WEHI Special Infection and Global Health Seminar hosted by Professor Aaron Jex

Professor Andre Buret

University of Calgary, Biological Sciences, Host Parasite Interactions, Inflammation Research Network, Canada

Enteric infections disrupt gut microbiota biofilms: From mechanisms to therapy

Davis Auditorium

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Including Q&A session

Intestinal infections are common causes of diarrhea, and may lead to post-infectious complications, via mechanisms that remain obscure. A host may be co-infected with multiple diarrheal-disease causing pathogens, and the final disease outcome results from the complex interactions between the host and this polymicrobial cross-talk. Using models of human tissues and live rodent models reproducing co-infections with Escherichia-coli, Campylobacter jejuni, and the Protozoan parasite Giardia sp., our studies shed new light on why the production of symptoms may be so variable and hence point towards new therapeutic targets. Indeed, direct immunomodulatory effects of Giardia attenuate the pathophysiological responses induced by gastrointestinal pathogens that cause disease via severe inflammation. These effects can be further demonstrated in human tissues obtained from patients with Crohn’s disease where administration of Giardia trophozoites significantly attenuate the contents of pro-inflammatory mediators. Co-infection with Giardia protects against intestinal disease induced by attaching-effacing enteropathogens. In addition, our findings demonstrate that high fat versus low fat diets may facilitate pathogenic factors in giardiasis, offering further support to the hypothesis that diet also plays a role in symptom variability. Finally, we have demonstrated how enteric infections can disrupt intestinal mucus barriers, fragment gut microbiota biofilms microbiota and transform commensals into invasive pathobionts that penetrate the intestinal barrier to cause intestinal inflammation. These alterations required the presence of environmental iron, and oral administration of novel therapeutics with anti-inflammatory and iron chelating properties were able to block these effects. In Giardia infections, the formation of microbiota pathobionts is triggered by a thermo-resistant and RNAse-sensitive cargo from extra-cellular vesicles. Together, these observations shed new light on the biology of polymicrobial infections in the gastrointestinal tract and underscore the multifactorial basis of the clinical variability in intestinal disorders. The findings point to new research directions in our attempts at the developing strategies to control enteric disease.

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