Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease

5-Aminovaleric acid betaine (5-AVAB) is a trimethylated compound associated with the gut microbiota, potentially produced endogenously, and related to the dietary intake of certain foods such as whole grains. 5-AVAB accumulates within the metabolically active tissues and has been typically found in higher concentrations in the heart, muscle, and brown adipose tissue. Furthermore, 5-AVAB has been associated with positive health effects such as fetal brain development, insulin secretion, and reduced cancer risk. However, it also has been linked with some negative health outcomes such as cardiovascular disease and fatty liver disease. At the cellular level, 5-AVAB can influence cellular energy metabolism by reducing β-oxidation of fatty acids. This review will focus on the metabolic role of 5-AVAB with respect to both physiology and pathology. Moreover, the analytics and origin of 5-AVAB and related compounds will be reviewed

Serum metabolites associated with wholegrain consumption using nontargeted metabolic profiling: a discovery and reproducibility study

Purpose: To identify fasting serum metabolites associated with WG intake in a free-living population adjusted for potential confounders. Methods: We selected fasting serum samples at baseline from a subset (n = 364) of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort. The samples were analyzed using nontargeted metabolomics with liquid chromatography coupled with mass spectrometry (LC–MS). Association with WG intake was investigated using both random forest followed by linear regression adjusted for age, BMI, smoking, physical activity, energy and alcohol consumption, and partial Spearman correlation adjusted for the same covariates. Features selected by any of these models were shortlisted for annotation. We then checked if we could replicate the findings in an independent subset from the same cohort (n = 200). Results: Direct associations were observed between WG intake and pipecolic acid betaine, tetradecanedioic acid, four glucuronidated alkylresorcinols (ARs), and an unknown metabolite both in discovery and replication cohorts. The associations remained significant (FDR<0.05) even after adjustment for the confounders in both cohorts. Sinapyl alcohol was positively correlated with WG intake in both cohorts after adjustment for the confounders but not in linear models in the replication cohort. Some microbial metabolites, such as indolepropionic acid, were positively correlated with WG intake in the discovery cohort, but the correlations were not replicated in the replication cohort. Conclusions: The identified associations between WG intake and the seven metabolites after adjusting for confounders in both discovery and replication cohorts suggest the potential of these metabolites as robust biomarkers of WG consumption

FADS1 rs174550 genotype and high linoleic acid diet modify plasma PUFA phospholipids in a dietary intervention study

Introduction: Fatty acid desaturase 1 (FADS1) gene encodes for delta-5 desaturase enzyme which is needed in conversion of linoleic acid (LA) to arachidonic acid (AA). Recent studies have shown that response to dietary PUFAs differs between the genotypes in circulating fatty acids. However, interactions between the FADS1 genotype and dietary LA on overall metabolism have not been studied. Objectives: We aimed to examine the interactions of FADS1 rs174550 genotypes (TT and CC) and high-LA diet to identify plasma metabolites that respond differentially to dietary LA according to the FADS1 genotype. Methods: A total of 59 men (TT n = 26, CC n = 33) consumed a sunflower oil supplemented diet for 4\ua0weeks. Daily dose of 30, 40, or 50\ua0ml was calculated based on body mass index. It resulted in 17–28\ua0g of LA on top of the usual daily intake. Fasting plasma samples at the beginning and at the end of the intervention were analyzed with LC–MS/MS non-targeted metabolomics method. Results: At the baseline, the carriers of FADS1 rs174550-TT genotype had higher abundance of long-chain PUFA phospholipids compared to the FADS1 rs174550-CC one. In response to the high-LA diet, LA phospholipids and long-chain acylcarnitines increased and lysophospholipids decreased in fasting plasma similarly in both genotypes. LysoPE (20:4), LysoPC (20:4), and PC (16:0_20:4) decreased and cortisol increased in the carriers of rs174550-CC genotype; however, these genotype–diet interactions were not significant after correction for multiple testing. Conclusion: Our findings show that both FADS1 rs174550 genotype and high-LA diet modify plasma phospholipid composition. Trial registration: The study was registered to ClinicalTrials: NCT02543216, September 7, 2015 (retrospectively registered)

Microbiota-derived metabolites as drivers of gut–brain communication

Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut–brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut–brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut–brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein. Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins

Metabolic profiles reflect weight loss maintenance and the composition of diet after very-low-energy diet

