Sex matters! The role of maternal gut microbiota in shaping in-​ creased susceptibility of females to stress-related psychiatric disorders

Overview of the Research

Stressors during childhood including parental neglect and poverty, increase risk to develop depression and anxiety disorders (Heim and Binder, 2012, O'Leary and Cryan, 2013). Biological sex is also a risk factor for these disorders. Depression is two times more prevalent in women and three times more prevalent in female adolescents compared to their male counterparts. Women are also uniquely vulnerable to postpartum depression.

Despite this sex difference in stress vulnerability, few studies have investigated its underlying mechanisms including the contribution of the maternal gut microbiome. In addition, 80% of preclinical drug development and neuroscience studies neglect to include females (Cahill, 2006, Klein et al., 2015). Moreover, pregnant or lactating females are rarely studied, a troubling fact considering that maternal mental health influences infant brain development and risk for developing stress-related psychiatric disorders later in life (Sawyer et al., 2019).

This inattention to females and pregnant or lactating females in particular, might explain the poor translation of drug discoveries made largely in male animal models to successful new treatments in the clinic where the majority of depressed individuals are female and where there is caution and reluctance in the use of antidepressant drugs in pregnant or breastfeeding women.

Evidence from our labs and others suggest that gut microbiota are involved in stress-induced depression and anxiety behaviors, and thus have therapeutic potential (Bravo et al., 2011; Burokas et al., 2018; Cruz-Pereira et al 2020; Kelly et al., 2016). We have also shown that the microbiome affects adult hippocampal neurogenesis (production of new neurons in the hippocampus area of the adult brain), an important stress-sensitive brain process that is required for antidepressant action (Levone et al., 2014; Ogbonnaya et al., 2014; O’Leary and Cryan, 2014; O’Leary et al., 2014; O’Leary et al., 2013;  Santarelli et al., 2003). Most studies however have been done in adult males. Moreover, the roles of the gut microbiota in maternal brain vulnerability to stress during the postpartum period, and in sex differences in adolescent-onset depression of their offspring have not yet been investigated.

Objectives of the Project

The objectives of this project are to :

(1) determine the role of the gut microbiota in postpartum maternal vulnerability to stress-induced depression and anxiety-like behaviours and hippocampal neurogenesis alterations; and

(2) determine if stress and gut microbial changes in the mother associate with vulnerability of male and female offspring to develop stress- depression- and anxiety-like behaviours upon reaching adolesence.

To this end, we will use a paradigm whereby mouse mothers (with or without gut microbiota manipulation by prebiotic supplementation) will rear their offspring (with or without gut microbiota manipulation by prebiotic supplementation) under either normal conditions or a stressful environment during postnatal days 4-11 (Goodwill et al., 2019).

Previous work in mice has shown that this paradigm which involves bedding restriction, induces fragmented maternal care, a chaotic early environment for developing pups, and induces depressionlike behaviour in the offspring particularly in females (Rice et al., 2008; Goodwill et al., 2019; Walker et al., 2017), but limited studies have been conducted on the impact of this stress on the mothers (i.e. dams), and whether any associated post-partum depression-like behaviours are related to alterations in the gut microbiota or hippocampal neurogenesis.

Therefore, we will investigate the impact of this postpartum stress on depression, anxiety & social behaviours, gut microbiota composition, and hippocampal neurogenesis in both mothers and their adolescent male and female offspring. These data will inform whether antenatal prebiotic supplementation to facilitate probiotic bacterial growth can counteract the negative effects of stress on brain and behaviour in mothers and offspring. These experiments will also identify gut bacteria that are important in shaping postpartum maternal mental health and adolescent mental health thus identifying consortia of gut bacteria which may be developed as dietary supplements to conteract the negative effects of postpartum stress and early life stress. This data will drive the development of prophylactic nutritional interventions for maternal mental health, infant brain development, and stress resilience.

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