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.
Methods: Rotavirus-infected mice were treated with 1 of 2 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 0, 1, and 2 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 1 day in all of the mice without increasing enterocyte proliferation. Both probiotic strains decreased concentrations of proinflammatory cytokines, including macrophage inflammatory protein-1α and interleukin-1β, in all of the animals, and increased rotavirus-specific antibodies in all but the 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.
*Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine
†Department of Pathology, Texas Children's Hospital
‡Department of Pathology & Immunology
§Department of Molecular Virology and Microbiology
||Bioinformatics Research Laboratory, Baylor College of Medicine
¶Human Genome Sequencing Center, Houston, TX
#Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA.
Address correspondence and reprint requests to James Versalovic, MD, PhD, Texas Children's Hospital, Feigin Center, Suite 830, 1102 Bates Ave, Houston, TX 77030 (e-mail: firstname.lastname@example.org).
Received 22 May, 2011
Accepted 26 January, 2012
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This work was supported by the US National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) F30 DK081269 (G.A.P.), R01 DK065075 (J.V.), UH3 DK083990 (J.V.), and P30 DK56338 (M.J.F. and J.V.); by the National Institute of Allergy and Infectious Diseases (NIAID) RO1 AI24998 (M.E.C.) and U01 AI26512 (R.L.G.); and by the National Center for Complementary and Alternative Medicine (NCCAM) R01 AT004326 (J.V.).
R.L.G. is a member of and paid consultant for Probiotics scientific advisory board Danone/Yakult; he is co-founder and co-owner of Albutamine LLC. J.V. received an unrestricted grant from Biogaia AB; he acts as an advisor/consultant to Danone. The other authors report no conflicts of interest.