Targeting opportunistic pathogens to improve maternal obesity-associated health outcomes in offspring

Maternal prepregnancy obesity predisposes offspring to cognitive dysfunction, yet little is known about the mechanisms underlying the transgenerational effects of maternal obesity on offspring brain function and behavior. This traditionally overlooked cognitive health problem is exacerbated by social determinants of health, given that women of disadvantaged socioeconomic status are disproportionately affected by obesity. Currently, there is no consensus on antenatal care for women with prepregnancy obesity or their infants, and new therapies are needed to prevent chronic disease burden in affected children. Genetic and nongenetic factors contribute to obesity; yet, epidemiological studies suggest that diet, independent of genetics, is the primary driver of pathological weight gain and high body mass index.

Importantly, host diet regulates the composition of the gut microbiome, and gut microbiota are emerging as powerful regulators of mammalian brain function and behavior. Given that maternal gut microbiota affect pre- and postnatal offspring brain development, contribute to neurodevelopmental programming, and are vertically transmitted from the mother to her offspring, elucidating the relationship between diet-induced dysbiosis of the maternal gut microbiome and adverse cognitive health outcomes in offspring could lead to innovative preventative treatments. Building on our recently published work and exciting preliminary data, we propose an interdisciplinary study combining metagenomics, metabolomics, and neuroscience to test our hypothesis that maternal Western diet (mWD)-induced upregulation of opportunistic pathogenic bacteria and associated changes in the microbially-derived metabolome are causally related to cognitive dysfunction in mWD offspring. With the proposed work, we aim to address key, yet unanswered questions: (1) Is WD-induced dysbiosis of the maternal gut microbiome causal in adverse cognitive outcomes in offspring? (2a) Can opportunistic pathogenic bacteria increased by mWD impair cognitive function in offspring? (2b) Which mWD-associated microbially-derived metabolites affect host cognitive function? (2c) And by what mechanism? (3) Could antenatal targeting of the maternal gut microbiome via pharmacological, probiotic, or combination therapies thereof rescue mWD-associated cognitive dysfunction in offspring?

Successful completion of the aims will reveal how WD alters microbial community structure in the maternal gut during pregnancy, identify microbially-derived, bioactive metabolites altered by mWD consumption, and the underlying mechanism by which WD-induced dysbiosis of the maternal gut microbiome impairs cognitive function in offspring. Most importantly, our findings have the potential to transform antenatal care for women with prepregnancy obesity by identifying a new class of preventative antenatal interventions to improve neurocognitive health outcomes in affected children.

Grant Number: 5R01HD109095-04
NIH Institute/Center: NIH
Principal Investigator: Shelly Buffington