more common in the low-GNRI group (3.6% vs. 0.6%, p = 0.002). After a mean follow-up of 21.1 months, all-cause mortality was significantly increased in the low-GNRI group compared with the normal-GNRI group (p < 0.001). This was confirmed in the validation cohort (p < 0.001). Low GNRI < 98 was identified as an independent risk factor for all-cause mortality (hazard ratio 1.44, 95% CI 1.01-2.04, p = 0.043). Other independent risk factors included albumin level < median of 4.0 g/dL, high-sensitive troponin T in the highest quartile (> 45.0 pg/mL), N-terminal pro-B-type natriuretic peptide in the highest quartile (> 3595 pg/mL), grade III-IV tricuspid regurgitation, pulmonary arterial hypertension, life-threatening bleeding, AKIN Stage 3 and disabling stroke. CONCLUSIONS: Low GNRI score was associated with an increased risk of all-cause mortality in patients undergoing TAVR, implying that this vulnerable group may benefit from improved preventive measures.

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.

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.

Circulating sDPP-4 is Increased in Obesity and Insulin Resistance but Is Not Related to Systemic Metabolic Inflammation.

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.

Differential effects of protein intake versus intake of a defined oligopeptide on FGF-21 in obese human subjects in vivo.

BACKGROUND: FGF-21 is described as a powerful metabolic regulator with beneficial effects including glucose-lowering and improvement of insulin sensitivity without hypoglycaemia. On the other hand, FGF-21 is activated when muscle and other tissues are stressed by external effects or internal cellular pathogens that lead to shortcomings in metabolic balance. Previous results suggested that FGF-21 could be a promising target to develop future metabolic therapeutics. PURPOSE: The present study was performed to gain deeper insight into the regulation of FGF-21 by protein metabolism in obese human subjects. METHODS: FGF-21 serum concentrations were measured in a cohort of n = 246 obese humans ± type 2 diabetes mellitus (T2DM) (median age 53.0 [46.0; 60.0] years and BMI 40.43 [35.11; 47.24] kg/m2) and related to the nutritional protein intake. In addition, the effect of a novel oligopeptide purified from a ß-casein hydrolysate on FGF-21 was examined in vitro in liver cells and in vivo in a human intervention study with the main focus on metabolic inflammation including 40 mainly obese subjects (mean age 41.08 ± 9.76 years, mean BMI 38.29 ± 9.4 kg/m2) in a randomized 20 weeks double-blind cross-over design. MAIN FINDINGS: In the cohort analysis, FGF-21 serum concentrations were significant lower with higher protein intake in obese subjects without T2DM but not in obese subjects with T2DM. Furthermore, relative methionine intake was inversely related to FGF-21. While global protein intake in obesity was inversely associated with FGF-21, incubation of HepG2 cells with a ß-casein oligopeptide increased FGF-21 expression in vitro. This stimulatory effect was also present in vivo, since in the clinical intervention study treatment of obese subjects with the ß-casein oligopeptide for 8 weeks significantly increased FGF-21 serum levels from W0 = 23.86 pg/mL to W8 = 30.54 pg/mL (p < 0.001), while no increase was found for placebo. CONCLUSION: While the total nutritional protein intake is inversely associated with FGF-21 serum levels, a purified and well characterised oligopeptide is able to induce FGF-21 serum levels in humans. These findings suggest a differential role of various components of protein metabolism on FGF-21, rather than this factor being solely a sensor of total nutritional protein intake.

Pros and Cons of Robotic Revisional Bariatric Surgery.

INTRODUCTION: Revisional procedures in bariatric surgery are regarded as technically more demanding and riskier than primary interventions. While the use of the surgical robot has not yet proven to be advantageous in primary bariatric interventions, the question remains whether its use is justified for more complex revisional procedures. OBJECTIVE: To show that revisional bariatric surgery can be performed safely using the da Vinci® Xi surgical system. METHODS: We performed a retrospective analysis of prospectively recorded data for revisional bariatric procedures between January 2016 and November 2019. RESULTS: Of 78 revision operations, four (5.1%) were performed by open surgery, 30 (38.5%) by laparoscopic surgery, and 44 (56.4%) by robotic surgery. A comparative analysis of robotic (n = 41) versus laparoscopic (n = 18) revisional Roux-en-Y gastric bypasses (rRYGB) revealed significant differences favoring the robotic approach for operative time (130.7 vs. 167.6 min), C-reactive protein values at days 1 (27.9 vs. 49.1 mg/L) and 2 (48.2 vs. 83.6 mg/L) after surgery, and length of stay (4.9 vs. 6.2 days). Lower complication rates (Clavien-Dindo II-V) were found after rRRYGB (7.3 vs. 22.2%, not significant). CONCLUSIONS: Revisional bariatric surgery using a robotic system is safe. The operative time performing rRRYGB is significantly shorter than rLRYGB in our experience. Otherwise, results were largely comparable. Due to different indications, different index operations and a wide range of revisional procedures, further studies are necessary to confirm these results.