Plant lignans and their microbial metabolites, e.g., enterolactone (ENL), may affect bile acid (BA) metabolism through interaction with hepatic receptors. We evaluated the effects of a flaxseed ...lignan extract (50 mg/day secoisolariciresinol diglucoside) compared to a placebo for 60 days each on plasma BA concentrations in 46 healthy men and women (20-45 years) using samples from a completed randomized, crossover intervention. Twenty BA species were measured in fasting plasma using LC-MS. ENL was measured in 24-h urines by GC-MS. We tested for (a) effects of the intervention on BA concentrations overall and stratified by ENL excretion; and (b) cross-sectional associations between plasma BA and ENL. We also explored the overlap in bacterial metabolism at the genus level and conducted in vitro anaerobic incubations of stool with lignan substrate to identify genes that are enriched in response to lignan metabolism. There were no intervention effects, overall or stratified by ENL at FDR < 0.05. In the cross-sectional analysis, irrespective of treatment, five secondary BAs were associated with ENL excretion (FDR < 0.05). In vitro analyses showed positive associations between ENL production and bacterial gene expression of the bile acid-inducible gene cluster and hydroxysteroid dehydrogenases. These data suggest overlap in community bacterial metabolism of secondary BA and ENL.
Biomarkers of low-grade systemic inflammation are used to study the associations of inflammation with chronic diseases, including cancer. However, relatively little is known about the intraindividual ...variability of most of these measures.
Fasting serum samples, collected at baseline and the end of ≥3-week washout periods in a four-diet crossover feeding trial, were used to measure the inflammatory markers high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-8, and soluble TNF receptor (sTNFR) I and II. Participants included 62 men and women for analyses of IL-6 and CRP and 56 for analyses of IL-8, TNF-α, and sTNFRs, aged 20 to 40, who were free of factors known to influence inflammation, for example, chronic disease, medication use, heavy alcohol use, smoking, and obesity (body mass index >30 kg/m(2)). Intraclass correlations (ICC) were estimated using random effects ANOVA, across all four time points (~6 weeks apart).
ICCs for TNF-α and sTNFR I and II were very high: ICC = 0.92 95% confidence interval (CI), 0.89-0.96, 0.92 (95% CI, 0.88-0.95), and 0.90 (95% CI, 0.85-0.94), respectively. ICCs for IL-8 and hsCRP were 0.73 (95% CI, 0.63-0.83) and 0.62 (95% CI, 0.49-0.75), respectively. The ICC for IL-6 was considerably lower, ICC = 0.48 (95% CI, 0.36-0.62). Three measures of IL-6 would be needed to achieve a reliability coefficient (Cronbach α) of 0.75.
With the exception of IL-6, reliability of all inflammatory markers in our panel was high.
This suggests that a single measure accurately captures the short-term (e.g., 4-6 months) variability within an individual.
Combined intakes of specific dietary fiber and fat subtypes protect against colon cancer in animal models. We evaluated associations between self-reported individual and combinations of fiber ...(insoluble, soluble, and pectins, specifically) and fat (omega-6, omega-3, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), specifically) and colorectal cancer (CRC) risk in the Women's Health Initiative prospective cohort (
= 134,017). During a mean 11.7 years (1993-2010), 1952 incident CRC cases were identified. Cox regression models computed multivariate adjusted hazard ratios to estimate the association between dietary factors and CRC risk. Assessing fiber and fat individually, there was a modest trend for lower CRC risk with increasing intakes of total and insoluble fiber (
0.09 and 0.08). An interaction (
= 0.01) was observed between soluble fiber and DHA + EPA, with protective effects of DHA + EPA with lower intakes of soluble fiber and an attenuation at higher intakes, however this association was no longer significant after correction for multiple testing. These results suggest a modest protective effect of higher fiber intake on CRC risk, but not in combination with dietary fat subtypes. Given the robust results in preclinical models and mixed results in observational studies, controlled dietary interventions with standardized intakes are needed to better understand the interaction of specific fat and fiber subtypes on colon biology and ultimately CRC susceptibility in humans.
