The Gut Microbiome and Emotional Distress During Pregnancy: Shaking the Foundations of Future Mental Health?

The first 1000 days of life from conception to 2 years of age includes critical time windows during which the aftershocks of maternal emotional experiences can be life-changing. During these critical periods in the journey toward psychological maturity, the gut microbiome has been heavily scrutinized as a potentially important pillar of the future foundations of brain health and development for the infant (1). Much of the emphasis of this research has been focused on the suboptimal assembly of the infant gut microbiome and the associated neurodevelopmental complications arising from disrupted gut-brain axis signaling. However, it is crucial to improve our understanding of how the interface between emotional distress and the remodeling of the maternal gut microbiome during pregnancy manifests in terms of negative consequences for the mental health and development of both mother and child. In a new paper in Biological Psychiatry: Global Open Science, Kimmel et al. shed some light on these microbial blueprints for brain function and behavior by characterizing the association between gut microbiome composition and functional potential and maternal mental distress (2).

As we strive to define what is meant exactly by a healthy human microbiome (3), the implications for women’s health also come into focus. The maternal gut microbiome is substantially remodeled across pregnancy, although we only have a rudimentary understanding of the factors shaping these alterations or the repercussions for maternal and infant gut and brain health when these processes deviate from the necessary core outcomes (4). Some of these cracks in the foundations may arise due to compositional alterations, as illustrated by Kimmel et al. in terms of associations between mental distress and metrics of alpha diversity (2). It will be interesting to expand this analysis to incorporate the recently defined health-associated core keystone index (5).

However, a true understanding of the remit of the gut microbiome needs to go beyond a summary of its composition, and making sense of the microbiome in psychiatry requires an appreciation of both form and function in recognition of the vast metabolic potential of the gut microbiome (1). Kimmel et al. satisfy this requirement, taking advantage of metagenomic sequencing data by evaluating the abundance of gut-brain modules (GBMs) (2), microbial metabolic pathways yielding neuroactive metabolites important for gut-brain axis signaling including short-chain fatty acids (SCFAs) (6,7). This elegant strategy predicted 4 functional clusters including microbial pathways for cortisol degradation, inositol and menaquinone synthesis, and SCFA synthesis. In doing so, they have provided important initial insights about the potential functional implications of the repertoire of neuroactive microbial metabolites associated with emotional distress during pregnancy.

Despite the intriguing observations reported in this article, the authors also acknowledge several limitations that need to be considered. Although the study evaluated 2 different cohorts at 2 different time points, a potentially important omission is the evaluation of samples during the first trimester, leaving a common knowledge gap around the early pregnancy microbiome in this field unbridged (4). Indeed, priming for future mental health may also require consideration of the preconception maternal and paternal microbiome (8). Maternal mental health outcomes may also be contingent on the postnatal recovery of the gut microbiome (4).

The need for future studies to verify that these functional predictions underpin the scaffolding of host-microbe interactions during the experience of maternal distress via metabolomic readouts is equally important. We have now accumulated a considerable amount of knowledge about the impact of mode of delivery, mode of feeding, and antibiotic usage on the assembly trajectory of the infant gut microbiome. The alterations described by Kimmel et al. (2) warrant further scrutiny when faced with such factors, which may amplify the consequences for both maternal mental health and infant neurodevelopment. The fact that the United States sample cluster with lower predicted gut microbial cortisol degradation also had significantly higher cortisol levels after exposure to an acute social stressor postpartum offers an important harbinger of concern in this regard.

However, it is not currently clear whether the membership of that cluster is constant or fluctuates, or whether concurrent membership is necessary for the physiological sequelae. This temporal gap between microbiome evaluation and measurement of acute stress responses thus requires further scrutiny. It is also important to note that these physiological stress outputs are not pathological per se, and the clinical significance of cluster membership for symptom expression should also be evaluated in future research. Interesting to note in this regard is that while there are 4 clear GBM clusters in the Swedish cohort, this is not true for the cohort in the United States. Future evaluation of the robustness of these clusters will require evaluation with increased methodological standardization and assessment of the contribution of dietary habits, which often change during pregnancy and are likely to be different prepregnancy between individuals recruited in Sweden and the United States.

Pregnancy can be a rewarding yet stressful experience, involving dynamic alterations that together comprise a physiological load leaving an imprint across many biological systems (9). Kimmel et al. (2) have revealed novel factors potentially influencing maternal mental health by emphasizing the reciprocal relationship between the maternal gut microbiome and psychological status. In doing so, they have advanced our understanding of the systems biology interface between emotional distress and the gut microbiome during pregnancy, offering important new leads to investigate further in an understudied area as we look to fix the shaken foundations of future mental health. If these findings generalize to other populations and are further validated in additional studies that demonstrate adverse clinically diagnosed mental health outcomes, the functional clusters identified by Kimmel et al. (2) may be amenable to interventions that can counteract the microbial subsidence induced by emotional distress–associated disruptions. Options include stress management or the broad list of options under the psychobiotic umbrella such as whole-diet approaches, probiotics, prebiotics, and postbiotics (10). Much work remains and is now warranted to accrue the full benefits that this interesting initial research suggests are possible, both to establish causality and define the mechanisms and to systematically evaluate the options that can therapeutically target these pathways.