Maternal gut bacteria linked to changes in fetal brain metabolism
By Pooja Toshniwal Paharia Reviewed by Lily Ramsey, LLM Aug 23 2024
In a recent study published in Molecular Metabolism, researchers evaluated the impact of Bifidobacterium breve's presence in the maternal gut during pregnancy on fetal brain metabolism.
Study: Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice . Image Credit: Prostock-studio/Shutterstock.com Background
Fetal growth restriction (FGR) is a severe disorder in which a fetus fails to attain full development due to placental insufficiency during pregnancy. FGR could result in postnatal neurodevelopmental abnormalities, including motor and cognitive dysfunction, learning disabilities, and cerebral palsy.
Pharmacological therapies like aspirin, heparin, and sildenafil citrate have inconsistent impacts on pregnancy outcomes. Thus, effective treatments are required to avoid or lessen the adverse effects of FGR.
The gut microbiome can impact brain function and behavior, and targeting the maternal gut microbiota with probiotics may result in particular alterations in brain development throughout the perinatal period.
Researchers previously demonstrated that giving three doses of Bifidobacterium breve to pregnant and non-pregnant germ-free mice leads to sustained gut colonization, enhanced fetal development, and structural alterations in the placenta. About the study
In the present study, researchers investigated whether the quantity of Bifidobacterium breve UCC2003 in the maternal gut corresponded to alterations in fetal brain growth and metabolism.
Researchers colonized germ-free pregnant mice with and without Bifidobacterium breve UCC2003. On gestational days 10, 12, and 14, C57BL/6J mice were given 100 mL of reconstituted lyophilized B. breve (BIF group) or a control (PBS, GF group) by oral gavage.
The team isolated fetal brain ribonucleic acid (RNA) for reverse transcription, real-time polymerase chain reaction (PCR), and measuring the expression of cellular, metabolic, and axonogenesis genes. Related StoriesStudy reveals genetic link between Alzheimer's disease, lipid metabolism, and coronary artery diseaseAI-driven adaptive deep brain stimulation improves Parkinsons symptomsStudy uncovers oleic acid's role in restoring vaginal microbial balance in bacterial vaginosis
To analyze the molecular processes of B. breve, researchers used their previous biobank samples to quantify messenger RNA (mRNA) expressions of critical genes involved in the cell cycle, growth, microglial activity, and neurogenesis.
They measured the mRNA levels of transporters involved in branched-chain amino acid absorption and metabolism in the embryonic brain and solute carrier family-2 member 1 (Slc2a1) and Slc2a3 genes that encode glucose transporter protein type 1 (GLUT1) and GLUT3, respectively, in embryonic brain tissue.
Brain proteins were isolated, followed by Western blotting, and fetal brain metabolites were analyzed using nuclear magnetic resonance (NMR) spectroscopy. Sex-determining region Y gene (SRY) detection provided the fetal sex.
Researchers investigated signaling pathways involved in brain activities such as cellular growth, proliferation, survival, nutrient absorption, dendritic structure, neuronal development and differentiation, astrogliogenesis, and cell fate transition.
They examined the levels of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α and the abundance of pyruvate dehydrogenase kinase 1 (PDHK1) in lysates obtained from the fetal brain.
They assessed mitochondrial adenosine triphosphate (ATP) generation capability by analyzing oxidative phosphorylation (OXPHOS) complexes. They used general linear and linear mixed models for analyses. Results
Maternal colonization with Bifidobacterium breve caused profound metabolic alterations in the embryonic brain. In particular, seven metabolites, including carnitine, citrate, and 3-hydroxyisobutyrate, were decreased in the embryonic brain. Enhanced glucose transporter levels and improved branch-chain amino acid absorption accompanied these changes.
Furthermore, Bifidobacterium breve supplementation stabilized HIF-2α and accelerated the activity of metabolic pathways such as phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT), AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 5 (STAT5), and Wingless-related integration site (Wnt)-β-catenin signaling, including its receptor Frizzled-7.
The findings indicate increased dendritic branching, cellular proliferation, and neuronal hypertrophy with alterations in protein stability, translational efficiency, and degradation rates in treated mouse fetuses.
The fetal brains of treated mice revealed decreased levels of forkhead box protein M1 (Foxm1) and cyclin-dependent kinase 1 (Cdk1) genes, downregulation of plexin A3 (Plxna3) and slit guidance ligand 1 (Slit1), and increased expression of glucose transporters and L-type amino acid transporter 1 (LAT1).
The mRNA level of Slc37a4 and solute carrier family 16 members 1, 2, 4, and 8 were likewise higher in the embryonic brain of the BIF group.
The treated group's fetuses had higher levels of total protein content and respiratory chain complex II. Achaete-scute homolog 1 (Ascl1) levels also increased in the brains of fetuses from BIF-treated mice. Bifidobacterium breve in maternal intestines increased oxidative phosphorylation in fetal brain mitochondria.
B. breve produces short-chain fatty acids that can impact the vagus nerve and blood-brain barrier permeability in the mother and fetus. Additionally, bacterial extracellular vesicle (BEV) release influences host immunity. Fetal developmental changes could be associated with structural and functional alterations in the placental transport labyrinth region in BIF mice. Conclusion
The study showed that maternal oral consumption of probiotics, especially Bifidobacterium breve, during pregnancy significantly impacted fetal organogenesis, affecting brain metabolism, cell development, and axonogenesis pathways.
The bifidobacterium can improve gestational health and fetal development through microbiota-focused therapies.
In vitro and animal studies could elucidate mechanisms, while structural and histological analysis could determine changes in cell division, cell death, and axon development. Postnatal investigations, including behavioral studies, could assess the implications of B. breve on neurocognition. Journal reference:
Jorge Lopez-Tello et al., (2024) Maternal gut Bifidobacterium breve modifies Q1,8 fetal brain metabolism in germ-free mice, Molecular Metabolism. doi: https://doi.org/10.1016/j.molmet.2024.102004. https://www.sciencedirect.com/science/article/pii/S2212877824001352?via%3Dihub
