Abstract
Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (IEMs). Maternal hyperglycemia exerts epigenetic effects on genes that encode IEM-associated enzymes, resulting in changes in the neonatal blood metabolome. However, the relationship between maternal gut microbiota and the neonatal blood metabolome remains poorly understood. This study aimed at understanding the connections between maternal gut microbiota and the neonatal blood metabolome in GDM. 1H-NMR-based untargeted metabolomics was performed on maternal fecal samples and targeted metabolomics on the matched neonatal dry blood spots from a cohort of 40 pregnant women, including 22 with GDM and 18 controls. Multi-omic association methods (including Co-Inertia Analysis and Procrustes Analysis) were applied to investigate the relationship between maternal fecal metabolome and the neonatal blood metabolome. Both maternal fecal metabolome and the matched neonatal blood metabolome could be separated along the vector of maternal hyperglycemia. A close relationship between the maternal and neonatal metabolomes was observed by multi-omic association approaches. Twelve out of thirty-two maternal fecal metabolites with altered abundances from 872 1H- NMR features (Bonferroni-adjusted P < 0.05) in women with GDM and the controls were identified, among which 8 metabolites contribute (P < 0.05 in a 999-step permutation test) to the close connection between maternal and the neonatal metabolomes in GDM. Four of these eight maternal fecal metabolites, including lysine, putrescine, guanidinoacetate, and hexadecanedioate, were negatively associated (Spearman rank correlation, coefficient value < −0.6, P < 0.05) with maternal hyperglycemia. Biotin metabolism was enriched (Bonferroni-adjusted P < 0.05 in the hypergeometric test) with the four-hyperglycemia associated fecal metabolites. The results of this study suggested that maternal fecal metabolites contribute to the connections between maternal fecal metabolome and the neonatal blood metabolome and may further affect the risk of IEMs.
Highlights
Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (IEMs)
Because plasma metabolome is significantly affected by the gut microbiota[20,21], we further examined whether hyperglycemia could differentiate the fecal metabolomes between GDM and the NDM controls
From the score scatter plot of Principle Component Analysis (PCA) (Fig. 1b) and Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) (Fig. 1d, the OPLS-DA model validated by a permutation test in Fig. S2a) of the offspring-matched maternal fecal metabolome, pregnant women with GDM were clearly separated from the NDM controls
Summary
Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (IEMs). Twelve out of thirty-two maternal fecal metabolites with altered abundances from 872 1H- NMR features (Bonferroni-adjusted P < 0.05) in women with GDM and the controls were identified, among which 8 metabolites contribute (P < 0.05 in a 999-step permutation test) to the close connection between maternal and the neonatal metabolomes in GDM Four of these eight maternal fecal metabolites, including lysine, putrescine, guanidinoacetate, and hexadecanedioate, were negatively associated (Spearman rank correlation, coefficient value < −0.6, P < 0.05) with maternal hyperglycemia. Because gestational hyperglycemia has been associated with increased risk of IEMs (featured by metabolic disorders), and maternal gut microbiota is proved to be a contributor of hyperglycemia, we hypothesized that GDM related changes of maternal gut microbiota contributes to the neonatal IEMs. To assess possible connections between maternal gut microbiota and the neonatal IEM-related metabolic disorders, we applied multi-omic association approaches to investigated the relationship between maternal fecal metabolome and the neonatal blood metabolome (Fig. S1). We further identified maternal fecal metabolites that are responsible for the variations of neonatal blood metabolome between GDM and the healthy control, and provide a discussion of the potential underlying connections
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