Proline betaine and its biotransformation products in fasting urine samples are potential biomarkers of habitual citrus fruit consumption
Open accessAbstract
The lack of robust measures of dietary exposure hinders a quantitative understanding of causal relationships between diet and health. Non-targeted metabolite fingerprinting was used to explore the relationships between citrus exposure in free-living human subjects, estimated by a FFQ, and the chemical content of urine. Volunteers (study 1, n 12; study 2, n 11) were classified into high-, medium- and low-frequency citrus consumption groups. Overnight and spot fasting urine samples were obtained after exposure to a standardised citrus-free evening meal. The urine samples were analysed by flow injection electrospray-ionisation MS followed by supervised multivariate data classification analysis to discover discriminatory features associated with the level of citrus exposure. Good separation of high and low citrus consumption classes was achieved. Deeper exploration of high-ranked explanatory mass signals revealed several correlated signals derived from proline betaine. Targeted analysis of the relative levels of proline betaine in both fasting and overnight urine samples demonstrated good correlation with FFQ exposure data. Acute exposure of volunteers to orange juice resulted in the appearance of proline betaine and several biotransformed products in postprandial urine samples. Biomarker validation showed sensitivities of 80·8-92·2 % and specificities of 74·2-94·1 % (false discovery rate-adjusted P values < 0·05) for elevated proline betaine in participants who reported high citrus consumption. Proline betaine biotransformation products displayed weaker quantitative relationships with habitual citrus exposure. Targeted screening for the presence of biotransformation products of hesperidin and narirutin, known to be abundant in oranges, revealed that they were relatively poor indicators of citrus exposure.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Proline betaine and lycopene are well-established biomarkers for citrus fruit and tomato products, respectively.
“Proline betaine and lycopene are well-established biomarkers for citrus fruit and tomato products, respectively (44,45).”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Development, validation and utilisation of food-frequency questionnaires – a review
Cade, J., Thompson, R., Burley, V., & Warm, D. (2002) · Public Health Nutrition · doi:10.1079/phn2001318 · Cited by 1,423 · see citing works
Human metabolic phenotype diversity and its association with diet and blood pressure
Holmes, E., Loo, R. L., Stamler, J., Bictash, M., Yap, I. K. S., Chan, Q., Ebbels, T., De Iorio, M., Brown, I. J., Veselkov, K. A., et al. (2008) · Nature · doi:10.1038/nature06882 · Cited by 1,054 · see citing works
Bingham, S. A., Gill, C., Welch, A., Day, K., Cassidy, A., Khaw, K. T., Sneyd, M. J., Key, T. J. A., Roe, L., & Day, N. E. (1994) · British Journal of Nutrition · doi:10.1079/bjn19940064 · Cited by 749 · see citing works
Bingham, S. (1997) · International Journal of Epidemiology · doi:10.1093/ije/26.suppl_1.s137 · Cited by 634 · see citing works
Scalbert, A., Brennan, L., Fiehn, O., Hankemeier, T., Kristal, B. S., van Ommen, B., Pujos-Guillot, E., Verheij, E., Wishart, D., & Wopereis, S. (2009) · Metabolomics · doi:10.1007/s11306-009-0168-0 · Cited by 565 · see citing works
Spencer, J. P. E., Mohsen, M. M. A. E., Minihane, A.-M., & Mathers, J. C. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507798938 · Cited by 490 · see citing works
Self-citationBiomarkers in nutritional epidemiology: applications, needs and new horizons
Jenab, M., Slimani, N., Bictash, M., Ferrari, P., & Bingham, S. A. (2009) · Human Genetics · doi:10.1007/s00439-009-0662-5 · Cited by 448 · see citing works
Is It Time to Abandon the Food Frequency Questionnaire?
Kristal, A. R., Peters, U., & Potter, J. D. (2005) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-ed1 · Cited by 427 · see citing works
Polyphenols and health: What compounds are involved?
