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Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

Significance Comparing germ-free mice with those colonized at birth or later provides a way to determine how gut microbial community exposure affects the chromatin landscape of cells along the gut or at remote sites, ascertain how alterations in chromatin accessibility are correlated with functional features of different lineages, and determine whether there is a critical window of exposure when microbial signals must be received to alter the landscape durably. Genome-wide analysis of chromatin accessibility in intraepithelial lymphocytes and circulating T cells purified from gnotobiotic mice revealed enhancers and flanking genes involved in signaling and metabolic pathways that are sensitive to colonization status. Colonization does not fundamentally alter lineage-specific cis-regulatory landscapes but induces quantitative changes in the accessibility of preestablished enhancer elements. The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ+ and γδ+ intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling–weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.