Host Response to Probiotics Determined by Nutritional Status of Rotavirus-Infected Neonatal Mice

Abstract

OBJECTIVES:

Beneficial microbes and probiotics are promising agents for the prevention and treatment of enteric and diarrheal diseases in children. However, little is known about their in vivo mechanisms of action. We used a neonatal mouse model of rotavirus diarrhea to gain insight into how probiotics ameliorate acute gastroenteritis.

MATERIALS AND METHODS:

Rotavirus-infected mice were treated with one of two strains of human-derived Lactobacillus reuteri. We assessed intestinal microbiome composition with 16S metagenomic sequencing, enterocyte migration and proliferation with 5-bromo-2'-deoxyuridine, and antibody and cytokine concentrations with multiplex analyses of intestinal explant cultures.

RESULTS:

Probiotics reduced diarrhea duration, improved intestinal histopathology, and enhanced intestinal microbiome richness and phylogenetic diversity. The magnitude of reduction of diarrhea by probiotics was strain-specific and influenced by nutritional status. L. reuteri DSM 17938 reduced diarrhea duration by zero, one, and two days in underweight, normal weight, and overweight pups, respectively. The magnitude of reduction of diarrhea duration correlated with increased enterocyte proliferation and migration. Strain ATCC PTA 6475 reduced diarrhea duration by one day in all mice without increasing enterocyte proliferation. Both probiotic strains decreased concentrations of proinflammatory cytokines, including MIP-1α and IL-1β, in all animals, and increased rotavirus-specific antibodies in all but underweight animals. Body weight also influenced the host response to rotavirus, in terms of diarrhea duration, enterocyte turnover, and antibody production.

CONCLUSIONS:

These data suggest that probiotic enhancement of enterocyte proliferation, villus repopulation, and virus-specific antibodies may contribute to diarrhea resolution, and that nutritional status influences the host response to both beneficial microbes and pathogens.
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