The neurodevelopmental impact of stress and inflammation during pregnancy: influence of the maternal microbiome and gut health

Maternal immune disruption profoundly impacts developmental origins of disease. Infections, pregnancy complications, or adverse lifestyle factors disrupt the maternal-fetal immune balance, thereby compromising optimal neurodevelopment of the fetus. The health of the developing fetus is also determined by the maternal microbiome, which has been previously shown to shape and modulate long-term offspring outcomes. The unique bidirectional relationship between the maternal microbiome and immune system allows for potential manipulation of the maternal immune system through microbial modulation, and in turn, can influence neurodevelopment. This thesis explores how inflammatory stimuli and microbiome modulation influence brain development, offering novel insights into how these exposures can exert lasting effects on long-term offspring health. First, the bioactive potential of maternal serum was examined from the previously completed Screening for Pregnancy Endpoints study. Identification of a biological “high-stress” group was based on inflammatory markers, measures of gut permeability, and tryptophan metabolism. Exposure to serum from “high-stress” pregnant women reduced neurite length in partially differentiated SH-SY5Y cells. This potentially harmful effect was due in part to phosphorylation of NF-κB p65 through a TNFα-dependent mechanism, highlighting the influential role of maternal inflammation. Next, the dual-hit effect of prenatal exposure to lipopolysaccharide, acting as an inflammatory stimulus, and a cocktail of antibiotics, to disrupt the maternal microbiome, was investigated. There was a minor effect of a double-hit of inflammation exposure and microbial disruption on embryonic anthropometry and placental growth. Primarily, inflammation exposure led to significant behavioural deficits. The reported increase in anxiety-like behaviours is likely associated with a reduced expression of 5-HT1a receptors in the prefrontal cortex. Finally, the potential of prenatal Lacticaseibacillus rhamnosus exposure in modifying neurodevelopment processes and behavioural outcomes via modulation of the maternal microbiome in a healthy pregnancy was explored. Here, a significant improvement in sociability and repetitive-restrictive behaviours was observed. However, probiotic exposure was also found to increase anxiety-like behaviours, likely associated with an increase in active microglia in the amygdala and a reduction of butyrate-producing bacteria. This effect may be credited to an immunostimulatory response in the dams. Overall, the results of this thesis provide novel insights into the harmful effects of maternal inflammation and a dysbiotic maternal microbiome during the development of the fetal brain and highlights the pressing need for appropriate microbiome-targeted therapeutics. These findings suggest a need for early identification of “at-risk” women in clinic, and careful consideration of probiotic consumption in expectant mothers.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Deady, Clara

Advisors dc:contributor.advisor

• O'Mahony, Siobhain M.
• O'Keeffe, Gerard W.
• McCarthy, Cathal
• McCarthy, Fergus

• Pregnancy
• Microbiome
• Neurodevelopment
• Microbiome-gut-brain axis
• Inflammation

Statement dc:rights

• © 2025, Clara Deady.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18796

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18796