Effect of Maternal IBD, Microbiome and Early Life Events on the Bacterial Colonization and Mucosal Immunity in the Offspring

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SUMMARY Inflammatory bowel disease (IBD) is a chronic condition of the gastrointestinal tract that is caused by the loss of mucosal tolerance towards the commensal microbiota resulting in chronic inflammation. Importantly, IBD affects women during their reproductive years and 25% become pregnant after their initial diagnosis. The bacterial composition in the gut, or microbiome, has emerged as an important determinant of IBD pathogenesis. Moreover, increasing evidence suggests that early life exposures may modulate the risk of IBD later in life and that maternal health and microbiota composition during pregnancy may influence the baby’s gut colonization and play an essential role in shaping the immune system. We demonstrated that pregnant women with IBD and their babies have a significantly less diverse and more pro-inflammatory microbiota compared to no-IBD controls, and that the microbiome of 3-month old babies born to IBD mothers, when inoculated into germ-free mice, triggers the development of an imbalanced immune system. Yet, it remains largely unknown how maternal IBD and other early life events affect the offspring’s microbiome assembly and mucosal immunity. Therefore, the objectives of this proposal are to 1) track particular bacterial strains originated from or informed by the maternal gut microbiota, bacterial metabolites in the umbilical cord blood, and inflammatory proteins in the breast milk that colonize the gut of babies born to mothers with and without IBD; 2) determine how maternal IBD and other early life events can modify the priming of the initial microbiome and mucosal immunity, and 3) validate if bacterial strains or metabolites enriched in babies born to mothers with IBD are detected in high IBD risk first degree relatives prior to IBD diagnosis using two independent cohorts. We will expand on the ongoing MECONIUM (MEChanisms Of disease traNsmission In Utero through the Microbiome) study that follows 430 pregnant women with and without IBD and their babies with >5,500 samples collected. We will use extensive data, including 16S rRNA gene sequencing during pregnancy and in babies at numerous time points over the first 3 years of life, metagenomic data on mother-baby pairs, cord blood metabolomics, and breast milk proteomics, coupled with health status, clinical information, medications, mode of delivery, feeding behavior, etc., to identify the sources and predictors of the early microbiome colonization. Next, given that fecal calprotectin is a significant predictor of IBD incidence in high risk individuals, we will characterize the degree of mucosal inflammation, assessed by fecal calprotectin, in babies born to mothers with and without IBD. This multifaceted study will shed new light on the origin and maturation of the early life microbiome in the setting of maternal health and disease during the most sensitive time for the priming of the immune system. Study findings, validated in two independent prospective cohorts, can help develop novel strategies for early interventions to minimize disease transmission, and foster the development of a healthy microbiome.