Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

[Socio-demographic and employment-related factors in the German National Cohort (GNC; NAKO Gesundheitsstudie)]. / Soziodemografische und erwerbsbezogene Merkmale in der NAKO Gesundheitsstudie.

BACKGROUND: In epidemiologic studies, standardised measurement of socio-demographic and employment-related factors is becoming increasingly important, as variables such as gender, age, education or employment status are factors influencing health and disease risks. AIMS: The article gives an overview of the scientific background and assessment of socio-demographic factors in the German National Cohort Study. In addition, the distribution of individual characteristics in the cohort as well as relationships with health-related measures are presented by way of example. MATERIAL AND METHODS: The analysis is based on the data of the first half of the baseline survey (n = 101,724). On this basis, we present the distribution of key socio-demographic characteristics and analyse relationships with exemplary selected health indicators (body mass index, self-reported health) to assess the validity of socio-demographic data measurements. RESULTS: On average, study participants were 52.0 years old (SD = 12.4). Of the participants, 53.6% were women, 54.3% had high education, 60.1% were married and 72% were employed while 3.4% were unemployed. Well-established correlations between socio-demographic factors and health could be reproduced with the German National Cohort data. For example, low education, old age and unemployment were associated with an increased prevalence of obesity and poor self-reported health. DISCUSSION: The German National Cohort provides a comprehensive measurement of socio-demographic characteristics. Combined with a wide range of health data and the longitudinal measurements available in the future, this opens up new opportunities for health science and social epidemiological research in Germany.

[Design and quality control of the oral health status examination in the German National Cohort (GNC)]. / Design und Qualitätskontrolle der zahnmedizinischen Untersuchung in der NAKO Gesundheitsstudie.

BACKGROUND: Caries and periodontitis are highly prevalent worldwide. Because detailed data on these oral diseases were collected within the framework of the German National Cohort (GNC), associations between oral and systemic diseases and conditions can be investigated. OBJECTIVES: The study protocol for the oral examination was designed to ensure a comprehensive collection of dental findings by trained non-dental staff within a limited examination time. At the mid-term of the GNC baseline examination, a first quality evaluation was performed to check the plausibility of results and to propose measures to improve the data quality. MATERIALS AND METHODS: A dental interview, saliva sampling and oral diagnostics were conducted. As part of the level­1 examination, the number of teeth and prostheses were recorded. As part of the level­2 examination, detailed periodontal, cariological and functional aspects were examined. All examinations were conducted by trained non-dental personnel. Parameters were checked for plausibility and variable distributions were descriptively analysed. RESULTS: Analyses included data of 57,967 interview participants, 56,913 level­1 participants and 6295 level­2 participants. Percentages of missing values for individual clinical parameters assessed in level 1 and level 2 ranged between 0.02 and 3.9%. Results showed a plausible distribution of the data; rarely, implausible values were observed, e.g. for measurements of horizontal and vertical overbite (overjet and overbite). Intra-class correlation coefficients indicated differences in individual parameters between regional clusters, study centres and across different examiners. CONCLUSIONS: The results confirm the feasibility of the study protocol by non-dental personnel and its successful integration into the GNC's overall assessment program. However, rigorous dental support of the study centres is required for quality management.

[Nighttime transportation noise annoyance in Germany: personal and regional differences in the German National Cohort Study]. / Nächtliche Verkehrslärmbelästigung in Deutschland: individuelle und regionale Unterschiede in der NAKO Gesundheitsstudie.

BACKGROUND: Noise annoyance is associated with adverse health-related conditions and reduced wellbeing. Thereby, subjective noise annoyance depends on the objective noise exposure and is modified by personal and regional factors. OBJECTIVE: How many participants of the German National Cohort Study (GNC; NAKO Gesundheitsstudie) were annoyed by transportation noise during nighttime and what factors were associated with noise annoyance? MATERIALS AND METHODS: This cross-sectional analysis included 86,080 participants from 18 study centers, examined from 2014 to 2017. We used multinomial logistic regression to investigate associations of personal and regional factors to noise annoyance (slightly/moderately or strongly/extremely annoyed vs. not annoyed) mutually adjusting for all factors in the model. RESULTS: Two thirds of participants were not annoyed by transportation noise during nighttime and one in ten reported strong/extreme annoyance with highest percentages for the study centers Berlin-Mitte and Leipzig. The strongest associations were seen for factors related to the individual housing situation like the bedroom being positioned towards a major road (OR of being slightly/moderately annoyed: 4.26 [95% CI: 4.01;4.52]; OR of being strongly/extremely annoyed: 13.36 [95% CI: 12.47;14.32]) compared to a garden/inner courtyard. Participants aged 40-60 years and those in low- and medium-income groups reported greater noise annoyance compared to younger or older ones and those in the high-income group. CONCLUSION: In this study from Germany, transportation noise annoyance during nighttime varied by personal and regional factors.

