Novel therapies based on enhancement of gut innate immunity in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), in particular Crohn's disease (CD) and ulcerative colitis (UC), results from several known and unknown genetic and environmental factors, altering the gut innate immunity and the gut adaptive immunity. The first genetic discoveries pointed to dysfunctions of the sensing systems in the intestinal tract towards dangerous as well as innumerable commensal bacteria of the gut lumen, confirming their role as main environmental factors. Recent advances in the pathophysiology of innate immunity are reviewed, concerning chiefly microbial–epithelial interactions, with the role of the mucus barrier (mucins, trefoil factors), the localisation of the microbiota normally absent beneath the mucus layer and present and invasive in IBD, the numerous defensive functions of the epithelial barrier that could be altered in IBD (tight junction proteins, defence receptors: Toll-like receptors, NOD2/CARD15, peroxysome proliferator activated receptor-γ (PPAR- γ), secretion of microcidal β-defensins, release of exosomes, autophagocytosis etc.). In the lamina propria, natural killer cells, macrophages and dendritic cells play an important role in innate immunity, particularly the dendritic cells, potent sensing and antigen- presenting cells, triggering either adaptive immunity with its potentially serious inflammatory consequences or inducing immunotolerance through T regulatory cells. By studying in-depth innate immunity, including the role of mesenteric fat in CD, it may be possible to discover the aetiological primary events of IBD and also to design more therapies based on enhancement of innate immunity. These therapies are reviewed with the impetus of various patented drugs and the still-too-rare randomised clinical trials: agents reinforcing the mucus barrier, the epithelial barrier and the lamina propria cell functions for innate immunity. As recent studies confirmed dysfunctions of granulocytes, particularly neutrophils in IBD, trials aimed at stimulating granulocytes and macrophages were interesting and gave encouraging results. PPAR-γ agonists are also effective in UC patients and may explain one of the modes of actions of sulfasalazine, beside its inhibition of the NF-κB. Many studies underlined the role of some probiotics in enhancement of the intestinal epithelial barrier function, but so far randomised clinical trials were positive only for the prevention and treatment of UC and pouchitis. Genetically modified probiotics delivering trefoil factor or IL-10 are very promising. Finally, treatments based on the enhancement of innate immunity might lower the risks of treatments based on reduction of adaptive immunity (immmunosuppressants and biologicals).