A microbiome meta-transcriptomics pipeline identifies a neutrophil elastase inhibitor that protects the colonic epithelial barrier

Inflammatory Bowel Diseases (IBD) are lifelong conditions. Current therapeutic approaches target inflammatory signalling rather than improving barrier permeability or repair. The gut microbiome provides an exciting opportunity for novel drug discovery to leverage its role in healthy gut homeostasis. There is a clear need to identify bioactive molecules within the microbiota that could protect the intestinal barrier. Our group has developed a systematic pipeline using metatranscriptomic data to identify, produce, purify, and test microbial proteins in IBD, pinpointing multiple novel microbiota-derived proteins linked to disease activity. We identified a new microbiota protein (BMG-1), that specifically inhibits human neutrophil elastase, a pathogenic protease in IBD. This protease inhibition allows protection of the intestinal epithelial barrier from permeability and promotes epithelial healing. BMG-1 also reduces colon damage in a mouse model of colitis. Finally, we show that the native BMG-1 protein is not only present in human stool, but also significantly decreased in patients with high IBD activity. These findings demonstrate the gut microbiota can specifically regulate the balance of protease/anti-protease activity in the colon, and this represents a novel therapeutic strategy for IBD.