Stability of the human gut virome and effect of gluten-free diet

The human gut microbiome consists of bacteria, archaea, eukaryotes, and viruses. The gut viruses are relatively underexplored. Here, we longitudinally analyzed the gut virome composition in 11 healthy adults: its stability, variation, and the effect of a gluten-free diet. Using viral enrichment and a de novo assembly-based approach, we demonstrate the quantitative dynamics of the gut virome, including dsDNA, ssDNA, dsRNA, and ssRNA viruses. We observe highly divergent individual viral communities, carrying on an average 2,143 viral genomes, 13.1% of which were present at all 3 time points. In contrast to previous reports, the Siphoviridae family dominates over Microviridae in studied individual viromes. We also show individual viromes to be stable at the family level but to vary substantially at the genera and species levels. Finally, we demonstrate that lower initial diversity of the human gut virome leads to a more pronounced effect of the dietary intervention on its composition

Metabolomics Profile in Depression:A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q <.05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity

Intestinal microbiome composition and its relation to joint pain and inflammation

Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain

КЛИНИЧЕСКАЯ И ПАТОГЕНЕТИЧЕСКАЯ ВЗАИМОСВЯЗЬ ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТИ, САХАРНОГО ДИАБЕТА 2 ТИПА И ОСТЕОПОРОЗА

Aim.. To study clinical and pathogenic relationships between the development of chronic heart failure (CHF) of ischemic genesis associated with type 2 diabetes mellitus (DM) and osteoporosis in postmenopausal women and to evaluate the effects of anti-osteoporotic therapy on CHFMethodsMethods. A total of 178 women were recruited in the study. All patients were assigned to three groups: Group 1 (n = 48) women with CHF and type 2 DM, Group 2 (n = 93) – women with osteoporosis and CHF, Group 3 (n = 37) women with osteoporosis, heart failure and type 2 diabetes mellitus. The control group comprised 35 healthy women in postmenopausal period without clinical signs and symptoms of cardiovascular disease, diabetes and osteoporotic process. 35 patients in Group 2 received bisphosphonates for the treatment of osteoporosis. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and osteoprotegerin were measured with the ELISA.Results. A significant inverse correlation between levels of total cholesterol, triglycerides and low-density lipoproteins, blood pressure, and bone mineral density has been found. Levels of TNF-α and IL-1β were significantly higher in Group 3 compared with patients in Groups 1 and 2. Women in the control group had significantly lower levels of cytokines compared with patients in all study groups. All women with comorbidities had significantly higher levels of osteoprotegerin compared with the control group. A significant inverse correlation between levels of TNF-α, IL-1β, osteoprotegerin and glycated hemoglobin and bone mineral density has been determined, as well as a direct correlation with the severity of CHF. A significant association between levels of TNF-α and IL-1β, and reduced bone mineral density and unfavorable course of CHF has been established as well. A significant association between bisphosphonates therapy and a favorable course of CHF has been identified.Conclusion. Increased production of cytokines and osteoprotegerin is of crucial importance for the development of comorbidities, including CHF, type 2 diabetes mellitus and osteoporosis. Understanding of the key mechanisms determining the relationships between these diseases is essential for the development of novel approaches for evaluating risk factors and new methods for prevention and treatment of these diseases.Цель. Изучить клиническую и патогенетическую взаимосвязь развития хронической сердечной недостаточности (ХСН) ишемического генеза, ассоциированной с сахарным диабетом (СД) 2 типа и остеопорозом у женщин в постменопаузальном периоде, а также оценить влияние антиостеопоретической терапии на течение ХСН.Материалы и методы.  исследование были включены 178 женщин: 48 женщин – с ХСН и СД 2 типа (группа 1), 93 пациентки – c остеопорозом и ХСН (группа 2), 37 женщин – с остеопорозом, ХСН и СД 2 типа (группа 3). В группу контроля вошли 35 женщин, находящихся в постменопаузе, без клинических и инструментальных признаков патологии сердечно-сосудистой системы, СД и остеопоротического процесса. Во 2-й группе у 35 женщин для лечения остеопороза применялись препараты, относящиеся к группе бисфосфонатов. Определение концентрации фактора некроза опухоли-α (ФНО-α), интерлейкина-1β (ИЛ-1β) и остеопротегерина в сыворотке крови проводилось методом твердофазного иммуноферментного анализа.Результаты. Показана достоверная обратная зависимость между уровнями общего холестерина, триглицеридов и липопротеидов низкой плотности, а также уровнями артериального давления и минеральной плотности кости. Концентрация ФНО-α и ИЛ-1β была достоверно выше в группе 3 по сравнению с пациентками групп 1 и 2. Женщины контрольной группы имели достоверно более низкие уровни цитокинов по сравнению с больными всех групп наблюдения. Во всех группах женщин с коморбидной патологией концентрация остеопротегерина была достоверно выше, чем в группе контроля. Концентрация ФНО-α, ИЛ-1β, остеопротегерина и уровень гликированного гемоглобина достоверно обратно коррелировали с минеральной плотностью кости и имели прямую корреляционную зависимость с тяжестью течения ХСН. Выявлены значимые ассоциации уровней ФНО-α и ИЛ-1β и сниженной минеральной плотности кости с неблагоприятным течением ХСН. Также выявлена значимая ассоциация терапии бисфосфонатами с благоприятным течением ХСН.Заключение. Пошенная продукция цитокинов и остеопротегерина имеет важное значение в развитии коморбидной патологии, включающей ХСН, СД 2 типа и остеопороз. Расшифровка механизмов, определяющих связь между развитием данных заболеваний, имеет существенное значение для разработки новых подходов к изучению факторов риска, разработки новых методов профилактики и лечения этих заболеваний

