Protein Malnutrition Modifies Innate Immunity and Gene Expression by Intestinal Epithelial Cells and Human Rotavirus Infection in Neonatal Gnotobiotic Pigs
Anastasia N. Vlasova,
Francine C. Paim,
Sukumar Kandasamy,
Moyasar A. Alhamo,
David D. Fischer,
Stephanie N. Langel,
Loic Deblais,
Anand Kumar,
Juliet Chepngeno,
Lulu Shao,
Huang-Chi Huang,
Rosario A. Candelero-Rueda,
Gireesh Rajashekara,
Linda J. Saif
Affiliations
Anastasia N. Vlasova
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Francine C. Paim
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Sukumar Kandasamy
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Moyasar A. Alhamo
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
David D. Fischer
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Stephanie N. Langel
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Loic Deblais
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Anand Kumar
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Juliet Chepngeno
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Lulu Shao
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Huang-Chi Huang
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Rosario A. Candelero-Rueda
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Gireesh Rajashekara
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
Linda J. Saif
Food Animal Health Research Program (FAHRP), Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, Ohio, USA
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. IMPORTANCE Malnutrition 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.
