eNews January 06, 2016

A stressed vaginal microbiome during pregnancy has consequences for offspring

Have you heard about the gut microbiome yet?

Many research disciplines have taken an interest in the gut microbiome’s role in mediating aspects of health and disease. Contemplating how the gut microbiome might influence disease is not much of a stretch for scientists who study metabolic disorders, inflammatory bowel disease, and colorectal cancer. For scientists who study brain disorders, however, potential influences of the gut microbiome, although less obvious, have created something of a neuroscience renaissance. Researchers have identified many direct and indirect mechanisms by which the gut and central nervous system communicate, and rodent studies have revealed that the gut microbiota influences brain development and behavior.

Colonization of a newborn’s gut begins at parturition, when it is first exposed to a complex microbial environment.  The bacteria in the vagina constitute some of the earliest colonizers of the neonate gut. A recent study from Dr. Tracy Bale’s laboratory at the University of Pennsylvania suggests that maternal stress during pregnancy may increase risks for neurodevelopmental disorders in offspring via changes in microbial ecosystems of both the mother and offspring (Jašarević E, Howerton CL, Howard CD, Bale TL. 2015).  

Stress disrupts microbial ecosystems and alters metabolites available to the developing brain

Dr. Bale’s group set out to explore how pregnancy stress changes the microbial flora in the vagina, the gut microbiota in the offspring, and the metabolite availability in an offspring’s colon, plasma, and brain.  They bred C57BL6/J (000664) X 129S1/SvImJ (002448) F1 hybrid parents to produce F2 hybrid offspring and induced early prenatal stress during the first seven days of gestation by subjecting pregnant females to various stressors, including restraint stress, fox odor exposure, excess light, novel noise, novel objects, wet bedding, and cage changes.

Stress did alter the vaginal microbial mileu. Specifically, stressed females had reduced abundance of Lactobacillus, a microbe that has been shown in other work to influence emotional behavior and the expression of receptors to gamma-aminobutyric acid, an anxiolytic neurotransmitter (Bravo et al, 2011). Moreover, the Bale team observed concordant decreases in Lactobacillus populations in the guts of the stressed females’ offspring.  Further, these same offspring of stressed mothers also showed a more broadly disrupted gut microbial composition.

Next, metabolite profiles were measured in the periphery and brains of the offspring on postnatal day 2. The offspring of stressed mothers had significant alterations in colon and plasma metabolites, and free amino acid availability in their brains was altered, too. Interestingly, maternal stress altered brain metabolite availability in offspring in a sex- and brain region-dependent manner. The male offspring of stressed females had reduced metabolite levels in the paraventricular nucleus of the hypothalamus relative to controls.  In contrast, female offspring of stressed mothers tended to display upregulation of metabolites relative to controls. Sex-specific differences are particularly interesting because some neurodevelopmental disorders are strongly sex-biased:  autism spectrum disorders, for example, affect males with a four-fold higher incidence than females. Early life is a critical period for neurodevelopment, and mechanisms by which the maternal stress leads to sex-specific neurodevelopmental reprogramming are expected to be complex. The Bale group’s study offers an important first step in defining associations among maternal stress, changes in microbial consortia, and metabolite profiles in the offspring.