Disorders of carnitine metabolism in premature infants with fan-associated pneumonia

We studied the concentration of carnitine and its fractions in peripheral blood in 22 premature infants with fan-associated pneumonia and in 20 conditionally healthy premature infants by tandem mass spectrometry. The birth body weight of children was 2,086.32 ± 117.13 and 2,140.9 ± 74.4 g, gestational age was 33.7 ± 0.41 and 34.16 ± 0.51 weeks, respectively. The concentration of  total carnitine was at the lower limit or decreased in 10 (45%) children in the acute period of the disease. 4 newborns with fan-associated pneumonia demonstrated persistent carnitine deficiency: the content of free carnitine was very low: 7.47 – 8, 37 μmol/l (7.97 ± 0.197 μmol/l), the concentration of total carnitine was also reduced (21.55 – 22.01 μmol/l, 21.7 ± 0.366 μmol/l). The fractions of acylcarnitines varied widely throughout the disease. One child had high rates of C18OH (0.282 μmol/l; norm 0–0.110 μmol/l) and C18:1OH (0.282 μmol/l; norm 0–0.180 μmol/l) during the entire neonatal period. It could be associated with mitochondrial trifunctional protein deficiency. The study of total carnitine and its fractions in premature infants with fan-associated pneumonia allowed us to identify violations of its metabolism, both secondary and hereditary at early stage

Stability of the human gut virome and effect of gluten-free diet

The human gut microbiome consists of bacteria, archaea, eukaryotes, and viruses. The gut viruses are relatively underexplored. Here, we longitudinally analyzed the gut virome composition in 11 healthy adults: its stability, variation, and the effect of a gluten-free diet. Using viral enrichment and a de novo assembly-based approach, we demonstrate the quantitative dynamics of the gut virome, including dsDNA, ssDNA, dsRNA, and ssRNA viruses. We observe highly divergent individual viral communities, carrying on an average 2,143 viral genomes, 13.1% of which were present at all 3 time points. In contrast to previous reports, the Siphoviridae family dominates over Microviridae in studied individual viromes. We also show individual viromes to be stable at the family level but to vary substantially at the genera and species levels. Finally, we demonstrate that lower initial diversity of the human gut virome leads to a more pronounced effect of the dietary intervention on its composition

Osteoprotegerin is a new independent predictor of the progression of cardiovascular pathology: chronic heart failure associated with type 2 diabetes and osteoporosis

Aim. To study the link of increased serum concentrations of osteoprotegerin (OPG) in patients with chronic heart failure (CHF) associated with type 2 diabetes mellitus (DM 2), osteoporosis or osteopenia with the development of cardiovascular events (primarily, decompensation of CHF, including those requiring hospitalization, death from cardiovascular disease, acute coronary syndrome or acute ischemic stroke) to determine the possibility of using this biomarker as a predictor of a severe course of cardiovascular disease in these patients.Materials and methods. In a 12-month cohort observational study included 75 patients (mean age 57.4 ± 5.4 years) with CHF associated with DM 2, osteoporosis or osteopenia. Cardiovascular events were analyzed in three groups of patients formed based terteling ranges of concentration of the OPG level in serum: in the 1st group (n = 25) included patients with serum OPG concentration is less than 5.0 pmol/l; in the 2nd group (n = 25) OPG level of 5.0–7.2 pmol/l; in the 3rd group (n = 25) - with the content of OPG more than 7.2 pmol/L. The serum OPG, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) serum levels were determined by ELISA. Assessment of bone mineral density (BMD) was performed by a densitometric method using dual-energy X-ray absorptiometry.Results. Highly reliable increased expression of OPG in 2 and 3th tertiles was found in patients with CHF associated with type 2 diabetes in comparison with the control group. The frequency of adverse events gradually increased from the 1st tertile to the 3rd tertile OPG. With the median for OPG more than 5.2 pmol/L and BMD less than -2.5 standard deviations, the highest frequency (60.9%) of adverse cardiovascular events was identified. A close correlation of OPG with the values of pro-inflammatory cytokines-TNF-α (r = 0.46; p = 0.019) and IL-1β (r = 0.4; p = 0.01), glycated hemoglobin (r = 0.55; p = 0.009) and the severity of CHF (r = 0.49; p = 0.013).Conclusions. Osteoprotegerin is an independent risk factor for the development of comorbid cardiovascular pathology: CHF associated with DM 2 and osteoporosis. It seems clinically justified to use OPG to stratify the risk of progression of cardiovascular pathology

Fat metabolism is associated with telomere length in six population-based studies

Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or F1owFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold P me t a = 6.5 x 10(-4)). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 x 10(-4)). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 x 10(-4)). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.Molecular Epidemiolog