Experimental inflammatory bowel disease: insights into the host-microbiota dialog

Abstract

Inflammatory bowel disease appears to result from an abnormal host immune response to the intestinal microbiota. Experimental models have allowed the dissection of the complex dialog between the host and its microbiota. Through genetic manipulation of the host genome the immune compartments, cells, molecules, and genes that are critical for maintenance of intestinal homeostasis are being identified. Genetic association studies in humans have identified over 100 susceptibility loci. Although there is remarkable coherence between the experimental model and the human genetic data, a full understanding of the mechanisms involved in genetic susceptibility to IBD and of gene-gene and gene-environmental interactions will require a "next generation" of experimental models.

Figure 1

Intestinal homeostasis is maintained through a dialogue between the host immune system (innate, adaptive and regulatory) and the microbiota, a crosstalk modified by host genetics (e.g. susceptibility loci identified by GWAS) and environmental triggers (e.g. DSS, norovirus, H. hepaticus). Various commensal bacterial species enhance mutualism with the host (e.g. Bacteroides fragilis and clostridium species) and others induce intestinal pathology (e.g. SFB, Klebsiella pneumonia and Proteus mirabilis). Epithelial defenses include mucus production by goblet cells, defensin production by paneth cells and colonocytes, intact tight junctions between intestinal epithelial cells (IECs), IEC anti-apoptotic mechanisms and autophagy. Pattern recognition receptors of the innate immune system, including TLRs, NLRP3 and NOD2, sense microbial and danger motifs and are required for mucosal regeneration and tissue repair. In addition, they are necessary for activation and sculpting of the adaptive and regulatory immune responses.