title: Protein Malnutrition Modifies Innate Immunity and Gene Expression by Intestinal Epithelial Cells and Human Rotavirus Infection in Neonatal Gnotobiotic Pigs.
abstract: Malnutrition affects millions of children in developing countries, compromising immunity and contributing to increased rates of death from infectious diseases. Rotavirus is a major etiological agent of childhood diarrhea in developing countries, where malnutrition is prevalent. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. In this study, we used neonatal gnotobiotic (Gn) pigs transplanted with the fecal microbiota of a healthy 2-month-old infant (HIFM) and fed protein-deficient or -sufficient bovine milk diets. Protein deficiency induced hypoproteinemia, hypoalbuminemia, hypoglycemia, stunting, and generalized edema in Gn pigs, as observed in protein-malnourished children. Irrespective of the diet, human rotavirus (HRV) infection early, at HIFM posttransplantation day 3 (PTD3), resulted in adverse health effects and higher mortality rates (45 to 75%) than later HRV infection (PTD10). Protein malnutrition exacerbated HRV infection and affected the morphology and function of the small intestinal epithelial barrier. In pigs infected with HRV at PTD10, there was a uniform decrease in the function and/or frequencies of natural killer cells, plasmacytoid dendritic cells, and CD103+and apoptotic mononuclear cells and altered gene expression profiles of intestinal epithelial cells (chromogranin A, mucin 2, proliferating cell nuclear antigen, SRY-Box 9, and villin). Thus, we have established the first HIFM-transplanted neonatal pig model that recapitulates major aspects of protein malnutrition in children and can be used to evaluate physiologically relevant interventions. Our findings provide an explanation of why nutrient-rich diets alone may lack efficacy in malnourished children.IMPORTANCEMalnutrition and rotavirus infection, prevalent in developing countries, individually and in combination, affect the health of millions of children, compromising their immunity and increasing the rates of death from infectious diseases. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. We have established the first human infant microbiota-transplanted neonatal pig model of childhood malnutrition that reproduced the impaired immune, intestinal, and other physiological functions seen in malnourished children. This model can be used to evaluate relevant dietary and other health-promoting interventions. Our findings provide an explanation of why adequate nutrition alone may lack efficacy in malnourished children.
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Anastasia N
authors.identifier: 0000-0002-1447-6283
authors.initials: AN
authors.lastname: Vlasova
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Francine C
authors.initials: FC
authors.lastname: Paim
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Sukumar
authors.initials: S
authors.lastname: Kandasamy
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Moyasar A
authors.initials: MA
authors.lastname: Alhamo
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Fischer
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Langel
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Deblais
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Juliet
authors.initials: J
authors.lastname: Chepngeno
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Shao
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Huang-Chi
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Rosario A
authors.initials: RA
authors.lastname: Candelero-Rueda
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Gireesh
authors.initials: G
authors.lastname: Rajashekara
authors.affiliation: Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Saif
keywords: gnotobiotic piglets; human infant fecal microbiota; human rotavirus; innate immunity; intestinal epithelial barrier; intestinal epithelial cells; natural killer cells; plasmacytoid dendritic cells; protein deficiency