Background & aims: Diet and weight loss affect circulating metabolome. However, metabolite profiles induced by different weight loss maintenance diets and underlying longer term weight loss maintenance remain unknown. Herein, we investigated after-weight-loss metabolic signatures of two isocaloric 24-wk weight maintenance diets differing in satiety value due to dietary fibre, protein and fat contents and identified metabolite features that associated with successful weight loss maintenance. Methods: Non-targeted LC-MS metabolomics approach was used to analyse plasma metabolites of 79 women and men (mean age \ub1 SD 49.7 \ub1 9.0 years; BMI 34.2 \ub1 2.5 kg/m2) participating in a weight management study. Participants underwent a 7-week very-low-energy diet (VLED) and were thereafter randomised into two groups for a 24-week weight maintenance phase. Higher satiety food (HSF) group consumed high-fibre, high-protein, and low-fat products, while lower satiety food (LSF) group consumed isocaloric low-fibre products with average protein and fat content as a part of their weight maintenance diets. Plasma metabolites were analysed before the VLED and before and after the weight maintenance phase. Metabolite features discriminating HSF and LSF groups were annotated. We also analysed metabolite features that discriminated participants who maintained ≥10% weight loss (HWM) and participants who maintained <10% weight loss (LWM) at the end of the study, irrespective of the diet. Finally, we assessed robust linear regression between metabolite features and anthropometric and food group variables. Results: We annotated 126 metabolites that discriminated the HSF and LSF groups and HWM and LWM groups (p < 0.05). Compared to LSF, the HSF group had lower levels of several amino acids, e.g. glutamine, arginine, and glycine, short-, medium- and long-chain acylcarnitines (CARs), odd- and even-chain lysoglycerophospholipids, and higher levels of fatty amides. Compared to LWM, the HWM group in general showed higher levels of glycerophospholipids with a saturated long-chain and a C20:4 fatty acid tail, and unsaturated free fatty acids (FFAs). Changes in several saturated odd- and even-chain LPCs and LPEs and fatty amides were associated with the intake of many food groups, particularly grain and dairy products. Increase in several (lyso)glycerophospholipids was associated with decrease in body weight and adiposity. Increased short- and medium-chain CARs were related to decreased body fat-free mass. Conclusions: Our results show that isocaloric weight maintenance diets differing in dietary fibre, protein, and fat content affected amino acid and lipid metabolism. Increased abundances of several phospholipid species and FFAs were related with greater weight loss maintenance. Our findings indicate common and distinct metabolites for weight and dietary related variables in the context of weight reduction and weight management. The study was registered in isrctn.org with identifier 67529475

Serum metabolites associated with wholegrain consumption using nontargeted metabolic profiling: a discovery and reproducibility study

Purpose To identify fasting serum metabolites associated with WG intake in a free-living population adjusted for potential confounders. Methods We selected fasting serum samples at baseline from a subset (n = 364) of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort. The samples were analyzed using nontargeted metabolomics with liquid chromatography coupled with mass spectrometry (LC-MS). Association with WG intake was investigated using both random forest followed by linear regression adjusted for age, BMI, smoking, physical activity, energy and alcohol consumption, and partial Spearman correlation adjusted for the same covariates. Features selected by any of these models were shortlisted for annotation. We then checked if we could replicate the findings in an independent subset from the same cohort (n = 200). Results Direct associations were observed between WG intake and pipecolic acid betaine, tetradecanedioic acid, four glucuronidated alkylresorcinols (ARs), and an unknown metabolite both in discovery and replication cohorts. The associations remained significant (FDRConclusions The identified associations between WG intake and the seven metabolites after adjusting for confounders in both discovery and replication cohorts suggest the potential of these metabolites as robust biomarkers of WG consumption.</p

Inhibition of the glycaemic response by onion : a comparison between lactose-tolerant and lactose-intolerant adults

This document is the Accepted Manuscript of the following article: R Hoffman, G Ranjbar and A M Madden, ‘Inhibition of the glycaemic response by onion: a comparison between lactose-tolerant and lactose-intolerant adults’, European Journal of Clinical Nutritin, (2016), 70: 1089-1091. The Version of Record is available online at doi: 10.1038/ejcn.2016.44.This pilot study compared inhibition of the glycaemic response to glucose by a dietary source of quercetin glucosides (onion) in lactose-tolerant adults (n = 12) and lactose-intolerant adults (n = 12). We hypothesised that lactose-intolerant people (who do not express lactase) will retain intact quercetin glucosides that can inhibit glucose uptake via the glucose transporter SGLT1 whereas lactose-tolerant people (who do express lactase) will hydrolyse quercetin glucosides to free quercetin which does not inhibit glucose uptake. In a glucose tolerance test, reduction of peak glucose levels by an onion meal was higher in lactose-intolerant people than lactose-tolerant people (44.2% versus 19.3%, p = 0.04). Incremental area under the blood glucose curve was reduced more in lactose-intolerant people, but was not statistically significantly (54.5% versus 42.1%, p = 0.42). A diet containing quercetin glucosides may be of greater benefit for glycaemic control in lactose-intolerant people than in lactose-tolerant people.Peer reviewedFinal Accepted Versio

