Abstract
BackgroundWithin seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction.Methodology/Principal findingsSecondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum.Conclusion/SignificanceWith respect to the intestinal microbiota composition “humanized” mice display acute ileitis following peroral high dose T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation.
Highlights
Within one week following peroral infection with a high dose (i.e. 50 to 100 cysts) of the intracellular parasite Toxoplasma gondii strain ME49 susceptible mice develop severe ileitis and succumb to infection [1,2,3]
Generation of human microbiota associated mice by fecal microbiota transplantation In the present study we investigated intestinal, extra-intestinal and systemic sequelae of acute T. gondii induced ileitis in “humanized” mice
Acute ileitis is accompanied by pronounced shifts in the intestinal microbiota composition of hma mice
Summary
Within one week following peroral infection with a high dose (i.e. 50 to 100 cysts) of the intracellular parasite Toxoplasma gondii strain ME49 susceptible mice develop severe ileitis and succumb to infection [1,2,3]. Ileitis development has been shown to be highly microbiota dependent [8], given that secondary abiotic mice with a virtually depleted intestinal microbiota were unaffected following T. gondii infection, whereas upon reconstitution with the murine intestinal microbiota mice were suffering from overt disease [9]. Within seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction
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