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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:BackgroundThe maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts of maternal microbial metabolites, we compared full-term fetuses from germ-free and specific pathogen-free mouse dams by gene expression profiling and non-targeted metabolomics.ResultsIn the fetal intestine, critical genes mediating host-microbe interactions, innate immunity, and epithelial barrier were differentially expressed. Interferon and inflammatory signaling genes were downregulated in the intestines and brains of the fetuses from germ-free dams. The expression of genes related to neural system development and function, translation and RNA metabolism, and regulation of energy metabolism were significantly affected. The gene coding for the insulin-degrading enzyme (Ide) was most significantly downregulated in all tissues. In the placenta, genes coding for prolactin and other essential regulators of pregnancy were downregulated in germ-free dams. These impacts on gene expression were strongly associated with microbially modulated metabolite concentrations in the fetal tissues. Aryl sulfates and other aryl hydrocarbon receptor ligands, the trimethylated compounds TMAO and 5-AVAB, Glu-Trp and other dipeptides, fatty acid derivatives, and the tRNA nucleobase queuine were among the compounds strongly associated with gene expression differences. A sex difference was observed in the fetal responses to maternal microbial status: more genes were differentially regulated in male fetuses than in females.ConclusionsThe maternal microbiota has a major impact on the developing fetus, with male fetuses potentially more susceptible to microbial modulation. The expression of genes important for the immune system, neurophysiology, translation, and energy metabolism are strongly affected by the maternal microbial status already before birth. These impacts are associated with microbially modulated metabolites. We identified several microbial metabolites which have not been previously observed in this context. Many of the potentially important metabolites remain to be identified.

Project description:Studies have indicated that the ethanol exposure impairs the gut microbiota, At the same time, high levels of alcohol exposure damage sperm in mice. However, whether the gut microbiota is involved in mediating the effects of alcohol on sperm quality remains unclear. This study aimed to assess the effect of chronic alcohol consumption on intestinal microbiota in mice and analyze the potential pathophysiological effect of altered intestinal microbiota on sperm quality. We established a mouse model of chronic alcohol consumption by allowing male C57 mice to freely ingest 10% ethanol for 10 weeks, and collected the fecal microbiota of the male mice in the chronic drinking group (alcohol) and the control group (control) and transplanted the specimens into the transplant groups (the alcohol-fecal microbiota transplantation [FMT] group and the control-FMT group). Sperm quality was significantly decreased in the alcohol-FMT group compared with the control-FMT group. Gut microbiota analysis revealed that the abundance of 11 operational taxonomic units (OTUs) was altered in the alcohol-FMT group. Nontargeted metabolomics identified 105 differentially altered metabolites, which were mainly annotated to amino acids, lipids, glycerophosphoethanolamine, organic oxygenic compounds, organic acids and their derivatives, steroids, and flavonoids. In particular, the oxidative phosphorylation pathway, which is the key to spermatogenesis, was significantly enriched in the alcohol-FMT group. Moreover, compared with the control-FMT group, the alcohol-FMT group presented significantly higher serum endotoxin and inflammatory cytokine levels, with more pronounced T cell and macrophage infiltration in the intestinal lamina propria and elevated levels of testicular inflammatory cytokines. In addition, RNA sequencing showed significant differences in the expression of testis-related genes between the alcohol-FMT group and the control-FMT group. In particular, the expression of genes involved in gamete meiosis, testicular mitochondrial function, and the cell division cycle was significantly reduced in alcohol-FMT mice. In conclusion, these findings indicated that intestinal dysbiosis induced by chronic alcohol consumption may be an important factor contributing to impaired sperm quality. Chronic alcohol consumption induces intestinal dysbiosis, which then leads to metabolic disorders, elevated serum endotoxin and inflammatory cytokine levels, testicular inflammation, abnormal expression of related genes, and ultimately, impaired sperm quality. These findings are potentially useful for the treatment of male infertility.

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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