Research suggests that high intake of supplemental vitamin B
12
may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This ...investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999-2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B
12
supplement use and log-transformed serum B
12
levels. Persons taking vitamin B
12
through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B
12
intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%-30%) higher than nonusers, whereas MVMM-exclusive users' geometric mean was 61% (95% CI: 53%-70%) higher than nonusers (p-trend < 0.001). Although a positive trend (p-trend < 0.001) was observed for both men and women, the association was stronger among women (p-interaction < 0.001). No interaction was observed for smoking status (p-interaction = 0.45). B
12
supplementation is associated with higher levels of serum B
12
, with significant interaction by gender but not smoking. Further work is needed to better understand the interplay of B
12
and gender.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to ...identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings.
Metabolomic profiles were used to characterise the effects of consuming a high-phytochemical diet compared with a diet devoid of fruits and vegetables (F&V) in a randomised trial and cross-sectional ...study. In the trial, 8 h fasting urine from healthy men (n 5) and women (n 5) was collected after a 2-week randomised, controlled trial of two diet periods: a diet rich in cruciferous vegetables, citrus and soya (F&V), and a fruit- and vegetable-free (basal) diet. Among the ions found to differentiate the diets, 176 were putatively annotated with compound identifications, with forty-six supported by MS/MS fragment evidence. Metabolites more abundant in the F&V diet included markers of the dietary intervention (e.g. crucifers, citrus and soya), fatty acids and niacin metabolites. Ions more abundant in the basal diet included riboflavin, several acylcarnitines and amino acid metabolites. In the cross-sectional study, we compared the participants based on the tertiles of crucifers, citrus and soya from 3 d food records (n 36) and FFQ (n 57); intake was separately divided into the tertiles of total fruit and vegetable intake for FFQ. As a group, ions individually differential between the experimental diets differentiated the observational study participants. However, only four ions were significant individually, differentiating the third v. first tertile of crucifer, citrus and soya intake based on 3 d food records. One of these ions was putatively annotated: proline betaine, a marker of citrus consumption. There were no ions significantly distinguishing tertiles by FFQ. The metabolomic assessment of controlled dietary interventions provides a more accurate and stronger characterisation of the diet than observational data.
Artificial nutrition support is central to the care of critically ill patients and is primarily provided enterally (EN). There are circumstances when parenteral nutrition (PN) is considered ...necessary. We are uncertain how each of these approaches confer clinical benefits beyond simply providing calories. We sought to better understand how each of these techniques influence metabolism in critically ill patients using a broad-based metabolomics approach. Metabolic responses to EN and PN may differ in ways that could help us understand how to optimize use of these therapies.
We prospectively enrolled subjects over 7 months in 2015 at an urban, Level I trauma center. Subjects were included before starting either EN or PN during their inpatient admission. Plasma samples were obtained between 1 and 12 hours before initiation of artificial nutrition, and 3 and 7 days later. All samples were analyzed with liquid chromatography/mass spectrometry-based metabolomics. Differences in metabolite concentrations were assessed via principal component analyses and multiple linear regression.
We enrolled 30 subjects. Among the critically ill subjects, 10 received EN and 10 received PN. In subjects receiving EN, amino acid and urea cycle metabolites (citrulline, p = 0.04; ornithine, p = 0.05) increased, as did ribonucleic acid metabolites (uridine, p = 0.04; cysteine, 0 = 0.05; oxypurinol, p = 0.04). Oxidative stress decreased over time (increased betaine, p = 0.05; decreased 4-pyridoxic acid, p = 0.04). In subjects receiving PN, amino acid concentrations increased over time (taurine, p = 0.04; phenylalanine, p = 0.05); omega 6 and omega 3 fatty acid concentrations decreased over time (p = 0.05 and 0.03, respectively).
EN was associated with amino acid repletion, urea cycle upregulation, restoration of antioxidants, and increasing ribonucleic acid synthesis. Parenteral nutrition was associated with increased amino acid concentrations, but did not influence protein metabolism or antioxidant repletion. This suggests that parenteral amino acids are used less effectively than those given enterally. The biomarkers reported in this study may be useful in guiding nutrition therapy for critically ill patients.