Side-stream products of malting: a neglected source of phytochemicals

Whole grain consumption reduces the risk of several chronic diseases. A major contributor to the effect is the synergistic and additive effect of phytochemicals. Malting is an important technological method to process whole grains; the main product, malted grain, is used mainly for brewing, but the process also yields high amounts of side-stream products, such as rootlet. In this study, we comprehensively determined the phytochemical profile of barley, oats, rye, and wheat in different stages of malting and the subsequent extraction phases to assess the potential of malted products and side-streams as a dietary source of bioactive compounds. Utilizing semi-quantitative LC-MS metabolomics, we annotated 285 phytochemicals from the samples, belonging to more than 13 chemical classes. Malting significantly altered the levels of the compounds, many of which were highly increased in the rootlet. Whole grain cereals and the malting products were found to be a diverse and rich source of phytochemicals, highlighting the value of these whole foods as a staple. The characterization of phytochemicals from the 24 different sample types revealed previously unknown existence of some of the compound classes in certain species. The rootlet deserves more attention in human nutrition, rather than its current use mainly as feed, to benefit from its high content of bioactive components

Novel Biomarker Candidates for Febrile Neutropenia in Hematological Patients Using Nontargeted Metabolomics

Background. Novel potential small molecular biomarkers for sepsis were analyzed with nontargeted metabolite profiling to find biomarkers for febrile neutropenia after intensive chemotherapy for hematological malignancies. Methods. Altogether, 85 patients were included into this prospective study at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The plasma samples for the nontargeted metabolite profiling analysis by liquid chromatography-mass spectrometry were taken when fever rose over 38° and on the next morning. Results. Altogether, 90 differential molecular features were shown to explain the differences between patients with complicated (bacteremia, severe sepsis, or fatal outcome) and noncomplicated courses of febrile neutropenia. The most differential compounds were an androgen hormone, citrulline, and phosphatidylethanolamine PE(18:0/20:4). The clinical relevance of the findings was evaluated by comparing them with conventional biomarkers like C-reactive protein and procalcitonin. Conclusion. These results hold promise to find out novel biomarkers for febrile neutropenia, including citrulline. Furthermore, androgen metabolism merits further studies.</p

Metabolic changes in response to varying whole-grain wheat and rye intake

Epidemiological studies have shown associations between whole-grain intake and lowered disease risk. A sufficient level of whole-grain intake to reach the health benefits has not been established, and there is limited knowledge about the impact of whole-grain intake on metabolite levels. In this clinical intervention study, we aimed to identify plasma and urine metabolites associated with two different intake levels of whole-grain wheat and rye and to correlate them with clinical plasma biomarkers. Healthy volunteers (N = 68) were divided into two groups receiving either whole-grain wheat or whole-grain rye in two four-week interventions with 48 and 96 g/d of whole grains consumed. The metabolomics of the plasma samples was performed with UPLC–QTOF-MS. Plasma alkylresorcinols were quantified with GC-MS and plasma and urinary mammalian lignans with HPLC-ECD. The high-dose intervention impacted the metabolite profile, including microbial metabolites, more in the rye-enriched diet compared with wheat. Among the increased metabolites were alkylresorcinol glucuronides, sinapyl alcohol, and pipecolic acid betaine, while the decreased metabolites included acylcarnitines and ether lipids. Plasma alkylresorcinols, urinary enterolactone, and total mammalian lignans reflected the study diets in a dose-dependent manner. Several key metabolites linked with whole-grain consumption and gut microbial metabolism increased in a linear manner between the two interventions. The results reveal that an increase in whole-grain intake, particularly rye, is strongly reflected in the metabolite profile, is correlated with clinical variables, and suggests that a diet rich in whole grains promotes the growth and/or metabolism of microbes producing potentially beneficial microbial metabolites.Similar content being viewed by other