17 PERIPARTUM ANTIBIOTIC EXPOSURE INDUCES PERSISTENT GUT DYSBIOSIS, IMPAIRS THE DEVELOPMENT OF IMMUNE TOLERANCE, AND INCREASES RISK FOR INFLAMMATORY BOWEL DISEASE IN GENETICALLY SUSCEPTIBLE OFFSPRING

Abstract

The prevalence and incidence of inflammatory bowel diseases (IBD) has rapidly increased over the past century. Although the etiology of IBD remains unclear, changes in societal norms, environment, diet, and lifestyles are likely contributory factors that promote IBD on a background of genetic susceptibility. The imbalance of intestinal microbiota (dysbiosis) is caused by various factors and it has been suggested that dysbiosis results in disturbances in host-microbe interactions leading to the skewed immune system and IBD onset. Epidemiological studies suggest an association between antibiotic exposure in early childhood and increased risk for IBD development. Although dysbiosis in early life may be particularly profound since it could be a critical developmental window for both intestinal microbiota and the immune system, no direct causal links or mechanistic insights have yet been established. In the present study, we employed the IL-10 deficient (IL-10 KO) genetically susceptible murine colitis model to examine a causal link between antibiotic-induced dysbiosis in early life with the onset of IBD later life. We investigated the impacts of the broad-spectrum antibiotic, cefoperazone (CPZ), on the incidence of spontaneous colitis and chemical (dextran sulfate sodium; DSS)-induced colitis in offspring when administered during the preterm and post-natal (peripartum) periods. CPZ is an FDA-approved third-generation cephalosporin antibiotic that is commonly used during pregnancy and the neonatal period, therefore our study was designed to recapitulate common clinical practices. The 16S rRNA gene amplicon sequencing analysis was performed to assess the gut bacterial compositions. Peripartum CPZ exposure caused gut microbial dysbiosis in dams. This dysbiosis was vertically transmitted to litters and persisted into their adulthood. Furthermore, the metagenomic shot-gun sequencing analysis showed that not only was persistent community membership but also functional alterations of intestinal microbiota as a whole were evident in offspring. Fecal microbiota transplantation from untreated and CPZ-exposed dams into germ-free IL-10 KO females demonstrated that CPZ-induced dysbiosis resulted in a skewed immune system in their subsequent offspring. Together, our findings show that early life exposure to maternal CPZ-induced dysbiosis leads to a persistent dysbiosis, impaired development of immune tolerance to commensal microbiota, and increases IBD risk in IL-10KO offspring. This study supports a potential role of maternal dysbiosis during the peripartum period as a risk factor for IBD in genetically susceptible offspring but also the idea that acquisition of specific microbes early in life is essential for maintaining health later in life.