Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice.

BACKGROUND: Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored. OBJECTIVE: This study investigates the impact of Bifidobacterium breve UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy. METHODS: Germ-free pregnant mice were colonized with or without B. breve UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways. RESULTS: Maternal colonization with B. breve resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function. CONCLUSIONS: The presence of maternal B. breve during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that Bifidobacterium could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions. / This work was supported by (JL-T) Sir Henry Wellcome Postdoctoral Fellowship (220456/Z/20/Z), Newton International Fellowship from the Royal Society (NF170988 / RG90199) and Attraction of Talent Grant from the Community of Madrid (grant No.. 2023-T1/SAL-GL-28960, CESAR NOMBELA fellowship). L.J.H. is supported by Wellcome Trust Investigator Award 220876/Z/20/Z; the Biotechnology and Biological Sciences Research Council (BBSRC), Institute Strategic Programme Gut Microbes and Health BB/R012490/1, and its constituent projects BBS/E/F/000PR10353 and BBS/E/F/000PR10356, and the BBSRC Institute Strategic Programme Food Microbiome and Health BB/X011054/1 and its constituent project BBS/E/F/000PR13631. ANS-P is supported by a Lister Institute of Preventative Medicine Research Prize (RG93692). DvS is a member of the APC Microbiome Ireland research centre funded by Science Foundation Ireland (SFI) through the Irish Government’s National Development Plan (Grant numbers SFI/12/RC/2273a and SFI/12/RC/2273b).