Rio, D. D., Costa, L. G., Lean, M. E. J., & Crozier, A. (2009) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2009.05.015 · Cited by 367 · see citing works
Quantitation of Flavonoid Constituents in Citrus Fruits
Kawaii, S., Tomono, Y., Katase, E., Ogawa, K., & Yano, M. (1999) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf990153+ · Cited by 337 · see citing works
Walsh, M. C., Brennan, L., Malthouse, J. P. G., Roche, H. M., & Gibney, M. J. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/84.3.531 · Cited by 291 · see citing works
Heinzmann, S. S., Brown, I. J., Chan, Q., Bictash, M., Dumas, M.-E., Kochhar, S., Stamler, J., Holmes, E., Elliott, P., & Nicholson, J. K. (2010) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2010.29672 · Cited by 271 · see citing works
Biomarkers in nutritional epidemiology
Bingham, S. A. (2002) · Public Health Nutrition · doi:10.1079/phn2002368 · Cited by 246 · see citing works
Glycine betaine and glycine betaine analogues in common foods
de Zwart, F. J., Slow, S., Payne, R. J., Lever, M., George, P. M., Gerrard, J. A., & Chambers, S. T. (2003) · Food Chemistry · doi:10.1016/s0308-8146(03)00063-3 · Cited by 222 · see citing works
Urpí-Sardà, M., Monagas, M., Khan, N., Llorach, R., Lamuela-Raventós, R. M., Jáuregui, O., Estruch, R., Izquierdo-Pulido, M., & Andrés‐Lacueva, C. (2009) · Journal of Chromatography A · doi:10.1016/j.chroma.2009.07.058 · Cited by 182 · see citing works
Urinary flavonoids and phenolic acids as biomarkers of intake for polyphenol-rich foods
Mennen, L. I., Sapinho, D., Ito, H., Bertrais, S., Galan, P., Hercberg, S., & Scalbert, A. (2006) · British Journal Of Nutrition · doi:10.1079/bjn20061808 · Cited by 174 · see citing works
Draper, J., Enot, D. P., Parker, D., Beckmann, M., Snowdon, S., Lin, W., & Zubair, H. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-227 · Cited by 169 · see citing works
Self-citationUrinary metabolites as biomarkers of polyphenol intake in humans—a systematic review
Pérez-Jiménez, J., Hubert, J., Hooper, L., Cassidy, A., Manach, C., Williamson, G., & Scalbert, A. (2010) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2010.29924 · Cited by 159 · see citing works
Brett, G. M., Hollands, W. J., Needs, P. W., Teucher, B., Dainty, J. R., Davis, B. D., Brodbelt, J. S., & Kroon, P. A. (2008) · British Journal Of Nutrition · doi:10.1017/s000711450803081x · Cited by 152 · see citing works
Llorach, R., Urpi-Sarda, M., Jauregui, O., Monagas, M., & Andres-Lacueva, C. (2009) · Journal of Proteome Research · doi:10.1021/pr900470a · Cited by 144 · see citing works
Beckmann, M., Parker, D., Enot, D. P., Duval, E., & Draper, J. (2008) · Nature Protocols · doi:10.1038/nprot.2007.500 · Cited by 136 · see citing works
Self-citationBredsdorff, L., Nielsen, I. L. F., Rasmussen, S. E., Cornett, C., Barron, D., Bouisset, F., Offord, E., & Williamson, G. (2010) · British Journal Of Nutrition · doi:10.1017/s0007114509993679 · Cited by 129 · see citing works
Enot, D. P., Lin, W., Beckmann, M., Parker, D., Overy, D. P., & Draper, J. (2008) · Nature Protocols · doi:10.1038/nprot.2007.511 · Cited by 114 · see citing works
Self-citationNot the Time to Abandon the Food Frequency Questionnaire: Point
Willett, W. C., & Hu, F. B. (2006) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-06-0388 · Cited by 106 · see citing works
Major, H. J., Williams, R. E., Wilson, A., et al. (2006) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.2732 · Cited by 96 · see citing works
Urpí-Sardà, M., Garrido, I., Monagas, M., Gómez‐Cordovés, C., Medina‐Remón, A., Andrés‐Lacueva, C., & Bartolomé, B. (2009) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf901450z · Cited by 84 · see citing works
The betaine content of New Zealand foods and estimated intake in the New Zealand diet
Slow, S., Donaggio, M., Cressey, P. J., Lever, M., George, P. M., & Chambers, S. T. (2005) · Journal of Food Composition and Analysis · doi:10.1016/j.jfca.2004.05.004 · Cited by 84 · see citing works
Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics?