[The baseline assessment of the German National Cohort (NAKO Gesundheitsstudie): participation in the examination modules, quality assurance, and the use of secondary data]. / Die Basiserhebung der NAKO Gesundheitsstudie: Teilnahme an den Untersuchungsmodulen, Qualitätssicherung und Nutzung von Sekundärdaten.

BACKGROUND: The German National Cohort (NAKO) is an interdisciplinary health study aimed at elucidating causes for common chronic diseases and detecting their preclinical stages. This article provides an overview of design, methods, participation in the examinations, and their quality assurance based on the midterm baseline dataset (MBD) of the recruitment. METHODS: More than 200,000 women and men aged 20-69 years derived from random samples of the German general population were recruited in 18 study centers (2014-2019). The data collection comprised physical examinations, standardized interviews and questionnaires, and the collection of biomedical samples for all participants (level 1). At least 20% of all participants received additional in-depth examinations (level 2), and 30,000 received whole-body magnet resonance imaging (MRI). Additional information will be collected through secondary data sources such as medical registries, health insurances, and pension funds. This overview is based on the MBD, which included 101,839 participants, of whom 11,371 received an MRI. RESULTS: The mean response proportion was 18%. The participation in the examinations was high with most of the modules performed by over 95%. Among MRI participants, 96% completed all 12 MRI sequences. More than 90% of the participants agreed to the use of complementary secondary and registry data. DISCUSSION: Individuals selected for the NAKO were willing to participate in all examinations despite the time-consuming program. The NAKO provides a central resource for population-based epidemiologic research and will contribute to developing innovative strategies for prevention, screening and prediction of chronic diseases.

[Measuring physical fitness in the German National Cohort-methods, quality assurance, and first descriptive results]. / Messung der körperlichen Fitness in der NAKO Gesundheitsstudie ­ Methoden, Qualitätssicherung und erste deskriptive Ergebnisse.

Physical fitness is defined as an individual's ability to be physically active. The main components are cardiorespiratory fitness (CRF), muscle strength, and flexibility. Regardless of physical activity level, physical fitness is an important determinant of morbidity and mortality.The aim of the current study was to describe the physical fitness assessment methodology in the German National Cohort (NAKO) and to present initial descriptive results in a subsample of the cohort.In the NAKO, hand grip strength (GS) and CRF as physical fitness components were assessed at baseline using a hand dynamometer and a submaximal bicycle ergometer test, respectively. Maximum oxygen uptake (VO2max) was estimated as a result of the bicycle ergometer test. The results of a total of 99,068 GS measurements and 3094 CRF measurements are based on a data set at halftime of the NAKO baseline survey (age 20-73 years, 47% men).Males showed higher values of physical fitness compared to women (males: GS = 47.8 kg, VO2max = 36.4 ml·min-1 · kg-1; females: GS = 29.9 kg, VO2max = 32.3 ml · min-1 · kg-1). GS declined from the age of 50 onwards, whereas VO2max levels decreased continuously between the age groups of 20-29 and ≥60 years. GS and VO2max showed a linear positive association after adjustment for body weight (males ß = 0.21; females ß = 0.35).These results indicate that the physical fitness measured in the NAKO are comparable to other population-based studies. Future analyses in this study will focus on examining the independent relations of GS and CRF with risk of morbidity and mortality.

Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection.

OBJECTIVES: Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. METHODS: We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). RESULTS: The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8-AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. CONCLUSIONS: AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to existing markers and transvaginal ultrasound.

Analysis of the intestinal microbiota using SOLiD 16S rRNA gene sequencing and SOLiD shotgun sequencing.

