Abstract
BackgroundRotavirus vaccines have poor efficacy in infants from low- and middle-income countries. Gut microbiota is thought to influence the immune response to oral vaccines. Thus, we developed a gnotobiotic (Gn) pig model of enteric dysbiosis to study the effects of human gut microbiota (HGM) on immune responses to rotavirus vaccination, and the effects of rotavirus challenge on the HGM by colonizing Gn pigs with healthy HGM (HHGM) or unhealthy HGM (UHGM). The UHGM was from a Nicaraguan infant with a high enteropathy score (ES) and no seroconversion following administration of oral rotavirus vaccine, while the converse was characteristic of the HHGM. Pigs were vaccinated, a subset was challenged, and immune responses and gut microbiota were evaluated.ResultsSignificantly more rotavirus-specific IFN-γ producing T cells were in the ileum, spleen, and blood of HHGM than those in UHGM pigs after three vaccine doses, suggesting HHGM induces stronger cell-mediated immunity than UHGM. There were significant correlations between multiple Operational Taxonomic Units (OTUs) and frequencies of IFN-γ producing T cells at the time of challenge. There were significant positive correlations between Collinsella and CD8+ T cells in blood and ileum, as well as CD4+ T cells in blood, whereas significant negative correlations between Clostridium and Anaerococcus, and ileal CD8+ and CD4+ T cells. Differences in alpha diversity and relative abundances of OTUs were detected between the groups both before and after rotavirus challenge.ConclusionAlterations in microbiome diversity and composition along with correlations between certain microbial taxa and T cell responses warrant further investigation into the role of the gut microbiota and certain microbial species on enteric immunity. Our results support the use of HGM transplanted Gn pigs as a model of human dysbiosis during enteric infection, and oral vaccine responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-016-0136-y) contains supplementary material, which is available to authorized users.
Highlights
Rotavirus vaccines have poor efficacy in infants from low- and middle-income countries
The data demonstrate that the attenuated human rotavirus vaccine (AttHRV) vaccine induced significantly stronger anti-viral effector T cell immune responses in pigs colonized with healthy HGM (HHGM) than those with unhealthy HGM (UHGM)
In this study we demonstrated that Gn pigs colonized by UHGM can serve as a model system for enteric dysbiosis and impaired immunity
Summary
Rotavirus vaccines have poor efficacy in infants from low- and middle-income countries. We developed a gnotobiotic (Gn) pig model of enteric dysbiosis to study the effects of human gut microbiota (HGM) on immune responses to rotavirus vaccina‐ tion, and the effects of rotavirus challenge on the HGM by colonizing Gn pigs with healthy HGM (HHGM) or unhealthy HGM (UHGM). Histologic features include villous blunting, crypt hyperplasia, and lymphocytic infiltration of the epithelium and lamina propria in the small intestine [9]. The cause of this condition is unknown, but theories include constant exposure to enteropathogens in food, water, or the environment, imbalance of gut microbiota, and an altered immune response triggered by intestinal microbes [4, 9, 10]
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