微生物群
免疫系统
表观遗传学
失调
免疫学
炎症性肠病
生物
疾病
免疫失调
染色质
肠道菌群
遗传学
医学
基因
病理
作者
Isabella Fraschilla,Hajera Amatullah,Raza‐Ur Rahman,Kate L. Jeffrey
标识
DOI:10.1101/2022.03.29.486273
摘要
Abstract Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Epigenetics facilitate integration of environmental cues for transcriptional output. However, evidence of epigenetic dysregulation directly causing host-commensal dysbiosis and IBD is lacking. Speckled Protein 140 (SP140) is an immune-restricted chromatin ‘reader’ with homology to Autoimmune Regulator (AIRE). SP140 mutations associate with three immune diseases: Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL), but disease-causing mechanisms remain undefined. Here we identify a critical immune-intrinsic role for SP140 in preventing expansion of inflammatory Proteobacteria, including Helicobacter in mice and Enterobacteriaceae in humans. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis which was transmissible upon co-housing and ameliorated with antibiotics. SP140 was critical for calibration of macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive pathogens. Mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by the microbiome, such as IBD and MS.
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