Umbilical cord blood metabolome differs in relation to delivery mode, birth order and sex, maternal diet and possibly future allergy development in rural children

Abstract

Allergy is one of the most common diseases among young children yet all factors that affect development of allergy remain unclear. In a small cohort of 65 children living in the same rural area of south-west Sweden, we have previously found that maternal factors, including prenatal diet, affect childhood allergy risk, suggesting that in utero conditions may be important for allergy development. Here, we studied if metabolites in the umbilical cord blood of newborns may be related to development of childhood allergy, accounting for key perinatal factors such as mode of delivery, birth order and sex. Available umbilical cord blood plasma samples from 44 of the participants were analysed using gas chromatography-mass spectrometry metabolomics; allergy was diagnosed by specialised paediatricians at ages 18 months, 3 years and 8 years and included eczema, asthma, food allergy and allergic rhinoconjunctivitis. Nineteen cord blood metabolites were related to future allergy diagnosis though there was no clear pattern of up- or downregulation of metabolic pathways. In contrast, perinatal factors birth order, sex and mode of delivery affected several energy and biosynthetic pathways, including glutamate and aspartic acid—histidine metabolism (p = 0.004) and the tricarboxylic acid cycle (p = 0.006) for birth order; branched chain amino acid metabolism (p = 0.0009) and vitamin B6 metabolism (p = 0.01) for sex; and glyoxylate and dicarboxylic acid metabolism (p = 0.005) for mode of delivery. Maternal diet was also related to some of the metabolites associated with allergy. In conclusion, the cord blood metabolome includes individual metabolites that reflect lifestyle, microbial and other factors that may be associated with future allergy diagnosis, and also reflects temporally close events/factors. Larger studies are required to confirm these associations, and perinatal factors such as birth order or siblings must be considered in future cord-blood metabolome studies.

A Systematic Review of Metabolic Alterations Underlying IgE‐Mediated Food Allergy in Children

“…[42] As such, increased cellular energy requirement and a disrupted TCA cycle might be hypothesized, especially since mitochondrial function and elevated serum IgE levels are known to be correlated. [53][54][55] Moreover, a disrupted TCA cycle early in life could be hypothesized due to decreased levels of the TCA intermediates isocitrate and 𝛼-ketoglutarate in cord blood, [56] with the latter being a key molecule in the determination of the overall rate of the TCA cycle. [43]…”

Associations of maternal and infant metabolomes with immune maturation and allergy development at 12 months in the Swedish NICE-cohort

“…Metabolites previously associated with manifest allergy. We selected metabolites for targeted analyses from 13 previously published studies [34][35][36][37][39][40][41][42][43][45][46][47][48] where associations between metabolites and allergic outcomes were found, 151 metabolites based on analysis of plasma, 20 on urine and 11 on exhaled breath. Of all the 182 metabolites that were associated with manifest allergy in these studies, we found five of them in cord plasma to be associated with future allergy in our study.…”

“…Focusing on predictive biomarkers could help to identify individuals at risk before the onset of symptoms as well as to help identify targets for preventive strategies. In a previous pilot study in a smaller cohort, we have prospectively predicted allergy development from the umbilical cord plasma GC–MS/MS metabolome 45 . To extend this, we here investigate the cord blood metabolome as well as the maternal metabolome in a larger cohort.…”

“…The aim of this study was to determine if there are relationships of the plasma metabolomes from mothers taken in the early third trimester and at delivery, and from infant umbilical cords at delivery with subsets of infant immune cells up to 4 months after delivery. Furthermore, the study also aimed to investigate the capacity of the metabolomes to predict allergic outcomes (atopic eczema, food allergy and asthma) in the infant, and examine if biomarkers found in our pilot study 45 could be replicated. In addition, the study investigated whether previously reported biomarker candidates of manifest disease could be observed in the metabolic profiles of the present study and prospectively associated with allergy.…”

Metabolic Phenotypes in Asthmatic Adults: Relationship with Inflammatory and Clinical Phenotypes and Prognostic Implications

“…A study that used GC–MS to retrospectively analyse the metabolome in preserved umbilical cord blood from 44 children (who were 8 years old at the time of the study) showed that, among several modulatory factors, sex also had a significant influence on observed differences in metabolic pathways and their possible impact on the subsequent development of allergy [ 131 ]. This study showed that sex significantly influenced branched amino acid metabolism and vitamin B6 metabolism.…”