BIOpaneX: a comprehensive screening for Paneth cells-targeting immunomodulatory drug applied to Crohn's disease. – BIOpaneX

Crohn’s disease (CD) is a polygenic form of inflammatory bowel disease (IBD) that affects millions of individuals worldwide through the influence of environmental factors, such as tobacco smoking. The CD-associated inflammatory lesions have a tendency to develop where the bacterial load is the highest, while antibiotic treatment has long been used as unspecific therapy in some CD patients [1]. However, at present, the therapeutic management of CD is not curative and far from optimal. An overall of 25-30% of patients fail to respond to current biologics and/or to immunosuppressive drugs, resulting in accumulation of adverse events, including malignancies and serious infections.
CD patients primarily experienced transmural inflammatory lesions at the terminal ileum, where Paneth cells are found more numerous. Importantly, Paneth cells showed abnormal granule formation, enhanced necroptosis and impaired secretion of antimicrobial peptides in CD [2]. By combining human genetic studies with animal model research, we and others have recently emphasized the pathophysiological role of Paneth cells in CD by identifying the major CD-predisposing NOD2 gene as a positive regulator of antimicrobial peptides secretion by Paneth cells in response to bacterial muramyl dipeptide [3, 4]. Consistently, genome-wide association studies revealed additional inborn errors in several regulatory factors involved in the maintenance of function of Paneth cells, arguing that a defective biology of secretory epithelial cells may lead to disease onset. Given that most current therapies for CD failed to modulate Paneth cells functionality [5], we now aim to select commensals that promote the antimicrobial response of Paneth cells.
Our probiotic screening program identified that certain strains of probiotics triggered secretion of antimicrobial peptides by intestinal epithelial cells and of Th17-dependent signals that are thought to control innate antimicrobial immunity. More recently, we provided an explanation for the inefficiency of a selected Lactobacilli in clinical trials in CD by identifying that this probiotic strain improved disease severity in an experimental model of colitis through the CD-predisposing NOD2 gene [6]. Thanks to a national partnership between three academic institutions, a Foundation recognized as non-profit organization of public utility and a French industrial company, namely Bioprox, our project aims to select the most efficient combination of probiotic strains that can both exhibit anti-inflammatory potential and restore Paneth cell functionality.
The BIOpaneX project is therefore focused on the further understanding of which and how certain anti-inflammatory symbionts may govern optimal Paneth cell secretion of antimicrobial peptides. Our specific goals are to i) identify which probiotics trigger Paneth cells-derived antimicrobial response, ii) dissect how selected probiotics coordinate Paneth cells function and iii) identify anti-inflammatory probiotic strains in two novel and relevant spontaneous models of CD. These experimental models provide us with unique tools to screen for more efficient probiotics leading to more rational therapies that do not depend on the major CD-predisposing NOD2 gene. That knowledge will not only advance our understanding of the biology of Paneth cells, but will also provide new therapies for physicians aimed at restoring topically defective antimicrobial immunity in CD.

References:
1 Asquith M, Powrie F. J Exp Med 2010;207:1573-7.
2 Chamaillard M, Dessein R. World J Gastroenterol 2011;17:567-71.
3 Chamaillard M, Philpott D, Girardin SE, et al. Proc Natl Acad Sci U S A 2003;100:3455-60.
4 Kobayashi KS, Chamaillard M, Ogura Y, et al. Science 2005;307:731-4.
5 Kubler I, Koslowski MJ, Gersemann M, et al. Influence Aliment Pharmacol Ther 2009;30:621-33.