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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #352707
Title: Concentrations of purine metabolites are elevated in human fluids from adults and infants and in livers from mice fed diets depleted of bovine milk exosomes and their RNA cargos

Author
item AGUILAR-LOZANO, ANA - University Of Nebraska
item BAIER, SCOTT - University Of Nebraska
item GROVE, RYAN - University Of Nebraska
item SHU, JIANG - University Of Nebraska
item LEIFERMAN, AMY - University Of Nebraska
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item CUI, JUAN - University Of Nebraska
item Badger, Thomas
item ADAMEC, JIRI - University Of Nebraska
item ANDRES, ALINE - Arkansas Children'S Nutrition Research Center (ACNC)
item ZEMPLENI, JANOS - University Of Nebraska

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2018
Publication Date: 12/5/2018
Citation: Aguilar-Lozano, A., Baier, S., Grove, R., Shu, J., Leiferman, A., Mercer, K., Cui, J., Badger, T.M., Adamec, J., Andres, A., Zempleni, J. 2018. Concentrations of purine metabolites are elevated in human fluids from adults and infants and in livers from mice fed diets depleted of bovine milk exosomes and their RNA cargos. Journal of Nutrition. 148(12):1886-1894. https://doi.org/10.1093/jn/nxy223.
DOI: https://doi.org/10.1093/jn/nxy223

Interpretive Summary: Children and adults consuming milk, and infants consuming cow's milk-based formula, are provided a variety of milk-derived factors that can impact health. For instance, humans can absorb the naturally-occurring bovine (cow) milk macromolecules called exosomes, which ferry a variety of factors including microRNAs. Previously, in mouse studies, consumption of a milk exosome-depleted diet was found to cause a decrease in blood plasma microRNAs and an increase in liver purine pathway metabolites compared to mice fed an exosome sufficient diet. The origins of this change in purine metabolism remain to be fully elaborated, and the role of milk exosomes in human purine metabolism is not known. The first objective of the study was to conduct a comprehensive analysis of liver purine metabolites and purine enzymes expression from mice consuming diets replete with or depleted of bovine milk exosomes. The second objective was to assess the effects of dairy milk intake on purine metabolites in human adults and infants. A murine model was used to collect hepatic samples at age 7 weeks from mice fed diets containing or depleted of bovine milk exosomes. Plasma and urine samples were collected from adults who consumed dairy products or avoided dairy products. Urine samples were collected from infants fed human milk, milk formula or soy formula at age 3 months. The concentrations of 9 purine metabolites were higher in livers from mice fed a milk exosome-depleted diet compared to mice fed a milk exosome-containing diet. Key enzymes involved in purine metabolism were differentially expressed between the two groups. The concentrations of purine metabolites in plasma and urine in a group of dairy-avoiding adult humans were 1.6 fold higher compared to diary consumers. The urinary concentrations of 13 purine metabolites were significantly higher in soy-based formula fed infants compared to breastfed infants or those fed dairy-based infant formula. This study provides evidence that bovine milk exosomes and their contents can alter purine metabolism pathways in liver, and suggest that these observations in animal studies translate to humans, as well. The results highlight a new mechanism by which milk intake modifies adult and infant physiology and health.

Technical Abstract: Humans and mice absorb bovine milk exosomes and their RNA cargos. The objectives of this study were to determine whether milk exosome– and RNA-depleted (ERD) and exosome- and RNA-sufficient (ERS) diets alter the concentrations of purine metabolites in mouse livers, and to determine whether diets depleted of bovine milk alter the plasma concentration and urine excretion of purine metabolites in adults and infants, respectively. C57BL/6 mice were fed ERD (providing 2% of the microRNA cargos compared with ERS) and ERS diets starting at age 3 wk; livers were collected at age 7 wk. Plasma and 24-h urine samples were collected from healthy adults who consumed (DCs) or avoided (DAs) dairy products. Spot urine samples were collected from healthy infants fed human milk (HM), milk formula (MF), or soy formula (SF) at age 3 mo. Purine metabolites were analyzed in liver, plasma, and urine; mRNAs and microRNAs were analyzed in the livers of female mice. We found that 9 hepatic purine metabolites in ERD-fed mice were 1.76 +/- 0.43 times the concentrations in ERS-fed mice (P < 0.05). Plasma concentrations and urine excretion of purine metabolites in DAs was <=1.62 +/- 0.45 times the concentrations in DCs (P < 0.05). The excretion of 13 purine metabolites in urine from SF infants was <=175 +/- 39 times the excretion in HM and MF infants (P < 0.05). mRNA expression of 5-nucleotidase, cytosolic IIIB, and adenosine deaminase in mice fed ERD was 0.64 +/- 0.52 and 0.60 +/- 0.28 times the expression in mice fed ERS, respectively. Diets depleted of bovine-milk exosomes and RNA cargos caused increases in hepatic purine metabolites in mice, and in plasma and urine from human adults and infants, compared with exosome-sufficient controls. These findings are important, because purines play a role in intermediary metabolism and cell signaling.