Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
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Evaluation Summary:
This well-executed study looks at the association of urinary metabolites to the types of diets consumed by European children. Using NMR they find four metabolites that are predictive of a Mediterranean diet. This presents both an approach additional to traditional dietary questionnaire methods and potential insights into biological pathways and will be of interest to nutritionists and epidemiologists.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewer remained anonymous to the authors.)
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Abstract
Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1 H NMR spectroscopy in a multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N -methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.
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Author Response:
Reviewer #1 (Public Review):
This is a well-executed study looking at the association of urinary metabolites to the types of diets consumed by European children. They focus on four analytes that have opposing patterns from a "good" KIDMED Mediterranean style diet versus a "bad" diet with processed foods and high sugars. They then create an association with levels of C-peptide, which has in turn been linked to health outcomes.
Overall there is extensive data provided in the supplementary data to justify their findings. The one omission is the effects of activity levels and total caloric consumption. There is an attempt to link body weight to C-peptide associations, but in a minor revision, it would be nice to also include MBI as a parameter for the concentrations of metabolites.
We thank the reviewer for his/her …
Author Response:
Reviewer #1 (Public Review):
This is a well-executed study looking at the association of urinary metabolites to the types of diets consumed by European children. They focus on four analytes that have opposing patterns from a "good" KIDMED Mediterranean style diet versus a "bad" diet with processed foods and high sugars. They then create an association with levels of C-peptide, which has in turn been linked to health outcomes.
Overall there is extensive data provided in the supplementary data to justify their findings. The one omission is the effects of activity levels and total caloric consumption. There is an attempt to link body weight to C-peptide associations, but in a minor revision, it would be nice to also include MBI as a parameter for the concentrations of metabolites.
We thank the reviewer for his/her positive feedback. We agree that inclusion of information on physical activity levels and total caloric consumption would strengthen our study. Unfortunately, we do not have available data on these variables. To counteract this, we adjusted all our models for child sedentary behavior (minutes/day of time spent watching TV, playing computer games or other sedentary games) which has been shown to associate to physical activity levels - this association could be due to the fact that the time devoted to sedentary screen-time activities affects availability of time devoted for exercise, or vice versa.(1-3) Further, we adjusted our models for child body mass index (BMI), a measure that strongly correlates to energy intake, and assessed ultra-processed food intake as proportion of total food intake in order to take into account inter-individual differences in total food (and hence caloric) consumption. We clarify these points in the discussion section.
Regarding the second part of reviewer’s comment to consider BMI as a parameter for the concentrations of metabolites, we considered, and controlled for, any potential influence of BMI on the associations of both diet and C-peptide with the urinary metabolites as all our models were adjusted for this measure. We have previously reported the associations of children’s BMI with the urinary metabolome in the same study population (Lau CHE et al (4)) and hence we did not repeat this analysis in our manuscript. In our previous HELIX study by Lau CHE at al, we found significant associations between children’s BMI z-score and three urinary metabolites; positive associations with valine and 4-deoxyerythronic acid and a negative association with pantothenic acid. Of these metabolites, we found that KIDMED score was positively associated with pantothenic acid after adjustment for BMI (Supplementary Table 5), suggesting that Mediterranean diet adherence could affect urinary levels of this metabolite independently of BMI. Further, in our analysis, we found that UPF intake was negatively associated with the branched-chain amino acid (BCAA) valine after adjustment for BMI. Even though the importance of the BCAAs in adiposity has been reported previously, our findings provide an important foundation for future research to better understand the role of UPF intake on BCAA metabolism. Throughout the discussion section, we now discuss our results in context with our previous HELIX analysis examining associations of BMI with the urinary metabolites.
Modified manuscript text:
"We did not have data available on children’s physical activity. Nevertheless, we adjusted all our models for sedentary behavior (including time spent in front of the screen) which has been shown to associate to physical activity levels, as the time devoted to sedentary screen-time activities might affect availability of time devoted for exercise, or vice versa.(1-3) Further, we did not have data available to control for energy intake. However, in all our models, we included BMI of the children, a measure strongly correlated to energy intake,(5) and assessed ultra-processed food intake as proportion of total food intake."
"In addition, adherence to the Mediterranean diet was also positively associated with urinary levels of pantothenic acid and acetate. Both compounds have a central role in human biochemistry and the metabolism and synthesis of carbohydrates, proteins, and fats. Pantothenic acid (vitamin B5, necessary to form coenzyme-A) is present in many foods, and we have previously reported a positive association between consumption of dairy products and urinary pantothenic acid in the same study population.(4) Further, we have previously shown that BMI is negatively associated with urinary levels of this metabolite,(4) and our results suggest that higher adherence to the Mediterranean diet associates with pantothenic acid independently of the potential influence of BMI."
"Moreover, we found that UPF intake was negatively associated with two urinary amino acids, valine and tyrosine. Tyrosine is regarded as a conditionally essential amino acid in adults and essential in children. Foods high in dietary tyrosine include dairy, meat, eggs, beans, nuts, grains. Tyrosine is a precursor for neurotransmitters and hormones, increases dopamine availability which in turn could enhance cognitive performance.(6) Valine is an essential branch chain amino acid (BCAA) critical to energy homeostasis, protein and muscle metabolism.(7,8) In many studies, it has been observed that elevated BCAAs are associated with insulin resistance and diabetes.(9) Also, in our previous HELIX study,(4) we found that urinary valine was associated with higher children’s BMI. However, it remains to be eludicated whether these associations are causal (e.g. via mTOR activation) or consequential (e.g. due to reduced mitochondrial oxidation) in metabolic disease,(9) and whether UPF intake plays a role in the etiology of the association of BCAAs with metabolic health."
References:
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- Lau CE, Siskos AP, Maitre L, et al. Determinants of the urinary and serum metabolome in children from six European populations. BMC Med. 2018;16(1):202.
- Jakes RW, Day NE, Luben R, et al. Adjusting for energy intake--what measure to use in nutritional epidemiological studies? Int J Epidemiol. 2004;33(6):1382-1386.
- Kühn S, Düzel S, Colzato L, et al. Food for thought: association between dietary tyrosine and cognitive performance in younger and older adults. Psychological Research. 2019;83(6):1097-1106.
- Brosnan JT, Brosnan ME. Branched-Chain Amino Acids: Enzyme and Substrate Regulation. The Journal of Nutrition. 2006;136(1):207S-211S.
- Nie C, He T, Zhang W, Zhang G, Ma X. Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int J Mol Sci. 2018;19(4).
- Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10(12):723-736.
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Evaluation Summary:
This well-executed study looks at the association of urinary metabolites to the types of diets consumed by European children. Using NMR they find four metabolites that are predictive of a Mediterranean diet. This presents both an approach additional to traditional dietary questionnaire methods and potential insights into biological pathways and will be of interest to nutritionists and epidemiologists.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewer remained anonymous to the authors.)
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Public Review:
This is a well-executed study looking at the association of urinary metabolites to the types of diets consumed by European children. They focus on four analytes that have opposing patterns from a "good" KIDMED Mediterranean style diet versus a "bad" diet with processed foods and high sugars. They then create an association with levels of C-peptide, which has in turn been linked to health outcomes.
Overall there is extensive data provided in the supplementary data to justify their findings. The one omission is the effects of activity levels and total caloric consumption. There is an attempt to link body weight to C-peptide associations, but in a minor revision, it would be nice to also include MBI as a parameter for the concentrations of metabolites.
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