Pathogenic utoinflammatory responses triggered by dysregulated microbial interactions may lead to intestinal disorders and malignancies. The use of beneficial microbiota to reset gastrointestinal homeostasis holds therapeutic potential to treat chronic inflammatory conditions, such as inflammatory bowel diseases and colitis-associated maladies, like colorectal cancer. For this purpose, we genetically modified the commensal bacterium Lactobacillus acidophilus and tested the molecular signals induced in immune cells by its specific surface layer proteins (Slps). Previously, we demonstrated that a lipoteichoic acid (LTA)-deficient L. acidophilus strain ameliorated inflammation-induced colitis, significantly reduced the number of polyps in a colonic polyposis cancer model, and restored physiological homeostasis in both cases. Nonetheless, the regulatory signals delivered by LTA- deficient L. acidophilus to reprogram the gastrointestinal microenvironment, and thus resist colonic cancer progression, remain unknown. Consequently, the objectives of this proposal are to elucidate and investigate the immunoregulatory gene products expressed by LTA-deficient L. acidophilus, and their specific contributions, respectively. The hypothesis underlying this application is that SlpA is the main regulatory protein moderating destructive intestinal mucosal inflammation. Knowledge acquired from these studies will enhance our understanding of the molecular mechanisms regulating intestinal immunity.
Tolerance of the host immune system toward gut microbiota is mediated by an interplay of resident immune cells, the microorganisms themselves, and the gut epithelium. A collapse of homeostatic balance results in pathogenic intestinal inflammation and predisposition to cancer. This proposal strives to establish the immunomodulatory effects of SlpA of Lactobacillus acidophilus in experimental models of colonic polyposis and invasive colon cancer with the use of a novel L. acidophilus strain, NCK2187, that is LTA, SlpB, and SlpX-deficient, but retains SlpA expression.
| Lightfoot, Yaíma L; Selle, Kurt; Yang, Tao et al. (2015) SIGNR3-dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis. EMBO J 34:881-95 |
