Infoscience

Thesis

The microbiota provides colonisation resistance against intestinal helminths by regulating intestinal physiology

Intestinal helminth infections are a global health problem affecting particularly people living in poor countries. Heavy worm burdens can lead to nutritional and cognitive deficiencies. Type-two immunity plays a crucial role in promoting tissue repair and limiting parasite burdens; however, our knowledge as to how these responses lead to protection is limited. Moreover, intestinal helminths have co-evolved with their mammalian hosts and are well known to possess potent immuno-modulatory capacities allowing them to establish chronic and repeated infections. As adult worms reside in the gut, we asked whether the presence of intestinal bacterial communities (commonly referred to as the microbiota) impacted on worm burdens or type-two immunity following infection. For this purpose, we infected germ-free (living in a sterile environment) or antibiotic-treated mice with the natural murine parasite Heligmosomoides polygyrus bakeri. As worms are normally hatched from faecal cultures and carry their own microbiota, we first developed a system to generate bacteriologically-sterile (axenic) infective larvae. In germ-free and antibiotic-treated mice, the number of adult worms and their egg production were both increased, despite the presence of a slightly increased helminth-elicited type-two immune response, as shown by cytokine and antibody responses. The increased worm fitness in the absence of microbiota was already detected early following infection and was associated with a more anterior distribution of larvae along the intestinal tract. Thus, we hypothesised that the microbiota may impact on parasite burdens through observed alterations of intestinal physiology, such as increased bile acid production and deregulated smooth muscle cell contractility. To test the importance of these factors, we performed experiments in which we treated mice with an excess of bile acids or altered intestinal transit through drug treatment. Both interventions lead to changes in worm infectivity or location, mirroring different observations generated in our germ-free and antibiotic-treated mice. In summary, our data indicate that a complex microbiota affords 'colonisation resistance' against intestinal helminths, in a manner that is independent of the immune response but dependent on changes to intestinal physiology.

    Keywords: helminths ; intestines ; microbiota ; antibiotics ; immunology ; physiology

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 7670 (2017)
    Programme doctoral Approches moléculaires du vivant
    Faculté des sciences de la vie
    Institut de recherche en infectiologie
    Unité de la Prof. Harris
    Jury: Prof. Joachim Lingner (président) ; Prof. Nicola Harris (directeur de thèse) ; Prof. Melanie Blokesch, Dr Dominique Velin, Dr Philippe Krebs (rapporteurs)

    Public defense: 2017-6-23

    Reference

    Record created on 2017-06-12, modified on 2017-07-04

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