Intestinal epithelial cells interact with both microbes in the gut lumen and host immune cells. In this issue, Kaser et al., 2008 link a key mediator of endoplasmic reticulum stress, the protein XBP1, with survival of intestinal secretory epithelial cells and inflammatory bowel disease.

Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We hypothesized that a stressful environmental milieu in a rapidly proliferating tissue might instigate a proinflammatory response. We report that Xbp1 deletion in intestinal epithelial cells (IECs) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell dysfunction and an epithelium that is overly reactive to inducers of IBD such as bacterial products (flagellin) and TNFα. An association of XBP1 variants with both forms of human IBD (Crohn's disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 × 10−5) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IECs, thus linking cell-specific ER stress to the induction of organ-specific inflammation.

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.

In general, people coexist peacefully with the innumerable microorganisms that colonize the gut. Some gut microbes, however, are potential pathogens; moreover, inappropriate immune responses directed against gastrointestinal flora may be involved in the pathogenesis of inflammatory bowel diseases (IBDs) such as ulcerative colitis. Mazmanian et al. used a mouse model of IBD in which naïve effector T cells were introduced into immunodeficient mice, along with the bacterium Helicobacter hepaticus, to investigate the hypothesis that IBDs may involve an imbalance between potentially harmful and potentially beneficial commensal bacteria. Co-colonization with the bacterium Bacteroides fragilis protected these mice from colitis, whereas B. fragilis lacking the surface polysaccharide PSA (B. fragilis {Delta}PSA) were not protective. Colon cultures revealed increased abundance of pro-inflammatory cytokines like tumor necrosis factor-{alpha} (TNF-{alpha}) in mice with experimental colitis, an increase blocked by colonization with B. fragilis but not B. fragilis {Delta}PSA. Oral PSA protected against this model of colitis as well--and also against a chemically induced model of colitis. PSA increased expression of the transcript encoding the anti-inflammatory cytokine interleukin-10 (IL-10) in mouse colon and also in cocultures of bone marrow-derived dendritic cells and naïve CD4+ T cells (BMDC-T cell cocultures). PSA decreased production of TNF-{alpha} in BMDC-T cell cocultures infected with H. hepaticus, an effect blocked by neutralizing antibodies directed against the IL-10 receptor. Furthermore, such antibodies inhibited the protective effect of PSA in the T cell-transfer model of colitis, and PSA failed to protect against colitis when the naïve effector T cells were derived from mice lacking IL-10. The authors thus conclude that B. fragilis PSA can modulate the inflammatory response associated with H. hepaticus and thereby protect against IBD. Kullberg discusses the results and provides thoughtful commentary.