BACKGROUND: Metagenomics seeks to understand microbial communities and assemblages by DNA sequencing. Technological advances in next generation sequencing technologies are fuelling a rapid growth in the number and scope of projects aiming to analyze complex microbial environments such as marine, soil or the gut. Recent improvements in longer read lengths and paired-sequencing allow better resolution in profiling microbial communities. While both 454 sequencing and Illumina sequencing have been used in numerous metagenomic studies, SOLiD sequencing is not commonly used in this area, as it is believed to be more suitable in the context of reference-guided projects. RESULTS: To investigate the performance of SOLiD sequencing in a metagenomic context, we compared taxonomic profiles of SOLiD mate-pair sequencing reads with Sanger paired reads and 454 single reads. All sequences were obtained from the bacterial 16S rRNA gene, which was amplified from microbial DNA extracted from a human fecal sample. Additionally, from the same fecal sample, complete genomic microbial DNA was extracted and shotgun sequenced using SOLiD sequencing to study the composition of the intestinal microbiota and the existing microbial metabolism. We found that the microbiota composition of 16S rRNA gene sequences obtained using Sanger, 454 and SOLiD sequencing provide results comparable to the result based on shotgun sequencing. Moreover, with SOLiD sequences we obtained more resolution down to the species level. In addition, the shotgun data allowed us to determine a functional profile using the databases SEED and KEGG. CONCLUSIONS: This study shows that SOLiD mate-pair sequencing is a viable and cost-efficient option for analyzing a complex microbiome. To the best of our knowledge, this is the first time that SOLiD sequencing has been used in a human sample.

Micronutrient deficiency in obese subjects undergoing low calorie diet.

BACKGROUND: The prevalence of micronutrient deficiencies is higher in obese individuals compared to normal-weight people, probably because of inadequate eating habits but also due to increased demands among overweight persons, which are underestimated by dietary reference intakes (DRI) intended for the general population. We therefore evaluated the dietary micronutrient intake in obese individuals compared to a reference population and DRI recommendations. Furthermore, we determined the micronutrient status in obese subjects undergoing a standardized DRI-covering low-calorie formula diet to analyze if the DRI meet the micronutrient requirements of obese individuals. METHODS: In 104 subjects baseline micronutrient intake was determined by dietary record collection. A randomly assigned subgroup of subjects (n = 32) underwent a standardized DRI-covering low-calorie formula diet over a period of three months. Pre- and post-interventional intracellular micronutrient status in buccal mucosa cells (BMC) was analyzed, as well as additional micronutrient serum concentrations in 14 of the subjects. RESULTS: Prior to dietetic intervention, nutrition was calorie-rich and micronutrient-poor. Baseline deficiencies in serum concentrations were observed for 25-hydroxyvitamin-D, vitamin C, selenium, iron, as well as ß-carotene, vitamin C, and lycopene in BMC. After a three-month period of formula diet even more subjects had reduced micronutrient levels of vitamin C (serum, BMC), zinc, and lycopene. There was a significant negative correlation between lipophilic serum vitamin concentrations and body fat, as well as between iron and C-reactive protein. CONCLUSIONS: The present pilot study shows that micronutrient deficiency occurring in obese individuals is not corrected by protein-rich formula diet containing vitamins and minerals according to DRI. In contrast, micronutrient levels remain low or become even lower, which might be explained by insufficient intake, increased demand and unbalanced dispersal of lipophilic compounds in the body. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT01344525). The study protocol comprises only a part of the approved trial protocol.

Fructose-Induced Intestinal Microbiota Shift Following Two Types of Short-Term High-Fructose Dietary Phases.

High consumption of fructose and high-fructose corn syrup is related to the development of obesity-associated metabolic diseases, which have become the most relevant diet-induced diseases. However, the influences of a high-fructose diet on gut microbiota are still largely unknown. We therefore examined the effect of short-term high-fructose consumption on the human intestinal microbiota. Twelve healthy adult women were enrolled in a pilot intervention study. All study participants consecutively followed four different diets, first a low fructose diet (< 10 g/day fructose), then a fruit-rich diet (100 g/day fructose) followed by a low fructose diet (10 g/day fructose) and at last a high-fructose syrup (HFS) supplemented diet (100 g/day fructose). Fecal microbiota was analyzed by 16S rRNA sequencing. A high-fructose fruit diet significantly shifted the human gut microbiota by increasing the abundance of the phylum Firmicutes, in which beneficial butyrate producing bacteria such as Faecalibacterium, Anareostipes and Erysipelatoclostridium were elevated, and decreasing the abundance of the phylum Bacteroidetes including the genus Parabacteroides. An HFS diet induced substantial differences in microbiota composition compared to the fruit-rich diet leading to a lower Firmicutes and a higher Bacteroidetes abundance as well as reduced abundance of the genus Ruminococcus. Compared to a low-fructose diet we observed a decrease of Faecalibacterium and Erysipelatoclostridium after the HFS diet. Abundance of Bacteroidetes positively correlated with plasma cholesterol and LDL level, whereas abundance of Firmicutes was negatively correlated. Different formulations of high-fructose diets induce distinct alterations in gut microbiota composition. High-fructose intake by HFS causes a reduction of beneficial butyrate producing bacteria and a gut microbiota profile that may affect unfavorably host lipid metabolism whereas high consumption of fructose from fruit seems to modulate the composition of the gut microbiota in a beneficial way supporting digestive health and counteracting harmful effects of excessive fructose.

Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study.

BACKGROUND: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans. METHODS: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations. RESULTS: Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk. CONCLUSIONS: This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.

Effects of Weight-Loss Interventions on Short-Chain Fatty Acid Concentrations in Blood and Feces of Adults: A Systematic Review.

Short-chain fatty acids (SCFAs, mainly acetate, propionate, and butyrate), which are primarily derived from the gut microbiome, may exert anti-inflammatory and immunomodulatory effects, and regulate energy homeostasis. It has been suggested that weight loss may affect SCFA metabolism, but a systematic review of intervention studies is lacking. We aimed to systematically assess the effects of dietary, physical activity-based, and surgical weight-loss interventions among overweight [body mass index (BMI) 25-29.9 kg/m2)] or obese (BMI ≥30 kg/m2) adults (≥18 y) on concentrations of acetate, propionate, butyrate, and total SCFAs in blood, urine, or feces. We conducted a systematic literature search in PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 30, 2018 for randomized and nonrandomized weight-loss trials among overweight or obese adults, in which the concentrations of individual and total SCFAs were assessed. A total of 9 studies consisting of 2 randomized parallel-arm trials, 4 crossover trials, and 3 nonrandomized clinical or surgical trials were included. In the majority of studies, changes in fecal SCFA concentrations were assessed, whereas changes in serum SCFAs were reported from 1 trial. Individual and total SCFA concentrations either remained unchanged or decreased significantly following weight loss. Three of the dietary interventions that resulted in decreased SCFA concentrations were low (≤5% of energy) in total carbohydrates. Most of the studies had a high risk of bias. Decreases in SCFA concentrations may accompany weight loss induced by bariatric surgery or dietary restriction among overweight or obese adults, particularly when carbohydrate intake is reduced. However, findings were inconsistent and based on studies with high to unclear risk of bias, and small sample sizes. Because measurements of fecal SCFAs may not be ideal due to limited sample standardization, well-powered trials with repeated blood measurements of SCFAs are required. This review was registered at PROSPERO as CRD42018088716.

Changes in Plasma Acylcarnitine and Lysophosphatidylcholine Levels Following a High-Fructose Diet: A Targeted Metabolomics Study in Healthy Women.

BACKGROUND: The consumption of high amounts of fructose is associated with metabolic diseases. However, the underlying mechanisms are largely unknown. OBJECTIVE: To determine the effects of high fructose intake on plasma metabolomics. STUDY DESIGN: We enrolled 12 healthy volunteers (six lean and six obese women, age 24⁻35 years) in a crossover intervention study. All participants carried out three diets: (1) low fructose (<10 g/day); (2) high fructose (100 g/day) from natural food sources (fruit); and (3) high fructose (100 g/day) from high fructose syrup (HFS). OUTCOME MEASURES: The primary outcome was changes in plasma metabolites measured by targeted metabolomics. RESULTS: High compared to low fructose diets caused a marked metabolite class separation, especially because of changes in acylcarnitine and lysophosphatidylcholine levels. Both high fructose diets resulted in a decrease in mean acylcarnitine levels in all subjects, and an increase in mean lysophosphatidylcholine and diacyl-phosphatidylcholine levels in obese individuals. Medium chain acylcarnitines were negatively correlated with serum levels of liver enzymes and with the fatty liver index. DISCUSSION: The metabolic shifts induced by high fructose consumption suggest an inhibition of mitochondrial ß-oxidation and an increase in lipid peroxidation. The effects tended to be more pronounced following the HFS than the fruit diet.

Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction.

BACKGROUND: Obesity and associated metabolic disorders are related to impairments of the intestinal barrier. OBJECTIVE: We examined lactulose:mannitol (Lac:Man) permeability in obese individuals with and without liver steatosis undergoing a weight-reduction program to test whether an effective weight-loss program improves gut barrier function and whether obese patients with or without liver steatosis differ in this function. DESIGN: Twenty-seven adult, nondiabetic individuals [mean ± SD body mass index (BMI; in kg/m2): 43.7 ± 5.2; 78% with moderate or severe liver steatosis] were included in the follow-up intervention study (n = 13 by month 12). All patients reduced their weight to a mean ± SD BMI of 36.4 ± 5.1 within 12 mo. We assessed barrier functions by the oral Lac:Man and the fecal zonulin tests. Insulin resistance was assessed by the homeostatic model assessment index (HOMA), and liver steatosis by sonography and the fatty liver index (FLI). RESULTS: The Lac:Man ratio and circulating interleukin (IL) 6 concentration decreased during intervention from 0.080 (95% CI: 0.073, 0.093) to 0.027 (95% CI: 0.024, 0.034; P < 0.001) and from 4.2 ± 1.4 to 2.8 ± 1.6 pg/mL (P < 0.01), respectively. At study start, the Lac:Man ratio was higher in patients with moderate or severe steatosis than in those without any steatosis (P < 0.001). The Lac:Man ratio tended to correlate with HOMA (ρ = 0.55, P = 0.052), which correlated with FLI (ρ = 0.75, P < 0.01). A multiple-regression analysis led to a final model explaining FLI best through BMI, waist circumference, and the Lac:Man ratio. CONCLUSIONS: Intestinal permeability is increased in obese patients with steatosis compared with obese patients without. The increased permeability fell to within the previously reported normal range after weight reduction. The data suggest that a leaky gut barrier is linked with liver steatosis and could be a new target for future steatosis therapies. This trial was registered at clinicaltrials.gov as NCT01344525.

A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure-Cancer Associations.

The World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure-cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a "hypothesis-free" approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness-IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure-cancer associations. On the basis of our experience, we provide recommendations for future users. Cancer Epidemiol Biomarkers Prev; 26(11); 1583-94. ©2017 AACR.

Characterization of the Gut Microbial Community of Obese Patients Following a Weight-Loss Intervention Using Whole Metagenome Shotgun Sequencing.

BACKGROUND/OBJECTIVES: Cross-sectional studies suggested that obesity is promoted by the gut microbiota. However, longitudinal data on taxonomic and functional changes in the gut microbiota of obese patients are scarce. The aim of this work is to study microbiota changes in the course of weight loss therapy and the following year in obese individuals with or without co-morbidities, and to asses a possible predictive value of the gut microbiota with regard to weight loss maintenance. SUBJECTS/METHODS: Sixteen adult patients, who followed a 52-week weight-loss program comprising low calorie diet, exercise and behavioral therapy, were selected according to their weight-loss course. Over two years, anthropometric and metabolic parameters were assessed and microbiota from stool samples was functionally and taxonomically analyzed using DNA shotgun sequencing. RESULTS: Overall the microbiota responded to the dietetic and lifestyle intervention but tended to return to the initial situation both at the taxonomical and functional level at the end of the intervention after one year, except for an increase in Akkermansia abundance which remained stable over two years (12.7x103 counts, 95%CI: 322-25100 at month 0; 141x103 counts, 95%CI: 49-233x103 at month 24; p = 0.005). The Firmicutes/Bacteroidetes ratio was higher in obese subjects with metabolic syndrome (0.64, 95%CI: 0.34-0.95) than in the "healthy obese" (0.27, 95%CI: 0.08-0.45, p = 0.04). Participants, who succeeded in losing their weight consistently over the two years, had at baseline a microbiota enriched in Alistipes, Pseudoflavonifractor and enzymes of the oxidative phosphorylation pathway compared to patients who were less successful in weight reduction. CONCLUSIONS: Successful weight reduction in the obese is accompanied with increased Akkermansia numbers in feces. Metabolic co-morbidities are associated with a higher Firmicutes/Bacteroidetes ratio. Most interestingly, microbiota differences might allow discrimination between successful and unsuccessful weight loss prior to intervention.

Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.

Evidence suggests a correlation between the gut microbiota composition and weight loss caused by caloric restriction. Laparoscopic sleeve gastrectomy (LSG), a surgical intervention for obesity, is classified as predominantly restrictive procedure. In this study we investigated functional weight loss mechanisms with regard to gut microbial changes and energy harvest induced by LSG and a very low calorie diet in ten obese subjects (n = 5 per group) demonstrating identical weight loss during a follow-up period of six months. For gut microbiome analysis next generation sequencing was performed and faeces were analyzed for targeted metabolomics. The energy-reabsorbing potential of the gut microbiota decreased following LSG, indicated by the Bacteroidetes/Firmicutes ratio, but increased during diet. Changes in butyrate-producing bacterial species were responsible for the Firmicutes changes in both groups. No alteration of faecal butyrate was observed, but the microbial capacity for butyrate fermentation decreased following LSG and increased following dietetic intervention. LSG resulted in enhanced faecal excretion of nonesterified fatty acids and bile acids. LSG, but not dietetic restriction, improved the obesity-associated gut microbiota composition towards a lean microbiome phenotype. Moreover, LSG increased malabsorption due to loss in energy-rich faecal substrates and impairment of bile acid circulation. This trial is registered with ClinicalTrials.gov NCT01344525.

Laparoscopic sleeve gastrectomy compared to a multidisciplinary weight loss program for obesity--effects on body composition and protein status.

BACKGROUND: Optimal obesity therapy is a matter of debate. Besides weight reduction, other criteria such as safety and nutritional status are of relevance. Therefore, we compared a favored surgical intervention with the most effective conservative treatment regarding anthropometry and nutritional status. METHODS: Fifty-four obese patients were included who underwent laparoscopic sleeve gastrectomy (LSG, n = 27) or a 52-week multidisciplinary intervention program (MIP, n = 27) for weight loss. Body weight, body composition assessed by bioelectrical impedance analysis, and serum protein levels were measured before and within 12 months after intervention. RESULTS: After 1 year of observation, excess weight loss was more pronounced following LSG (65 %) compared to MIP (38 %, p < 0.001). In both groups, body fat was clearly reduced, but a higher reduction occurred in the LSG group. However, protein status deteriorated particularly in the LSG group. Within 1 year, body cell mass declined from 37.1 to 26.9 kg in the LSG group, but only from 35.7 to 32.2 kg in the MIP group. This resulted in an increased mean extracellular mass/body cell mass ratio (1.42 versus 1.00, p < 0.001), in a decreased mean phase angle (4.4° versus 6.6°, p < 0.001), and in a lower prealbumin level in serum (p < 0.02) in the LSG group compared to the MIP group. CONCLUSIONS: LSG, compared to MIP, was more effective regarding excess weight loss and body fat loss within 1 year, however, induced more pronounced muscle mass and protein loss, possibly requiring particular interventions such as exercise or protein supplements.

Pre- and postoperative nutritional deficiencies in obese patients undergoing laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has been identified as an innovative surgical approach for the treatment of obesity and is increasingly applied worldwide. However, data on outcome of LSG regarding nutrient deficiencies, protein status, and body composition are scarce. METHODS: Obese subjects (54; f:m = 4:1) scheduled for LSG were included in this study. Micronutrient analysis, protein status assessment, and bioimpedance measures were performed before and 1, 3, 6, and 12 months after LSG. RESULTS: In 51% of the subjects, at least one micronutrient deficiency was found prior to surgery. Baseline concentrations were below normal for 25-OH vitamin D (27%), iron (29%), vitamin B6 (11%), vitamin B12 (9%), folate (6%), and potassium (7%). Frequencies of deficiencies for vitamin B12, folate, iron, and vitamin B6 tended to increase following LSG within the first year after intervention. Also, parameters of protein status (albumin, transferrin, cholinesterase, and total protein) decreased. After surgery, bioimpedance measures indicated a reduction of total body fat, but also of body cell mass. CONCLUSIONS: Preoperative micronutrient deficiencies were common in morbid obese individuals scheduled for LSG. LSG had a modest effect on micronutrient status by further reducing iron, vitamin B12, vitamin B6, and folate within the first year after intervention. Our data suggest that especially obese patients with preoperative deficits require control and supplementation of micronutrients and protein in the postoperative period.