Maternal-microbiome relationships in pregnancy and impact on offspring intestinal development

Abstract

Fetal intestinal and immune development prepares the neonate for life in a microbial world, and the environment within which this development occurs has implications for lifelong health and the prevention of chronic diseases. We hypothesized that obesity-associated shifts in the maternal gut microbiota contribute to a pro-inflammatory milieu through impaired maternal gut barrier function, resulting in altered fetal gut development, neonatal microbial colonization, and offspring intestinal structure and function. In Chapter 3, we found that microbial gut colonization does not occur before birth in healthy term infants. In Chapter 4, we investigated the normal course of microbial profiling in human pregnancy and the impact of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on this profiling. We found that the maternal gut microbiota composition changed less over the course of pregnancy in participants with higher pre-pregnancy BMI and that pre-pregnancy overweight/obesity was associated with a decreased relative abundance of short-chain fatty acid (SCFA) producers. In Chapter 5, we used an in vivo mouse model of high-fat (HF) diet-induced obesity during pregnancy and found that HF diet intake increased maternal intestinal permeability and increased levels of maternal circulating proinflammatory factors at term gestation, and induced fetal intestinal inflammation. In Chapter 6, we aimed to investigate the role of tumour necrosis factor (TNF) in inducing endoplasmic reticulum (ER) stress in maternal intestinal adaptations to pregnancy as well as fetal intestinal development in the context of diet-induced obesity. We found that pregnancy and HF diet-induced shifts in the gut microbiota were modestly modulated by TNF and that maternal HF diet-induced fetal intestinal inflammation was dependent on TNF. In Chapter 7, we investigated the relationship between early-life exposure to maternal HF diet and the offspring gut microbiota, as well as offspring gut permeability and susceptibility to postnatal HF challenge. We found that maternal HF diet intake resulted in changes in gut microbiota community composition that persisted to adulthood and that offspring born to HF mothers were predisposed to increased gut barrier permeability. Collectively, our data provide new insights into host-microbe relationships and their impact on the mother and offspring.