Intestinal epithelial Atg16l1 influences pregnancy-induced fecal microbiota shifts in mice

Abstract

Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase towards the end of pregnancy and comprise reduced α-diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in Atg16l1∆IEC mice carrying an intestinal epithelial deletion of the Crohn9s disease risk gene Atg16l1. Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between Atg16l1 wildtype and Atg16l1∆IEC pregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as Lachnospiraceae, Roseburia, Ruminococcus, and Turicibacter. Changes partially recovered after lactation. In addition, functional inference of metagenomic data suggest a reduced potential to biosynthesize mucosal protective polyamines and reduced capacity to metabolize acidic polysaccharides (ketogluconate metabolism). On the host side, we found that the immunological response of Atg16l1∆IEC mice is characterized by higher colonic mRNA levels of TNFA, and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improving precision care for managing pregnancies in IBD patients.