[Intestinal flora and Crohn's disease]

The pathogenesis of inflammatory bowel diseases (IBD) proceeds through stages of initiation, amplification and healing. Abundant clinical and experimental data incriminate luminal bacteria or bacterial products in both the initiation and perpetuation of chronic intestinal inflammation. Macrophage and T-cell activation with accompanying inflammatory cytokine production appears to be an early event. Studies of lymphocyte responsiveness to autologous and heterologous intestinal bacteria have suggested that this activation may result from a breakdown in tolerance to the enteric flora in IBD. This lack of tolerance might be due to an imbalance between protective and aggressive commensal luminal bacterial species (dysbiosis), a decreased barrier function and/or an impaired mucosal clearance allowing the access of bacteria to the mucosal immune system and lack of regulatory mediators or cells. There is still controversy over whether the virulence traits of bacteria are expressed broadly or just in a small subset of bacteria. Individual bacterial species within the indigenous flora vary in their capacity to drive intestinal inflammation. In experimental models, some bacteria such as Bacteroides vulgatus can cause colitis alone when monoassociated in the HLA-B27 transgenic rat model. Others, including Lactobacillus and Bifidobacterium species have no proinflammatory capacity and have been used as probiotics. In patients with IBD, systematic approach to this issue is hampered by the limited knowledge of intestinal flora. Adherent-invasive Escherichia coli are a possible candidate for the onset and/or persistence of intestinal inflammation in patients with Crohn's disease, since they possess all the virulence factors that allow the bacteria to cross the intestinal barrier, to move to deep tissues, and to continuously activate macrophages. The recent identification of NOD2/CARD15 as a susceptibility gene for Crohn's disease has provided another link between the immune response to enteric bacteria and the development of mucosal inflammation. NOD2/CARD15 is composed of two caspase recruitment domain (CARD), a nucleotide-binding domain (NBD) and a leucin-rich-repeat (LRR) region. The LRR domain of NOD2/CARD15 has binding activity for bacterial peptidoglycans and its deletion stimulates the NF-kappaB pathway. The most frequent variants of NOD2/CARD15 observed in Crohn's disease tend to cluster in the LRR and its adjacent regions. This suggests that the LRR domain of CD-associated variants is likely to be impaired in its recognition of microbial components. Continuing studies are investigating the pathophysiological mechanisms induced by NOD2/CARD15 variants in the intestinal mucosa.