Abstract
Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Speckled Protein 140 (SP140) is an immune-restricted chromatin "reader" that is associated with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the disease-causing mechanisms of SP140 remain undefined. Here, we identify an immune-intrinsic role for SP140 in regulating phagocytic defense responses to prevent the expansion of inflammatory bacteria. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis that was transmissible upon cohousing and ameliorated with antibiotics. Loss of SP140 results in blooms of Proteobacteria, including Helicobacter in Sp140-/- mice and Enterobacteriaceae in humans bearing the CD-associated SP140 loss-of-function variant. Phagocytes from patients with the SP140 loss-of-function variant and Sp140-/- mice exhibited altered antimicrobial defense programs required for control of pathobionts. Thus, mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by microbiota.