Integrated metabolome analysis reveals novel connections between maternal fecal metabolome and the neonatal blood metabolome in women with gestational diabetes mellitus

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. Gestational diabetes mellitus (GDM) has attracted worldwide public health concern due to its adverse maternal, fetal and neonatal outcomes. GDM is a serious pregnancy complication with various risk factors 1 , including overweight, obesity, a family history of diabetes, advanced maternal age, etc. GDM has been linked with an increased risk of inborn errors of metabolism (IEMs) in offspring 2,3. IEMs are caused by inherited genetic defects and can be influenced by environmental stimuli 4. Accumulating evidence suggests that maternal hyperglycemia is associated

Altered gut bacterial and metabolic signatures and their interaction in gestational diabetes mellitus

“…Previously, using untargeted metabolic profiling, Zhao et al 21 found that the overall fecal metabolomic signature of GDM was distinct from that of HC. They also found that fecal amino acid levels (e.g.…”

Current progress in metabolomics of gestational diabetes mellitus

“…Systems biology inaugurated a new era of biological and biomedical research, which is different from the traditional one-gene-at-a-time approach, which discovers detailed molecular functions of individual genes or proteins[ 13 ]. Systems biology includes genomics, transcriptomics, proteomics, and metabolomics to comprehensively research the changes in biological systems under physiological and pathological conditions[ 14 ]. Among them, the concept of metabolomics was first put forward by Nicholson et al [ 15 ] in 1999.…”

“…In previous studies, many risk factors for GDM have been identified, including advanced maternal age, family history of diabetes, prepregnancy overweight and obesity, and genetic components[ 14 ]. However, the etiology and pathogenesis of GDM are still unclear.…”

Epigenetic Issues. The Link Between Microbiota and Gestational Diabetes.

“…As mentioned above, it is now suspected that microbiota metabolites play a main part in maternal epigenetic regulation of GDM and in programming the child's metabolite profile. In the publication by Zhao et al [106], the relationship between maternal faecal matabolome and neonatal blood metabolome was investigated. The authors observed a negative prevalence in the presence of 4 different fecal metabolites in mothers with GDM compared to the control group -lysine, putrescine, guanidinoacetate and hexadecanedioate.…”