Diverse Effects of Tlr Signalling on Intestinal Inflammation

Probiotics are live commensal microorganisms of the intestinal tract that confer multiple gastro-intestinal health benefits to the host. Yet, the exact mechanisms by which probiotics ameliorate experimental colitis in animals and human inflammatory bowel disease are largely unknown. We tested whether the attenuation of experimental colitis by live probiotic bacteria is mediated by Toll-like receptor signalling and whether non-viable probiotics are similarly effective. Administration of probiotic DNA ameliorated the severity of experimental colitis whereas methylated probiotic DNA, calf thymus DNA and DNAse treated probiotics had no effect. The colitis severity was attenuated to the same extent by delivery of non-viable, γ-irradiated or viable probiotics, but not by heatkilled probiotics, in wild type mice, in mice deficient in Toll-like receptor 2 or in mice deficient in Toll like receptor 4. In contrast, we did not observe any inhibition of experimental colitis by probiotics, in mice deficient in MyD88 or Toll-like receptor 9. In subsequent studies, we identified that Toll-like receptor 9-induced type-1 IFN mediates the anti-inflammatory effects in experimental colitis. The addition of neutralisation antibodies to type-1 IFN abolished the anti-inflammatory effects whereas the administration of recombinant IFN-β mimicked the anti-inflammatory effects induced by Toll-like receptor 9 agonists. Taken together, these results indicate that the protective effects of probiotics are mainly mediated by their own DNA rather than by their metabolites or their ability to colonise the colon. These finding underscore the diverse effects of indigenous microbial TLR ligands in intestinal homeostasis and intestinal inflammation and suggest that strategies, which modulate type-1 IFN may be of therapeutic value for intestinal inflammatory conditions.