Integration of Traditional and Metabolomics Biomarkers Identifies Prognostic Metabolites for Predicting Responsiveness to Nutritional Intervention against Oxidative Stress and Inflammation

Abstract

Various statistical approaches can be applied to integrate traditional and omics biomarkers, allowing the discovery of prognostic markers to classify subjects into poor and good prognosis groups in terms of responses to nutritional interventions. Here, we performed a prototype study to identify metabolites that predict responses to an intervention against oxidative stress and inflammation, using a data set from a randomized controlled trial evaluating Korean black raspberry (KBR) in sedentary overweight/obese subjects. First, a linear mixed-effects model analysis with multiple testing correction showed that four-week consumption of KBR significantly changed oxidized glutathione (GSSG, q = 0.027) level, the ratio of reduced glutathione (GSH) to GSSG (q = 0.039) in erythrocytes, malondialdehyde (MDA, q = 0.006) and interleukin-6 (q = 0.006) levels in plasma, and seventeen NMR metabolites in urine compared with those in the placebo group. A subsequent generalized linear mixed model analysis showed linear correlations between baseline urinary glycine and N-phenylacetylglycine (PAG) and changes in the GSH:GSSG ratio (p = 0.008 and 0.004) as well as between baseline urinary adenine and changes in MDA (p = 0.018). Then, receiver operating characteristic analysis revealed that a two-metabolite set (glycine and PAG) had the strongest prognostic relevance for future interventions against oxidative stress (the area under the curve (AUC) = 0.778). Leave-one-out cross-validation confirmed the accuracy of prediction (AUC = 0.683). The current findings suggest that a higher level of this two-metabolite set at baseline is useful for predicting responders to dietary interventions in subjects with oxidative stress and inflammation, contributing to the emergence of personalized nutrition.

Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies

“…The third block comprises three studies that used metabolomics to predict weight loss (Geidenstam et al 2017a , b ; Stroeve et al 2016 ) and 11 randomized clinical trials (RCTs) aimed to assess the effects of weight loss interventions (both hypocaloric diet programs and exercise interventions) on the metabolomic profiles of overweight or obese human subjects (Table 2 ) (Almanza-Aguilera et al 2018 ; Duft et al 2017 ; Kang et al 2018 ; Leal-Witt et al 2018 ; Meucci et al 2017 ; Mills et al 2019 ; Munukka et al 2018 ; Palau-Rodriguez et al 2019 ; Perez-Cornago et al 2014 ; Zheng et al 2016a , b ). Additionally, the fourth block includes 11 articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans, such as inflammation or oxidative stress (Table 3 ) (Baldrick et al 2018 ; Gu et al 2013 ; Hernández-Alonso et al 2019 ; Hibberd et al 2019 ; Kim et al 2013 ; Kim et al 2017 ; Mayengbam et al 2019 ; Nieman et al 2012a , b ; Romo-Hualde et al 2018 ; Xu et al 2018 ).…”

“…Recently, other authors have investigated the effect of Korean black raspberry (KBR) supplement for 4 weeks on overweight or obese individuals with a sedentary lifestyle (Kim et al 2017 ) to identify metabolites that predict responses to such intervention against oxidative stress and inflammation (Table 3 ). Increased levels of several urinary AAs, organic acids and other type of metabolites were as betaine, N-phenylacetylglycine and phenylacetate were observed.…”

“…Other molecules reported in the literature have controversial roles, such as the nucleoside, adenosine. Although no evidence has suggested a possible correlation between the levels of this nucleoside and the obesity signature, polyphenol supplementation in overweight or obese adults decreases the plasma adenosine levels (Kim et al 2017 ). In contrast, a physical activity program increased urinary adenosine concentrations in overweight preadolescents (Meucci et al 2017 ).…”

Recent Advances in the Application of Metabolomics for Nutrition and Health

“…Such is the case when medical parameters e.g. glucose, HOMA-IR, enzyme activities or blood pressure records are associated with omics approaches (Drenos 2017, Kim, et al 2017, Sperisen, et al 2015, Yu and Zeng 2018. Lampe et al 2013 Accordingly, the complexity of the tools applied for processing and treatment of multiple data sets also increases at each level.…”

A big picture view of precision nutrition: from reductionism to holism

“…Meantime, metabolomics has begun to receive academic attention, serving as a useful alternative or complement to reveal the complex effects of diet on health [4]. Although limitations still exist, metabolomics also provides new opportunities to detect prognostic markers for predicting the responders to nutritional interventions [32].…”