Quantitative assessment of betainized compounds and associations with dietary and metabolic biomarkers in the randomized study of the healthy Nordic diet (SYSDIET).

BACKGROUND Recently, a group of betainized compounds have been suggested to play a role in health effects in relation to a whole-grain-rich diet. OBJECTIVES The aims of this study were to develop a quantitative mass spectrometric method for selected betainized compounds in human plasma, and to investigate their association with nutrient intake and measures of metabolic health in participants of the SYSDIET study. METHODS The SYSDIET study was a controlled randomized intervention including individuals with metabolic syndrome, where the healthy Nordic diet (HND) group increased intakes of whole grains, canola oil, berries, and fish, whereas the control diet (CD) group consumed low-fiber cereal products, milk fat, and restricted amounts of fish and berries. A quantitative LC combined with triple quadrupole MS method for betainized compounds was developed and applied to fasting plasma samples from baseline (week 0) and the end of the intervention (week 18 or 24). Concentrations of betainized compounds were correlated with intakes of selected nutrients and fiber and measures of metabolic health. RESULTS Pipecolic acid betaine (PAB) concentrations were significantly higher in the HND group than in the CD group (P = 0.00032) at the end of the intervention and correlated directly (P < 0.0001) with intakes of dietary fiber (r = 0.376) and a biomarker related to whole-grain rye intake, namely the ratio of alkylresorcinol C17:0 to C21:0 (r = 0.442). PAB was associated inversely with fasting plasma insulin consistently at the beginning and at the end of the intervention (P < 0.001, r = -0.300; P < 0.01, r = -0.250, respectively), as well as IL-1 receptor antagonist (P < 0.01, r = -0.232 at the beginning; P < 0.01, r = -0.236 at the end) and serum LDL/HDL cholesterol (P < 0.01, r = -0.239 at the beginning; P < 0.01, r = -0.241 at the end). CONCLUSIONS Among adults with the metabolic syndrome, PAB plasma concentrations were associated with fasting insulin, inflammation, and lipids and were significantly increased with adoption of the HND. Further studies are needed to clarify the biological functions of betainized compounds. This trial was registered at clinicaltrials.gov as NCT00992641.

[1]  K. Overvad,et al.  Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome – a randomized study (SYSDIET) , 2013, Journal of internal medicine.

[2]  M. Roghani,et al.  Trigonelline protects hippocampus against intracerebral Aβ(1–40) as a model of Alzheimer’s disease in the rat: insights into underlying mechanisms , 2018, Metabolic Brain Disease.

[3]  H. Boeing,et al.  Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies. , 2017, The American journal of clinical nutrition.

[4]  Donna Spiegelman,et al.  Whole Grain, Bran, and Germ Intake and Risk of Type 2 Diabetes: A Prospective Cohort Study and Systematic Review , 2007, PLoS medicine.

[5]  L. B. Larsen,et al.  Association between the bovine milk metabolome and rennet-induced coagulation properties of milk. , 2014, Journal of dairy science.

[6]  Ben-Yang Liao,et al.  Identification of TMAO-producer phenotype and host–diet–gut dysbiosis by carnitine challenge test in human and germ-free mice , 2018, Gut.

[7]  C. Reinhardt,et al.  The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease , 2018, European journal of immunology.

[8]  S. Innis,et al.  Hypaphorine is present in human milk in association with consumption of legumes. , 2013, Journal of agricultural and food chemistry.

[9]  P. Ueland,et al.  Betaine: a key modulator of one-carbon metabolism and homocysteine status , 2005, Clinical chemistry and laboratory medicine.

[10]  Richard G. Lee,et al.  The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. , 2017, Cell reports.

[11]  R. Knott,et al.  Trigonelline prevents high cholesterol and high fat diet induced hepatic lipid accumulation and lipo-toxicity in C57BL/6J mice, via restoration of hepatic autophagy. , 2018, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[12]  A. Tjønneland,et al.  Rye and health - Where do we stand and where do we go? , 2018, Trends in Food Science & Technology.

[13]  M. Uusitupa,et al.  Plasma alkylresorcinols C17:0/C21:0 ratio, a biomarker of relative whole-grain rye intake, is associated to insulin sensitivity: a randomized study , 2014, European Journal of Clinical Nutrition.

[14]  M. Uusitupa,et al.  Whole Grain Rye Intake, Reflected by a Biomarker, Is Associated with Favorable Blood Lipid Outcomes in Subjects with the Metabolic Syndrome – A Randomized Study , 2014, PloS one.

[15]  K. B. Bach Knudsen,et al.  Mechanisms Whereby Whole Grain Cereals Modulate the Prevention of Type 2 Diabetes , 2016 .

[16]  Sang-Woon Choi,et al.  One-carbon metabolism and epigenetics. , 2017, Molecular aspects of medicine.

[17]  A. Giovane,et al.  Homostachydrine (pipecolic acid betaine) as authentication marker of roasted blends of Coffea arabica and Coffea canephora (Robusta) beans. , 2016, Food chemistry.

[18]  P. Ueland,et al.  Performance of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. , 2018, The American journal of clinical nutrition.

[19]  N. Rattanapanone,et al.  Quality and bioactive compounds of blends of Arabica and Robusta spray-dried coffee. , 2019, Food chemistry.

[20]  L. Qin,et al.  Whole-grain intake and total, cardiovascular, and cancer mortality: a systematic review and meta-analysis of prospective studies. , 2016, The American journal of clinical nutrition.