Favé, G., Beckmann, M., Draper, J., & Mathers, J. C. (2009) · Genes & Nutrition · doi:10.1007/s12263-009-0120-y · Cited by 76 · see citing works
Self-citationFavé, G., Beckmann, M., Lloyd, A. J., Zhou, S., Harold, G., Lin, W., Tailliart, K., Xie, L., Draper, J., & Mathers, J. C. (2011) · Metabolomics · doi:10.1007/s11306-011-0289-0 · Cited by 69 · see citing works
Self-citationJia, X., Craig, L. C. A., Aucott, L. S., Milne, A. C., & McNeill, G. (2008) · The journal of nutrition health & aging · doi:10.1007/bf03028622 · Cited by 63 · see citing works
Signorello, L. B., Buchowski, M. S., Cai, Q., Munro, H. M., Hargreaves, M. K., & Blot, W. J. (2010) · American Journal of Epidemiology · doi:10.1093/aje/kwp402 · Cited by 62 · see citing works
Biochemical validation of a self-administered semi-quantitative food-frequency questionnaire
Porrini, M., Gentile, M. G., & Fidanza, F. (1995) · British Journal Of Nutrition · doi:10.1079/bjn19950138 · Cited by 57 · see citing works
Atkinson, W., Downer, P., Lever, M., Chambers, S. T., & George, P. M. (2007) · European Journal of Nutrition · doi:10.1007/s00394-007-0684-5 · Cited by 54 · see citing works
Talegawkar, S. A., Johnson, E. J., Carithers, T., Taylor, H. A., Bogle, M. L., & Tucker, K. L. (2007) · Public Health Nutrition · doi:10.1017/s1368980007001310 · Cited by 52 · see citing works
Holmes, M. D., Powell, I. J., Campos, H., Stampfer, M. J., Giovannucci, E. L., & Willett, W. C. (2007) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1602641 · Cited by 48 · see citing works
Analysis of O -glucuronide conjugates in urine by electrospray ion trap mass spectrometry
Gu, J., Zhong, D., & Chen, X. Y. (1999) · Fresenius Journal of Analytical Chemistry · doi:10.1007/s002160051521 · Cited by 38 · see citing works
[HPLC-ESI/MS analysis of stachydrine and its metabolites in rat urine].
Chen, H., Shen, S.-L., Han, F., et al. (2006) · PubMed · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Box plots of the top positive-ion mode explanatory metabolite signals between 'high', 'medium' and 'low' habitual citrus fruit consumers. (a) m/z 144, fasting urine; (b) m/z 144, PRE urine; (c) m/z 166, fasting urine; (d) m/z 166, PRE urine; (e) m/z 182, fasting urine; (f) m/z 182, PRE urine; n 12 volunteers; between 'high' and 'low' citrus consumers, false discovery rate (FDR)-corrected P values , 0•05; between 'high' or 'low' and 'medium' consumers, FDR-corrected P values . 0•05 (see Table S6 of the supplementary material, available online at http://www.journals.cambridge.org/bjn, for complete t test results). The box indicates the interquar- tile range; the red horizontal bar indicates the median; vertical bars indicate the maximum and minimum values up to 1•5 £ interquartile range; error bars represent the standard error of twelve volunteers. 'PRE', pre-test day overnight urine voids; 'Fasting', spot urine sample after a 12 h (minimum) fast. TIC, total ion count.
