Diet- and Probiotic-mediated Modulation of the Maternal Gut Microbiome Impacts Early-life Programming of Neurodevelopment and Behavioral Outcomes in Offspring

Neurodevelopmental disorders are highly heritable; however, consensus is growing behind a two-hit model in which environmental exposures can promote disease in genetically predisposed individuals. Among environmental factors, those that impact the maternal gut microbiome during pregnancy are emerging as critical modulators of neurodevelopment and long-term behavioral outcomes in offspring. Specifically, disruption, or ‘dysbiosis,’ of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. Previously, we showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F1). For this thesis, we investigated whether MHFD similarly induces dysbiosis in female offspring (F1), which we hypothesized would recapitulate the adverse in utero environment experienced by the F1 males and resulting social dysfunction in the F2 generation, even in the absence of a dietary challenge. Metataxonomic sequencing revealed a significant reduction in microbial richness among female F1 MHFD offspring, with a specific decrease in the abundance of short-chain fatty acid (SCFA)-producing taxa. Despite recovery of richness in the F2 generation, F2 social behavior remained impaired, implicating dysbiosis of the maternal gut microbiome in offspring social deficits. Post-weaning supplementation with probiotic Limosilactobacillus (L.) reuteri was sufficient to rescue F2 generation social deficits. Unexpectedly, L. reuteri exerted a differential impact on the microbiome of control versus MHFD-descendant F2 mice, revealing a relative instability of the MHFD lineage microbiome. These differences were particularly strong among females, and this previously unreported heightened responsiveness of the female gut microbiome to probiotic modulation presented an opportunity for intervention: probiotic targeting of the maternal gut microbiome during pregnancy to relieve offspring social dysfunction. Hence, we developed a 7-strain probiotic cocktail consisting of immunomodulatory taxa and administered it to control and HFD-fed dams during pregnancy and lactation. Antenatal targeting of the maternal gut microbiome was sufficient to restore neurotypical social behavior in the MHFD-descendant F1 generation. Our results link maternal lineage HFD to instability of descendant microbial communities and maladaptive social behavior. Moreover, they highlight the potential for therapeutic targeting of the maternal gut microbiome to improve neurobehavioral outcomes in descendants.

Name thesis:degree_name

Neuroscience (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2022

Author dc:creator

• Di Gesu, Claudia

• Biology, Neuroscience
• Biology, Microbiology
• Health Sciences, Immunology

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12703

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12703