TY - JOUR

T1 - Fish-oil supplementation in pregnancy, child metabolomics and asthma risk

AU - Rago, Daniela

AU - Rasmussen, Morten A.

AU - Lee-Sarwar, Kathleen A.

AU - Weiss, Scott T.

AU - Lasky-Su, Jessica

AU - Stokholm, Jakob

AU - Bønnelykke, Klaus

AU - Chawes, Bo L.

AU - Bisgaard, Hans

PY - 2019

Y1 - 2019

N2 - Background: We recently demonstrated that maternal dietary supplementation with fish oil-derived n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy reduces the risk of asthma in the offspring but the mechanisms involved are unknown. Methods: Here we investigated potential metabolic mechanisms using untargeted liquid chromatography-mass spectrometry-based metabolomics on 577 plasma samples collected at age 6 months in the offspring of mothers participating in the n-3 LCPUFA randomized controlled trial. First, associations between the n-3 LCPUFA supplementation groups and child metabolite levels were investigated using univariate regression models and data-driven partial least square discriminant analyses (PLS-DA). Second, we analyzed the association between the n-3 LCPUFA metabolomic profile and asthma development using Cox-regression. Third, we conducted mediation analyses to investigate whether the protective effect of n-3 LCPUFA on asthma was mediated via the metabolome. Findings: The univariate analyses and the PLS-DA showed that maternal fish oil supplementation affected the child's metabolome, especially with lower levels of the n-6 LCPUFA pathway-related metabolites and saturated and monounsaturated long-chain fatty acids-containing compounds, lower levels of metabolites of the tryptophan pathway, and higher levels of metabolites in the tyrosine and glutamic acid pathway. This fish oil-related metabolic profile at age 6 months was significantly associated with a reduced risk of asthma by age 5 and the metabolic profile explained 24% of the observed asthma-protective effect in the mediation analysis. Interpretation: Several of the observed pathways may be involved in the asthma-protective effect of maternal n-3 LCPUFA supplementation and act as mediators between the intervention and disease development. Funding: COPSAC is funded by private and public research funds all listed on www.copsac.com.

AB - Background: We recently demonstrated that maternal dietary supplementation with fish oil-derived n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy reduces the risk of asthma in the offspring but the mechanisms involved are unknown. Methods: Here we investigated potential metabolic mechanisms using untargeted liquid chromatography-mass spectrometry-based metabolomics on 577 plasma samples collected at age 6 months in the offspring of mothers participating in the n-3 LCPUFA randomized controlled trial. First, associations between the n-3 LCPUFA supplementation groups and child metabolite levels were investigated using univariate regression models and data-driven partial least square discriminant analyses (PLS-DA). Second, we analyzed the association between the n-3 LCPUFA metabolomic profile and asthma development using Cox-regression. Third, we conducted mediation analyses to investigate whether the protective effect of n-3 LCPUFA on asthma was mediated via the metabolome. Findings: The univariate analyses and the PLS-DA showed that maternal fish oil supplementation affected the child's metabolome, especially with lower levels of the n-6 LCPUFA pathway-related metabolites and saturated and monounsaturated long-chain fatty acids-containing compounds, lower levels of metabolites of the tryptophan pathway, and higher levels of metabolites in the tyrosine and glutamic acid pathway. This fish oil-related metabolic profile at age 6 months was significantly associated with a reduced risk of asthma by age 5 and the metabolic profile explained 24% of the observed asthma-protective effect in the mediation analysis. Interpretation: Several of the observed pathways may be involved in the asthma-protective effect of maternal n-3 LCPUFA supplementation and act as mediators between the intervention and disease development. Funding: COPSAC is funded by private and public research funds all listed on www.copsac.com.

KW - Childhood asthma

KW - Fish oil

KW - Metabolomics

U2 - 10.1016/j.ebiom.2019.07.057

DO - 10.1016/j.ebiom.2019.07.057

M3 - Journal article

C2 - 31399385

AN - SCOPUS:85070729446

VL - 46

SP - 399

EP - 410

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -