Increased Incidence of Inflammatory Bowel Disease: The Price of the Decline of Infectious Burden?

Hélène Feillet; Jean-François Bach


Curr Opin Gastroenterol. 2004;20(6) 

In This Article

Contrasted Experimental Data

A number of experimental IBD models have been described, including colitis following administration of tri-nitrobenzene sulfonic acid (TNBS), dextran sodium sulfate (DSS) or oxazolone, disruption of IL-2 or IL-10 genes, and reconstitution of SCID mice with CD4+ T cells depleted of CD45RBlo T cells.[9,10] There is only limited data on the responsibility of infectious agents for disease triggering in these various models. Some data show that the presence of bacteria is necessary, since germ-free IL-10-deficient mice do not develop spontaneous colitis,[11] and germ-free SCID mice do not develop DSS acute colitis, unlike conventionally reared SCID mice.[12] It has not been possible though to clearly identify the specific bacteria involved in the triggering of IBD. The role of proteins from commensal bacteria was studied in depth by Lodes. It was shown that in several models of experimental colitis, IgG2a antibodies were detected against flagellins with a flagellin-specific Th1 cell response. Serum IgGs to these flagellins were also detected in patients with Crohn disease but not in patients with ulcerative colitis. Flagellin-specific CD4+ T cells induced colitis after transfer in SCID mice.[13*] Similar results were obtained with a CD4+ T-cell clone specific for an epitope of Helicobacter hepaticus, a bacterium previously shown to induce colitis in IL-10-/- mice.[14] No colitis was observed in the absence of infection by H. hepaticus of RAG-/- recipient mice.[15*]

On the other hand, a number of recent data have shown that infection by various bacteria or parasites may prevent the onset of experimental colitis. Several studies have shown that bacteria have a protective effect in experimentally induced colitis. Thus, oral administration of extracts of anaerobic intestinal bacteria has been shown to reduce the severity of DSS-induced colitis.[16] Similarly, in the murine IL-10-/- model, oral administration of Lactobacillus salivarius and Bifidobacterium infantis significantly attenuated the development of colitis in prophylactic trials. Proinflammatory cytokine production by Peyer's patches and splenocytes was reduced without alteration in TGF-β production.[17**] Lactobacilli are also able to ameliorate established disease.[18] Other studies indicated that intragastric (or subcutaneous) administration of probiotics and Escherichia coli DNA reduced the severity of DSS-induced colitis, whereas methylated probiotic DNA had no effect. Live or killed probiotics had the same therapeutic effect. Mice genetically deficient in the TLR signaling molecule MyD88 did not respond to probiotics. The particular role of TLR9 in probiotics-induced protection is indicated by the loss of therapeutic effect in TLR9-/- mice (contrasting with the maintenance of the effect in TLR2-/- and TLR4-/- mice).[19**] Similarly, DNA prepared from a mixture of probiotics conferred protection against colitis in IL-10-/- mice.[20**] Other results were reported with a lysed solution of E. coli in the IL-10-/- and in the dextran-sodium sulphate models[21] and with live E. coli in DSS-induced chronic colitis with concomitant reduction of IFN-γ and IL-6.[22*] The lactobacillus approach was also used to provide a vehicle for local intestinal IL-10 delivery by administration of genetically engineered (IL-10 transduction) Lactococcus lactis.[23]

Some experiments have attempted to dissect the cellular and molecular mode of action of probiotics in vitro. Lactobacillus plantarum showed in vitro effects with increase of IL-10 synthesis and secretion in macrophages and T cells derived from inflamed human colon.[24**] Moreover, coculture with Lactobacillus casei or Lactobacillus bulgaricus of ileal mucosa specimens from Crohn disease patients has been shown to reduce significantly the release of TNF-α and the number of CD4 cells in the inflamed mucosa.[25] Additionally, DNA extracted from probiotics has been shown to reduce IL-8 production and to delay nuclear factor κB (NFκB) activation in HT-29 epithelial cells.[20**]

Protection from experimental colitis was also reported for helminths. Infestation of mice with schistosome eggs attenuated TNBS-induced colitis, protecting them from lethal inflammation with concomitant diminution of IFN-γ production and increased IL-4 and IL-10 production. The protection was shown to depend on signal transducer and activator of transcription 6 (STAT6)[26**] whose role in Th2 cell signaling is well established. Similarly, infection of rats with Schistosoma mansoni significantly reduced the duration of TNBS-induced colitis.[27] Another experiment showed that prior infection of mice with the intestinal nematode Trichinella spiralis reduced the severity of DNBS-induced colitis. Here again the result was correlated with a diminution of colonic IFN-γ expression and an increased production of IL-4 and IL-13.[28]

These observations, showing either triggering or protective effect of infectious agents on IBD, may appear as contradictory. In fact, one may assume that some bacteria are necessary for disease triggering (ie, colitis could be directly related to an antibacterial immune response). Other bacteria could be protective like probiotics. In spite of some efforts, no clear identification of triggering and protective bacteria has yet been achieved.


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