An Epigenetic Link Between the Gut Microbiome and Immune Responses in Atopy

Abstract Atopy is the most common childhood disease in developed countries. Dysbiosis of the microbiome is now understood to be a driving force behind the development and severity of allergy/atopy. We previously showed that antibiotic treatment of newborn mice leads to a life-long perturbation of the gut microbiome marked by reduced bacterial production of the short chain fatty acid, butyrate. These mice exhibit a striking pro-inflammatory phenotype, marked by a heightened Th2 response, that was completely reversible with dietary supplementation of butyrate. Butyrate is known to exert its effects on target cells via inhibition of histone deacetylases that have long term effects on gene expression. Consistent with a role for epigenetic skewing on the hematopoietic compartment of antibiotic treated mice, we found that bone marrow transplantation was sufficient to transfer the pro Th2 inflammatory phenotype into chimeric mice. Strikingly, we found unique regulatory states (H3K27ac) in purified hematopoietic stem and progenitor cells of these Th2 skewed mice. Single cell sequence analyses identified a distinct stem/progenitor cell transcriptomic signature in butyrate depleted mice that was reversed by butyrate supplementation. We identified a metagenomic gene signature present in fecal microbiome samples of 3-month-old children who subsequently developed atopy. Consistent with our observations in mice, this signature included depletion of the bacterial genes required for breakdown of indigestible carbohydrates in breast milk and the loss of genes required for butyrate fermentation. This work provides novel evidence for a butyrate-driven epigenetic process that links the fetal microbiome to long term sculpting of the immune response.