Cited by
Sorted by citations
The food metabolome: a window over dietary exposure
Scalbert, A., Brennan, L., Manach, C., Andres-Lacueva, C., Dragsted, L. O., Draper, J., Rappaport, S. M., van der Hooft, J. J., & Wishart, D. S. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.076133 · Cited by 519 · see citing works
Self-citationWastewater-based epidemiology biomarkers: Past, present and future
Choi, P. M., Tscharke, B. J., Donner, E., O'Brien, J. W., Grant, S. C., Kaserzon, S. L., Mackie, R., O'Malley, E., Crosbie, N. D., Thomas, K. V., et al. (2018) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2018.06.004 · Cited by 486 · see citing works
The biology of ergothioneine, an antioxidant nutraceutical
Borodina, I., Kenny, L. C., McCarthy, C. M., Paramasivan, K., Pretorius, E., Roberts, T. J., van der Hoek, S. A., & Kell, D. B. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422419000301 · Cited by 296 · see citing works
Biomarkers of Nutrition and Health: New Tools for New Approaches
Picó, C., Serra, F., Rodríguez, A. M., Keijer, J., & Palou, A. (2019) · Nutrients · doi:10.3390/nu11051092 · Cited by 287 · see citing works
Pujos-Guillot, E., Hubert, J., Martin, J.-F., Lyan, B., Quintana, M., Claude, S., Chabanas, B., Rothwell, J. A., Bennetau-Pelissero, C., Scalbert, A., et al. (2013) · Journal of Proteome Research · doi:10.1021/pr300997c · Cited by 166 · see citing works
Draper, J., Lloyd, A. J., Goodacre, R., & Beckmann, M. (2013) · Metabolomics · doi:10.1007/s11306-012-0449-x · Cited by 144 · see citing works
Lloyd, A. J., Favé, G., Beckmann, M., Lin, W., Tailliart, K., Xie, L., Mathers, J. C., & Draper, J. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.017921 · Cited by 130 · see citing works
Self-citationMetabolomics and microbiomes as potential tools to evaluate the effects of the Mediterranean diet
Jin, Q., Black, A., Kales, S. N., Vattem, D., Ruiz-Canela, M., & Sotos-Prieto, M. (2019) · Nutrients · doi:10.3390/nu11010207 · Cited by 100 · see citing works
Fruits and vegetables: measuring intake and encouraging increased consumption
Woodside, J. V., Young, I. S., & McKinley, M. C. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112003059 · Cited by 90 · see citing works
May, D. H., Navarro, S. L., Ruczinski, I., Hogan, J., Ogata, Y., Schwarz, Y., Levy, L., Holzman, T., McIntosh, M. W., & Lampe, J. W. (2013) · British Journal Of Nutrition · doi:10.1017/s000711451300127x · Cited by 69 · see citing works
Beckmann, M., Lloyd, A. J., Haldar, S., Seal, C., Brandt, K., & Draper, J. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200777 · Cited by 55 · see citing works
Self-citation
- Authors
- Lloyd, A. J., Beckmann, M., Favé, G., Mathers, J. C., & Draper, J.
- Affiliations
- Aberystwyth University (GB)
- Newcastle University (GB)
- Corresponding author
- Draper, John
- Venue
- British Journal Of Nutrition
- Publisher
- Cambridge University Press (CUP)
- Published
- 2011-05-09
- Volume
- 106
- Issue
- 6
- Pages
- 812-824
- ISSN
- 0007-1145 (ISSN-L)
- 1475-2662
- OpenAlex
- W2110263387
- Cited by
- 152
- References
- 37
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 5 · 2023: 9 · 2022: 4 · 2021: 9 · 2020: 14 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 13 · 2015: 7 · 2014: 12 · 2013: 14 · 2012: 9
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal Of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- University of Pennsylvania
- Newcastle University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Keywords
- proline betaine, citrus fruit consumption, dietary biomarkers, urinary metabolites, biotransformation products, hesperidin, narirutin, orange juice, dietary exposure assessment, metabolic fingerprinting, biomarker validation
- MeSH terms
- Biotransformation, Citrus, Diet, Disaccharides, Dose-Response Relationship, Drug, Hesperidin, Humans, Models, Chemical, Proline, Time Factors, Biomarkers, Urinalysis, Spectroscopy, Fourier Transform Infrared, Spectrometry, Mass, Electrospray Ionization, Flavanones, Metabolomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
