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Prenatal Alcohol Exposure Selectively Induces Gut Microbiota Alterations in male adolescent C57Bl/6 Mice

ABSTRACT: Background: Alcohol consumption during pregnancy may cause a complex syndrome known as Fetal Alcohol Spectrum Disorders (FASD), characterized by lasting physical, cognitive, and behavioral impairments. While several mechanisms and potential treatments have been identified, no cure exists for FASD. Recent studies indicated that gut microbiome (GM) research could lead to promising diagnostic or therapeutic option. However, the GM’s role in FASD is still poor explored. This study aimed to examine how early PAE affects the GM of adolescent offspring to identify potential targets for early diagnosis or treatment. Methods: Female C57Bl/6 mice were exposed to 10% ethanol solution during the first 10 days of pregnancy, and then to water for the rest of gestation (PAE group). Control mice received only water throughout their entire pregnancy (Control group). Fecal and blood samples were collected to analyze GM composition and short-chain fatty acids (SCFAs), using 16S rRNA gene sequencing and gas chromatography-mass spectrometry. Results: PAE mice showed a significant reduction in alpha diversity and notable changes in beta diversity of their GM compared to controls. Gender analysis revealed that PAE males had distinct microbial genera compared to controls, with significant increases in Bacteroides, Bilophila and Clostridioides. Moreover, fecal analysis in males revealed higher levels of isobutyric, isovaleric, and 2-methylbutyric acids—metabolites known for their anti-inflammatory properties. Conclusions: These results suggest that PAE causes sex-specific alterations in the microbiota-gut- brain axis, highlighting the gut microbiota as a promising target for preventive or supportive therapies aimed at reducing the cognitive and behavioral impairments linked to FASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE304156 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.

Project description:Fetal Alcohol Spectrum Disorder (FASD) encompasses an array of effects of prenatal alcohol exposure (PAE), including physical abnormalities and cognitive and behavioral deficits. Disruptions of cortical development have been implicated in multiple PAE studies, with deficits including decreased progenitor proliferation, disrupted neuronal differentiation, aberrant radial migration of pyramidal neurons, and decreased cortical thickness. While several mechanisms of alcohol teratogenicity have been explored, how specific cell types in the brain at different developmental time points may be differentially affected by PAE is still poorly understood. In this study, we used single nucleus RNA sequencing (snRNAseq) to investigate whether moderate PAE from neurulation through peak cortical neurogenesis induces cell type-specific transcriptomic changes in the developing murine brain. Cluster analysis identified 25 neuronal cell types, including subtypes of neural epithelial cells (NECs), radial glial cells (RGCs), intermediate progenitor cells (IPCs), projection neurons, and interneurons. Only Wnt-expressing NECs showed a significant decrease in the percentage of cells after PAE, with no cell types showing PAE-induced apoptosis as measured by caspase expression. Cell cycle analysis revealed only a subtype of RGCs expressing the downstream Wnt signaling transcription factor Tcf7l2 had a decreased percentage of cells in the G2/M phase of the cell cycle, suggesting decreased proliferation in this RGC subtype and further implicating disrupted Wnt signaling after PAE at this early developmental timepoint. An increased pseudotime score in IPC and projection neuron cell types indicated that PAE led to increased or premature differentiation of these cells. Biological processes affected by PAE included the upregulation of pathways related to synaptic activity and neuronal differentiation and downregulation of pathways related to chromosome structure and the cell cycle. Several cell types showed a decrease in Wnt signaling pathways, with several genes related to Wnt signaling altered by PAE in multiple cell types. As Wnt has been shown to promote proliferation and inhibit differentiation at earlier stages in development, the downregulation of Wnt signaling may have resulted in premature neuronal maturation of projection neurons and their intermediate progenitors. Overall, these findings provide further insight into the cell type-specific effects of PAE during early corticogenesis.

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Prenatal Alcohol Exposure Selectively Induces Gut Microbiota Alterations in male adolescent C57Bl/6 Mice

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