Modeling human enteric dysbiosis and rotavirus immunity in gnotobiotic pigs.
BACKGROUND
Rotavirus 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.


RESULTS
Significantly 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 betweenCollinsellaand CD8+ T cells in blood and ileum, as well as CD4+ T cells in blood, whereas significant negative correlations betweenClostridiumandAnaerococcus, 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.


CONCLUSIONS
Alterations 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.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Erica L
EL
Twitchell
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Christine
C
Tin
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Ke
K
Wen
Microbiome Core, Cancer Inflammation Program, National Cancer Institute, Bethesda, MD USA.
Husen
H
Zhang
Department of Family Medicine, University of North Carolina School of Medicine, Chapel Hill, NC USA.
Sylvia
S
Becker-Dreps
Department of Cell Biology and Physiology, School of Medicine and Microbiome Core Facility, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC USA.
M Andrea
MA
Azcarate-Peril
Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University of Nicaragua, León, Nicaragua.
Samuel
S
Vilchez
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Guohua
G
Li
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Ashwin
A
Ramesh
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Mariah
M
Weiss
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Shaohua
S
Lei
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Tammy
T
Bui
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Xingdong
X
Yang
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
Stacey
S
Schultz-Cherry
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA USA.
Lijuan
0000-0003-0709-5228
L
Yuan
Enteric dysbiosis; Enteric immunity; Gnotobiotic pig; Rotavirus; Vaccine