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.
Highlights
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
Comparison of blood parameters at the termination of the experiment revealed that pigs on the protein-deficient diet had significantly decreased levels of glucose, total protein, and albumin (Fig. 2, human infant fecal microbiota (HIFM)/HRVinfected pigs on deficient and sufficient diets; no-human RV (HRV)/no-HIFM controls, data not shown), as seen in malnourished children
The clinical signs in the affected piglets were consistent with hypoglycemia and septicemia in addition to extraintestinal recovery of Clostridium perfringens type A and nonhemolytic, avirulent Escherichia coli
Summary
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. 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. Contradictory evidence comes from a longitudinal study of a birth cohort in Bangladesh that demonstrated a positive association between healthy dwelling and adequate nutritional status of infants with the risk of symptomatic RV infection [16] This observation may be related to the preexisting damage of the intestinal epithelium of infants who had clinical or subclinical malnutrition and may lack the target mature enterocytes that support HRV infection. We established a human infant fecal microbiota (HIFM)-transplanted neonatal gnotobiotic (Gn) pig model of childhood malnutrition and investigated the impacts of early-life protein malnutrition on innate immunity, pathogenesis of an enteric infection (HRV), and IEC gene expression (chromogranin A [CgA], enteroendocrine cells; mucin 2 [MUC2], goblet cells; proliferating cell nuclear antigen [PCNA], transient amplifying progenitor cells; SRY-Box 9 [SOX9], IESCs; villin, enterocytes)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.