Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases, and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (engulfment and cell motility protein 1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem cell‐based ‘gut‐in‐a‐dish’ coculture model, we studied the interactions between microbes, epithelium, and monocytes in the context of IBD. To mimic the in vivo cell physiology, enteroid‐derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1−/− mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD‐associated microbes to monitor the inflammatory responses. ELMO1‐depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro‐inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro‐inflammatory cytokines, MCP‐1 and TNF‐α. MCP‐1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF‐α storm. These findings highlight that the dysregulated epithelial ELMO1 → MCP‐1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
BACKGROUND & AIMSLuminal 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.METHODSA 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.RESULTSExpression 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).CONCLUSIONSELMO1 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.
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