Prediction, mechanisms and causality: a systems biology approach to elucidate the role of the dynamic interplay between maternal and microbial systems in the pathobiology of perinatal depression

PROJECT SUMMARY Perinatal depression (PND), defined as depression during pregnancy and up to one year postpartum, affects more than 20% of pregnancies and disproportionately impacts Black Women and Latinas. PND increases risk of preterm birth and infant neurodevelopment deficits. Yet we still do not fully understand the pathobiology of

PND, which limits efforts to improve its prevention, identification and treatment. Interactions between the host and microbial communities that reside in the gut are essential for human health. Gut microorganisms play an important role in producing beneficial metabolites, including the neurotransmitters serotonin and gamma-

aminobutyric acid (GABA). The gut microbiota bidirectionally communicate with the brain, an interaction mediated by the neurological, immune, and endocrine systems and coined as the microbiota-gut-brain axis (MGBA). Our initial pilot results from a longitudinal study of low-income women of color (n=42) early in pregnancy,

which showed that multiple attributes of the MGBA were associated with depressive symptom severity, including production of short chain fatty-acids, metabolism of tryptophan and GABA, and systemic inflammation mediated by bile acid metabolism. Although our initial data points to new MGBA signatures linked to depressive symptom

severity in the first and second trimesters, additional work is needed to determine whether these signatures and their interactions extend beyond the second trimester. Further, microbial metabolism is driven both by the interactions between metabolites and by the interplay between microbial metabolic systems with maternal

inflammatory system and metabolism. Thus, determining the causal influence of these new MGBA signatures on depressive symptom severity during the perinatal period requires using approaches that can establish the effect of systems (networks) coupling in MGBA functioning. Here, we propose a clinical translational study to

determine the role of MGBA in PND by using a systems biology framework and an experimental animal model to assess causality. To test this, we will draw from our research infrastructure to recruit 158 women (55% Black, 30% Latina) early in pregnancy (