Therapeutic study, level III; prognostic study, level II.
Technologic advances now make it possible to collect large amounts of genetic, epigenetic, metabolomic and gut microbiome data. These data have the potential to transform approaches towards nutrition ...counselling by allowing us to recognise and embrace the metabolic, physiologic and genetic differences among individuals. The ultimate goal is to be able to integrate these multi-dimensional data so as to characterise the health status and disease risk of an individual and to provide personalised recommendations to maximise health. To this end, accurate and predictive systems-based measures of health are needed that incorporate molecular signatures of genes, transcripts, proteins, metabolites and microbes. Although we are making progress within each of these omics arenas, we have yet to integrate effectively multiple sources of biologic data so as to provide comprehensive phenotypic profiles. Observational studies have provided some insights into associative interactions between genetic or phenotypic variation and diet and their impact on health; however, very few human experimental studies have addressed these relationships. Dietary interventions that test prescribed diets in well-characterised study populations and that monitor system-wide responses (ideally using several omics platforms) are needed to make correlation-causation connections and to characterise phenotypes under controlled conditions. Given the growth in our knowledge, there is the potential to develop personalised dietary recommendations. However, developing these recommendations assumes that an improved understanding of the phenotypic complexities of individuals and their responses to the complexities of their diets will lead to a sustainable, effective approach to promote health and prevent disease - therein lies our challenge.
Brain glucose hypometabolism is an early sign of Alzheimer's disease (AD), and interventions which offset this deficit, such as ketogenic diets, show promise as AD therapeutics. Conversely, high-fat ...feeding may exacerbate AD risk. We analyzed the metabolomic profile of cerebrospinal fluid (CSF) in a pilot study of older adults who underwent saline and triglyceride (TG) infusions. Older adults (12 cognitively normal (CN), age 65.3 ± 8.1, and 9 with cognitive impairment (CI), age 70.9 ± 8.6) underwent a 5 h TG or saline infusion on different days using a random crossover design; CSF was collected at the end of infusion. Aqueous metabolites were measured using a targeted mass spectroscopy (MS) platform focusing on 215 metabolites from over 35 different metabolic pathways. Data were analyzed using MetaboAnalyst 4.0 and SAS. Of the 215 targeted metabolites, 99 were detectable in CSF. Only one metabolite significantly differed by treatment: the ketone body 3-hydroxybutyrate (HBA). Post hoc analyses showed that HBA levels were associated with age and markers of metabolic syndrome and demonstrated different correlation patterns for the two treatments. When analyzed by cognitive diagnosis group, TG-induced increases in HBA were over 3 times higher for those with cognitive impairment (change score CN +9.8 uM ± 8.3, CI +32.4 ± 7.4,
= 0.0191). Interestingly, individuals with cognitive impairment had higher HBA levels after TG infusion than those with normal cognition. These results suggest that interventions that increase plasma ketones may lead to higher brain ketones in groups at risk for AD and should be confirmed in larger intervention studies.
Demographic and clinical factors influence the metabolome. The discovery and validation of disease biomarkers are often challenged by potential confounding effects from such factors. To address this ...challenge, we investigated the magnitude of the correlation between serum and urine metabolites and demographic and clinical parameters in a well-characterized observational cohort of 444 post-menopausal women participating in the Women's Health Initiative (WHI). Using LC-MS and lipidomics, we measured 157 aqueous metabolites and 756 lipid species across 13 lipid classes in serum, along with 195 metabolites detected by GC-MS and NMR in urine and evaluated their correlations with 29 potential disease risk factors, including demographic, dietary and lifestyle factors, and medication use. After controlling for multiple testing (FDR < 0.01), we found that log-transformed metabolites were mainly associated with age, BMI, alcohol intake, race, sample storage time (urine only), and dietary supplement use. Statistically significant correlations were in the absolute range of 0.2-0.6, with the majority falling below 0.4. Incorporation of important potential confounding factors in metabolite and disease association analyses may lead to improved statistical power as well as reduced false discovery rates in a variety of data analysis settings.
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