Well, of course your very own medical student would have NEJM access! Here you go...
Inflammatory bowel disease results from a dysregulated immunologic response to commensal microbial flora residing in the intestinal lumen. Although this response is probably due at least in part to a genetic predisposition, patients with inflammatory bowel disease have also been reported to house an abnormal intestinal microbiota.1 Whether this altered flora is the cause or result of the associated chronic inflammation remains unclear. Also unclear is the exent to which inflammatory bowel disease may be transmissible.
A recent study by Garrett et al.2 sheds new light on this issue and on whether specific microbes contribute to the development of this disease. The authors have identified a new role for the transcription factor T-bet, known to regulate adaptive and innate proinflammatory immune responses, in controlling the host–commensal interface. They engineered mice that were deficient in both T-bet and the adaptive immune response since they lacked Rag2, which encodes a protein that processes antibodies. Severe colitis, which resembled human ulcerative colitis, developed in these mice (called TRUC mice).
Garrett et al. observed an increase in colonic levels of tumor necrosis factor (TNF-) when the mice were 2 weeks old. The TNF- level was associated with enhanced intestinal permeability and the extent of colonocyte apoptosis, which preceded the onset of colitis. It turned out that colonic dendritic cells, which sample the intestinal microbial flora, were the source of TNF- owing to their loss of negative TNF- transcriptional regulation by T-bet. Treatment of the mice with TNF- antibodies cured the colitis, and colitis did not develop in mice that were triply deficient in T-bet, Rag-2, and TNF receptor 1, which showed that TNF- is the key driver of disease in TRUC mice. Reconstitution of T regulatory cells in the TRUC mice controlled the colitis; microscopic imaging suggests that these cells interact with and thus down-regulate the proinflammatory program of the T-bet–deficient dendritic cells.
A role for microbes in inflammatory bowel disease is supported by the fact that mouse models develop colitis only in the presence of intestinal bacteria, and several human studies have shown a response of patients with inflammatory bowel disease to antibiotic therapy. However, the study by Garrett et al. is particularly exciting, since it includes a description of the development of a colitogenic gut flora. Colitis in TRUC mice abated after treatment with metronidazole, suggesting a role for anaerobes. Colitis was transmitted to progeny of untreated mothers but not to progeny of treated mothers; the disease was transmitted even to T-bet–sufficient Rag2–/– or wild-type progeny cross-fostered from birth by TRUC mothers, as well as to adult T-bet–sufficient mice that were housed with adult TRUC mice. However, TNF- levels were not elevated in T-bet–sufficient animals with colitis, which suggests that the microbiota from TRUC mice induce colitis in T-bet–sufficient hosts through a mechanism independent of signaling induced by TNF-.
The data described by Garrett et al. support a model for the development of inflammatory bowel disease in which the intestinal microbiota activate immune cells, leading to dysregulated cytokine production and ensuing intestinal inflammation. However, the immunologic milieu in the TRUC model is novel in engendering a colitogenic flora. Although the mechanism and the identity of the culprit organisms remain obscure, the observation indicates that increased concentrations of cytokines may affect other luminal processes — that is, increased cytokine production may modulate the composition of the commensal flora or alter gene expression in specific bacterial subgroups that are then responsible for the continuation and even transmission of colitis. For example, Pseudomonas aeruginosa binds interferon through an outer membrane protein, porin OprF, leading to activation of the quorum-sensing machinery that regulates the expression of virulence genes by detecting bacterial density and phase of growth. This, in turn, leads to downstream expression of virulence genes, including an adhesin.3
The study by Garrett et al. raises the interesting possibility that the appropriate environment leads to a colitogenic gut flora whose behavior is then modulated under various immunologic circumstances. Cytokine effects on bacteria are observed only in fresh isolates and are lost when these isolates are cultured in the absence of cytokines,4 suggesting that T-bet–sufficient colitic mice with normal TNF- levels may not communicate disease. Cytokines, including TNF-, have been reported to increase the growth rate of specific bacteria and to enhance virulence attributes, including adherence and invasion. It therefore seems reasonable to propose that dysregulated TNF- expression by colonic dendritic cells caused by T-bet deficiency increases intestinal permeability and apoptosis, leading to ulceration of the intestinal epithelium (Figure 1). Epithelial discontinuities allow influx of bacteria but also expose the intestinal microbiota to TNF-, which either shifts the composition of the microbiota or enhances the virulence of specific bacterial subgroups, possibly rendering them communicable.
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