Microbiota-sensitive epigenetic signature predicts inflammation in Crohn’s disease

Abstract

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.

Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease

“…Host DNA methylation and gene expression both displayed more pronounced gradients of inflammation than what was observed with the microbiota, suggesting that epigenetic factors mediate interactions between colonic microbiota and host gene expression. Microbiota-sensitive epigenetic signatures were recently observed for histone methylation in CD 48 . While the largest difference in methylation patterns was attributed to inflammation, as expected due to disproportionate composition of inflammatory cells 49 , we did observe significant epigenome-wide differences between CD and control groups (visualized by principal component 6 in Fig.…”

Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development

“…Kelly and colleagues [94] also recently identified a connection between the gut microbiome and certain histone modifications. Specifically, the location of histones with a H3K4 methylation mark was shown to be modified by the presence of gut microbes.…”

“…This analysis revealed an abundance of genes that belonged to pathways associated with inflammatory bowel disease. Importantly, many of these genes and pathways are also associated with cancer (that is, genes involved in maintaining the innate mucosal barrier, reactive oxygen species generation, or ephrin signaling), so although the authors did not highlight a link to cancer in their findings, their results can be readily applied to better understand how gut microbes affect histone methylation at genes that are known to be dysregulated in CRC [94].…”

“…Notably, many of the studies that identified CRC-related genes or pathways that are modified by the gut microbiome were not designed to examine CRC-related effects specifically. For example, Kelly and colleagues [94] sought to identify genes altered by the gut microbiome that showed different patterns of H3K4 methylation in individuals with inflammatory bowel disease, but these genes also relate to CRC because similar biological processes are disrupted in the two diseases. Similar to the computational analysis conducted by Liang and colleagues [119], in which microarray data (from a single laboratory) were reanalyzed to look for lncRNA changes induced by the gut microbiome, or the meta-analysis conducted by Drewes and colleagues [7], in which combined data from several groups were reanalyzed through a single computational pipeline, studies examining the impact of the gut microbiome on the epigenome should be reanalyzed to probe for CRC-related alterations that were not explored in the original analyses.…”

Profiling Non-Coding RNA Levels With Clinical Classifiers in Pediatric Crohn’s Disease

“…All biopsies were extracted and processed as previously described 14,15 with NEBNext Ultra RNA Library Prep Kit used for Illumina RNA sequencing library preparations by following set manufacturer's recommendations (NEB, Ipswich, MA, USA). Approximately 77% of the 274 CD ileal biopsies, n = 212, were used for our previous publication 10 .…”