Early Life Stress Patterning of the Gut-Brain Axis: An Intergenerational Approach

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PROJECT SUMMARY Adverse childhood experiences (ACEs), such as abuse or chronic stress, program a dysregulated neuroendocrine-neuroimmune axis that persists through adulthood and promotes elevated inflammation. A proinflammatory milieu during pregnancy may be particularly pernicious, with potential health effects on both mother and offspring. In African American (AA) women, childhood stress is associated with poor infant outcomes, independent of adulthood stress exposure. AA women have higher rates of ACE exposure and greater physiologic vulnerability to the inflammatory impact of stress than Caucasian women, and double the rate of preterm birth as Caucasians in the U.S., underlining the importance of studying stress and maternal- offspring health in this population. Data from our laboratory suggests that the gut microbiome may be a key link in the association between maternal ACE and elevated inflammation in pregnancy. While there are links between gut microbial composition and elevated proinflammatory cytokines, a gap in the research remains in establishing links from ACE to gut microbiome to inflammation, which our first aim addresses. Further, if ACE is associated with an altered gut microbiome during pregnancy, does this altered microbiome pass to the offspring during vaginal delivery? Our second aim addresses whether stress-induced alterations in the maternal gut microbiome are passed to the offspring, assessing offspring gut microbial community composition and metabolites (the metabolome). As the gut microbiome-metabolome shapes development of the offspring immune system and makes nutrients available for brain development, its function has important implications for offspring outcomes. Finally, our laboratory found that maternal dietary intake of omega-3 fatty acids may ameliorate the effects of ACE on inflammation during pregnancy. In women with a history of multiple ACEs (“high ACE”), those who consumed large amounts of omega-3 fatty acids had an inflammatory stress response similar to that of women with no ACE history, while high ACE women with low omega-3 consumption had elevated levels of proinflammatory cytokines. Our final aim assesses impact of maternal diet during pregnancy on the relationship between gut microbiome and inflammation, with implications for future intervention work in this high-risk pregnant AA population. To address these aims, we will study 200 mother-infant dyads from the existing Children’s Hospital of Philadelphia (CHOP) Infant Growth and Microbiome (IGRAM) cohort, with existing fecal and blood samples. We will measure gut microbial community composition at the sub/species level using leading-edge shotgun metagenomics sequencing, gut metabolites (short chain fatty acids; SCFAs) as an index of gut function, and serum proinflammatory cytokines in mothers and offspring. This would allow us to model the complex relationships among maternal ACEs, gut microbiome, and inflammation, and the relationship of these factors between mother and offspring.