Untangling Associations of Microbiomes of Pregnancy and Preterm Birth

Porphyromonas gingivalis (Pg) is an oral bacterial pathogen that has been associated with systemic inflammation and adverse pregnancy outcomes such as low birth weight and pre-term birth. Pg drives these sequalae through virulence factors decorating the outer membrane that are present on non-replicative outer membrane vesicles (OMV) that are suspected to be transmitted systemically. Given that Pg abundance can increase during pregnancy, it is not well known whether Pg-OMV can have deleterious effects on the brain of the developing fetus. We tested this possibility by treating pregnant C57/Bl6 mice with PBS (control) and OMV from ATCC 33277 by tail vein injection every other day from gestational age 3 to 17. At gestational age 18.5, we measured dam and pup weights and collected pup brains to quantify changes in inflammation, cortical neuron density, and Tau phosphorylated at Thr231. Dam and pup weights were not altered by Pg-OMV exposure, but pup brain weight was significantly decreased in the Pg-OMV treatment group. We found a significant increase of Iba-1, indicative of microglia activation, although the overall levels of IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ mRNA transcripts were not different between the treatment groups. Differences in IL-1β, IL-6, and TNFα concentrations by ELISA showed IL-6 was significantly lower in Pg-OMV brains. Cortical neuron density was modified by treatment with Pg-OMV as immunofluorescence showed significant decreases in Cux1 and SatB2. Overall Thr231 was increased in pups exposed to Pg-OMV with the appearance of a secondary band of 60 kD. Together these results demonstrate that Pg-OMV can significantly modify the embryonic brain and suggests that Pg may impact offspring development via multiple mechanisms.

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Calorie restriction during gestation impacts maternal and offspring fecal microbiome in mice

Gilley,

Ruebel,

Chintapalli

et al. 2024

Front. Endocrinol.

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BackgroundMaternal undernutrition is the most common cause of fetal growth restriction (FGR) worldwide. FGR increases morbidity and mortality during infancy, as well as contributes to adult-onset diseases including obesity and type 2 diabetes. The role of the maternal or offspring microbiome in growth outcomes following FGR is not well understood.MethodsFGR was induced by 30% maternal calorie restriction (CR) during the second half of gestation in C57BL/6 mice. Pup weights were obtained on day of life 0, 1, and 7 and ages 3, 4 and 16 weeks. Fecal pellets were collected from pregnant dams at gestational day 18.5 and from offspring at ages 3 and 4 weeks of age. Bacterial genomic DNA was used for amplification of the V4 variable region of the 16S rRNA gene. Multivariable associations between maternal CR and taxonomic abundance were assessed using the MaAsLin2 package. Associations between microbial taxa and offspring outcomes were performed using distance-based redundancy analysis and Pearson correlations.ResultsFGR pups weighed about 20% less than controls. Beta but not alpha diversity differed between control and CR dam microbiomes. CR dams had lower relative abundance of Turicibacter, Flexispira, and Rikenella, and increased relative abundance of Parabacteroides and Prevotella. Control and FGR offspring microbiota differed by beta diversity at ages 3 and 4 weeks. At 3 weeks, FGR offspring had decreased relative abundance of Akkermansia and Sutterella and increased relative abundance of Anaerostipes and Paraprevotella. At 4 weeks, FGR animals had decreased relative abundance of Allobaculum, Sutterella, Bifidobacterium, and Lactobacillus, among others, and increased relative abundance of Turcibacter, Dorea, and Roseburia. Maternal Helicobacter abundance was positively associated with offspring weight. Akkermansia abundance at age 3 and 4 weeks was negatively associated with adult weight.ConclusionsWe demonstrate gut microbial dysbiosis in pregnant dams and offspring at two timepoints following maternal calorie restriction. Additional research is needed to test for functional roles of the microbiome in offspring growth outcomes.

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Untangling Associations of Microbiomes of Pregnancy and Preterm Birth

Cited by 3 publications

References 88 publications

The right tool for the job: Chemical biology and microbiome science

The right tool for the job: Chemical biology and microbiome science

Porphyromonas gingivalisouter membrane vesicles alter neuronal architecture and Tau phosphorylation in the embryonic mouse brain

Calorie restriction during gestation impacts maternal and offspring fecal microbiome in mice

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