A Novel Probiotic Engineered for Enhanced Immunological Function for Treating Inflammatory Bowel Disease

Project Summary The goal of this project is to commercialize a novel, immunologically-enhanced version of Lactobacillus acidophilus for the treatment of inflammatory bowel disease (IBD). Over 1.6 million adults and children in the United States suffer from IBD, an umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tract: Crohnandapos;s disease (CD) and ulcerative colitis (UC)1. IBD is typically diagnosed in the second or third decades of life and there is no cure. IBD is most commonly treated with systemic immune suppressants or targeted cytokine blockers that can have serious side-effect profiles including infection and cancer. Thus, new therapeutic strategies that are safe and effective, particularly restoring the natural interaction between the immune system and gut microbiome, are needed and would be life-changing for patients suffering from these difficult diseases. Intestinal immune regulatory signals tightly govern healthy gut homeostasis. Breakdown of such regulatory mechanisms may result in IBD2. The human microbiome is a critical regulator of these mechanisms. Commensal bacteria function to maintain integrity of the intestinal epithelial barrier, as well as regulate innate and adaptive immune cell function. One common bacterial species sold over the counter as a probiotic that `promotes immune healthandapos; is Lactobacillus (L.) acidophilus. L. acidophilus contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA) that interact with pattern recognition receptors (PRR; e.g., C-type lectin receptors) expressed on innate immune intestinal cells to regulate immunity in steady state and disease conditions3-6. Recently, our research team demonstrated that a novel L. acidophilus strain (termed R-2187) that is reprogramed to selectively express SlpA, but not SlpB, SlpX and LTA, prevented experimentally induced colitis in multiple disease animal models by inducing colonic T regulatory cells, reducing inflammation, improving the intestinal membrane barrier, and restoring natural commensal flora7. SlpA binds to the C-type lectin Specific Intracellular adhesion molecule-3 Grabbing Non-integrin homolog-Related 3 (SIGNR3) receptor expressed on dendritic cells lining the gut. In contrast, protection was not observed in Signr3-/- mice, suggesting that SlpA interaction with SIGNR3 plays a key protective role in regulating the disease condition7. Our goal is to commercialize R-2187 as a novel, orally administered probiotic to reduce inflammation, improve maintenance of gastrointestinal mucosal barrier function, and restore natural flora make-up in IBD patients. The key objectives of this Phase I application are to: 1) produce a scale up batch of R-2187 and establish key analytical assays, 2) perform in vitro functional assessment on human immune cells to characterize potential biomarkers and create a potency assay, and 3) define the pharmacokinetics/pharmacodynamics relationship and characterize additional biomarkers in healthy and diseased mice.Project Narrative Over 1.6 million adults and children in the United States suffer from inflammatory bowel disease (IBD). This project aims to commercialize R-2187, a novel L. acidophilus strain reprogrammed with enhanced immune functionality, for the treatment of IBD. In our prior studies, oral delivery of R-2187 increased T regulatory cells that reduced gut inflammation, reestablished protection of gut mucosal barrier function, induced positive maintenance of the gastrointestinal microbiome, and eliminated symptoms of experimental colitis8. Successful commercialization of R-2187 would provide a profound medical advancement for treating of IBD.