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An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder.

ABSTRACT: Prenatal alcohol exposure (PAE) causes permanent cognitive disability. The enteric microbiome generates microbial-dependent products (MDPs) that may contribute to disorders including autism, depression, and anxiety; it is unknown whether similar alterations occur in PAE. Using a mouse PAE model, we performed untargeted metabolome analyses upon the maternal-fetal dyad at gestational day 17.5. Hierarchical clustering by principal component analysis and Pearson's correlation of maternal plasma (813 metabolites) both identified MDPs as significant predictors for PAE. The majority were phenolic acids enriched in PAE. Correlational network analyses revealed that alcohol altered plasma MDP-metabolite relationships, and alcohol-exposed maternal plasma was characterized by a subnetwork dominated by phenolic acids. Twenty-nine MDPs were detected in fetal liver and sixteen in fetal brain, where their impact is unknown. Several of these, including 4-ethylphenylsulfate, oxindole, indolepropionate, p-cresol sulfate, catechol sulfate, and salicylate, are implicated in other neurological disorders. We conclude that MDPs constitute a characteristic biosignature that distinguishes PAE. These MDPs are abundant in human plasma, where they influence physiology and disease. Their altered abundance here may reflect alcohol's known effects on microbiota composition and gut permeability. We propose that the maternal microbiome and its MDPs are a previously unrecognized influence upon the pathologies that typify PAE.

SUBMITTER: Virdee MS

PROVIDER: S-EPMC7794323 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder.

Virdee Manjot S MS Saini Nipun N Kay Colin D CD Neilson Andrew P AP Kwan Sze Ting Cecilia STC Helfrich Kaylee K KK Mooney Sandra M SM Smith Susan M SM

Scientific reports 20210108 1

Prenatal alcohol exposure (PAE) causes permanent cognitive disability. The enteric microbiome generates microbial-dependent products (MDPs) that may contribute to disorders including autism, depression, and anxiety; it is unknown whether similar alterations occur in PAE. Using a mouse PAE model, we performed untargeted metabolome analyses upon the maternal-fetal dyad at gestational day 17.5. Hierarchical clustering by principal component analysis and Pearson's correlation of maternal plasma (813 ...[more]

PMID: 33420159

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Project description:OBJECTIVES:Fetal alcohol spectrum disorders (FASD) is a worldwide problem. Maternal alcohol consumption is an important risk factor for FASD. It remains unknown which alcohol consumption patterns most strongly predict FASD. The objective of this study was to identify these. DESIGN:Systematic literature review. METHODS:We searched in PubMed, PsychINFO, PsycARTICLES, ERIC, CINAHL, Embase and MEDLINE up to August 2018. The query consisted of keywords and their synonyms related to FASD, pregnancy and behaviour. Studies were excluded when not published in English, were reviews or involved non-human subjects. Substantial heterogeneity precluded aggregation or meta-analysis of the data. Instead, data were qualitatively inspected. RESULTS:In total, 21 studies were eligible for further data analysis. All studies that measured both maternal alcohol drinking behaviours and FASD reported retrospective data on maternal drinking patterns, employing both continuous and categorical measures and exhibiting substantial heterogeneity in measures of alcohol consumption (eg, timing of exposure, quantification of alcohol measure and definition of a standard drink). Study quality improved over time and appeared higher for studies based on active case ascertainment, especially when conducted in schools and when behaviour was assessed through interviews. CONCLUSIONS:We aimed to identify specific maternal drinking behaviour(s) related to FASD. The state of the literature precludes such conclusions. Evidence-based preventive measures necessitate identifying which prenatal alcohol drinking behaviour(s) are most in need of intervention. Therefore, we formulate three recommendations for future research. First, future studies can optimise the value of the collected dataset through specifying measurements and reporting of maternal drinking behaviours and avoiding categorised measures (nominal or ordinal) whenever possible. Second, samples should not be selected based on FASD status, but instead, FASD status as well as maternal alcohol consumption should both be measured in a general population sample. Finally, we provide 10 reporting guidelines for FASD research.

Project description:Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated whether maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and we hypothesized that these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental efficiency (p = 0.0043). PAE downregulated placental transferrin receptor (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of the variability in fetal weight and 20% of the variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

Dataset Information

An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder.

Publications

An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder.

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