[21]  A. Giovane,et al.  Occurrence of pipecolic acid and pipecolic acid betaine (homostachydrine) in Citrus genus plants. , 2012, Journal of agricultural and food chemistry.

[22]  B. McEwen,et al.  Acetyl-l-carnitine deficiency in patients with major depressive disorder , 2018, Proceedings of the National Academy of Sciences.

[23]  W. Atkinson,et al.  Effects of orange juice and proline betaine on glycine betaine and homocysteine in healthy male subjects , 2007, European journal of nutrition.

[24]  S. Craig,et al.  Betaine in human nutrition. , 2004, The American journal of clinical nutrition.

[25]  A. Giovane,et al.  The betaine profile of cereal flours unveils new and uncommon betaines. , 2018, Food chemistry.

[26]  Li Li,et al.  A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat , 2015, BMC Genomics.

[27]  E. Riboli,et al.  Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies , 2016, British Medical Journal.

[28]  A. Giovane,et al.  Ruminant meat and milk contain δ-valerobetaine, another precursor of trimethylamine N-oxide (TMAO) like γ-butyrobetaine. , 2018, Food chemistry.

[29]  A. Tjønneland,et al.  Intake of whole grains is associated with lower risk of myocardial infarction: the Danish Diet, Cancer and Health Cohort. , 2016, The American journal of clinical nutrition.

[30]  J. Leppänen,et al.  Whole grain intake associated molecule 5-aminovaleric acid betaine decreases β-oxidation of fatty acids in mouse cardiomyocytes , 2018, Scientific Reports.

[31]  M. Uusitupa,et al.  Plasma alkylresorcinols reflect important whole-grain components of a healthy Nordic diet. , 2013, The Journal of nutrition.

[32]  M. Hulver,et al.  Inulin Supplementation Does Not Reduce Plasma Trimethylamine N-Oxide Concentrations in Individuals at Risk for Type 2 Diabetes , 2018, Nutrients.

[33]  A. Naska,et al.  A metabolomic study of biomarkers of meat and fish intake. , 2017, The American journal of clinical nutrition.

[34]  S. Hazen,et al.  γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. , 2014, Cell metabolism.

[35]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[36]  P. Åman,et al.  Alkylresorcinols in cereals and cereal products. , 2003, Journal of agricultural and food chemistry.

[37]  A. Ross.  Present Status and Perspectives on the Use of Alkylresorcinols as Biomarkers of Wholegrain Wheat and Rye Intake , 2012, Journal of nutrition and metabolism.

[38]  Blandine Comte,et al.  Mass spectrometry-based metabolomics for the discovery of biomarkers of fruit and vegetable intake: citrus fruit as a case study. , 2013, Journal of proteome research.

[39]  M. Burg,et al.  Intracellular Organic Osmolytes: Function and Regulation* , 2008, Journal of Biological Chemistry.

[40]  R. L. Nielsen,et al.  Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial , 2017, Gut.

[41]  G. Latkovskis,et al.  Determination of trimethylamine-N-oxide in combination with L-carnitine and γ-butyrobetaine in human plasma by UPLC/MS/MS. , 2015, Biomedical chromatography : BMC.

[42]  A. Gallagher,et al.  Biomarkers of intake for coffee, tea, and sweetened beverages , 2018, Genes & Nutrition.

[43]  L. Servillo,et al.  Carnitine Precursors and Short-Chain Acylcarnitines in Water Buffalo Milk. , 2018, Journal of agricultural and food chemistry.

[44]  F. Bushman,et al.  Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis , 2013, Nature Medicine.

[45]  L. T. Te Morenga,et al.  Carbohydrate quality and human health: a series of systematic reviews and meta-analyses , 2019, The Lancet.

[46]  H. Meltzer,et al.  Nordic Nutrition Recommendations 2004 – integrating nutrition and physical activity , 2004 .

[47]  S. Hazen,et al.  L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans , 2018, The Journal of clinical investigation.

[48]  A. Giovane,et al.  Betaines in fruits of Citrus genus plants. , 2011, Journal of agricultural and food chemistry.

[49]  A. Ross,et al.  Cereal foods are the major source of betaine in the Western diet--analysis of betaine and free choline in cereal foods and updated assessments of betaine intake. , 2014, Food chemistry.

[50]  Zuo Zhang,et al.  Trigonelline inhibits caspase 3 to protect &bgr; cells apoptosis in streptozotocin‐induced type 1 diabetic mice , 2018, European journal of pharmacology.

[51]  P. Ueland,et al.  Plasma choline, homocysteine and vitamin status in healthy adults supplemented with krill oil: a pilot study , 2018, Scandinavian journal of clinical and laboratory investigation.

[52]  Eric J. Brunner,et al.  Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes , 2009, Diabetes Care.

[53]  Jian Yan,et al.  Trimethylamine‐N‐oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial , 2017, Molecular nutrition & food research.

[54]  M. Jokela,et al.  Accelerated Increase in Serum Interleukin-1 Receptor Antagonist Starts 6 Years Before Diagnosis of Type 2 Diabetes , 2010, Diabetes.

[55]  Ville Koistinen,et al.  Diets rich in whole grains increase betainized compounds associated with glucose metabolism. , 2018, The American journal of clinical nutrition.

[56]  R. Bertolo,et al.  The nutritional burden of methylation reactions , 2013, Current opinion in clinical nutrition and metabolic care.

[57]  H. Adlercreutz,et al.  Alkylresorcinols from whole-grain wheat and rye are transported in human plasma lipoproteins. , 2007, The Journal of nutrition.