Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

BACKGROUND & AIMS Luminal dysbiosis is ubiquitous in inflammatory bowel disease (IBD), but how the microbes trigger pro-inflammatory cascades in the epithelial and phagocytic cells remains unknown. Here we investigated the role of the microbial sensor ELMO1 (Engulfment and Cell Motility Protein-1) in sensing and responding to IBD-associated microbes in the gut epithelium and in macrophages.

METHODS A stem cell-based technique is used to grow enteroids from WT and ELMO1^−/−mice and from colonic biopsies of patients with IBD and subsequently differentiate them into enteroid-derived monolayers (EDMs) that mimic the gut epithelium/Gut in a dish. EDMs infected with IBD-associated invasive E. coli-LF82 were analyzed for bacterial internalization, cytokine production and monocyte-recruitment when co-cultured with monocytes.

RESULTS Expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria in IBD, higher expression correlated with elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. ELMO1-/-murine EDMs displayed a significant reduction of bacterial internalization through epithelial tight junctions and in MCP-1 production compared to WT mice. MCP-1 that is released from the epithelium recruited monocytes. Once recruited, macrophages required ELMO1 to engulf the bacteria and propagate a robust pro-inflammatory cytokine storm (TNF-α).

CONCLUSIONS ELMO1 couples microbial-sensing to inflammation in both phagocytic and non-phagocytic host cells; it is required for the production of MCP-1 in the epithelium and TNF-α in macrophages. Findings raise the possibility that upregulation of epithelial ELMO1 and the epithelial ELMO1→MCP-1 axis may serve as an early biomarker and therapeutic target, respectively, in IBD and other disorders of inflammation.