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Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes

Mucosal Immunology (2018) | Download Citation

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Abstract

The beneficial effects of the gut microbiota on growth in early life are well known. However, knowledge about the mechanisms underlying regulating intestinal development by the microbiota is limited. p40, a Lactobacillus rhamnosus GG-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells for protecting the intestinal epithelium against injury and inflammation. Here, we developed p40-containing pectin/zein hydrogels for targeted delivery of p40 to the small intestine and the colon. Treatment with p40-containing hydrogels from postnatal day 2 to 21 significantly enhanced bodyweight gain prior to weaning and functional maturation of the intestine, including intestinal epithelial cell proliferation, differentiation, and tight junction formation, and IgA production in early life in wild-type mice. These p40-induced effects were abolished in mice with specific deletion of EGFR in intestinal epithelial cells, suggesting that transactivation of EGFR in intestinal epithelial cells may mediate p40-regulated intestinal development. Furthermore, neonatal p40 treatment reduced the susceptibility to intestinal injury and colitis and promoted protective immune responses, including IgA production and differentiation of regulatory T cells, in adult mice. These findings reveal novel roles of neonatal supplementation of probiotic-derived factors in promoting EGFR-mediated maturation of intestinal functions and innate immunity, which likely promote long-term beneficial outcomes.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grant R01DK081134 and the Crohn’s & Colitis Foundation Senior Research Award (to F.Y.), NIH grants R01DK56008 and R01DK54993 and the Crohn’s & Colitis Foundation Senior Research Award (to D.B.P.), NIH grants R01DK58587, R01CA77955, and P01CA116087 (to R.M.P.), and National Natural Science Foundation of China Grant 81372982 (to F.H.), and core services performed through Vanderbilt University Medical Center’s Digestive Disease Research Center supported by NIH grant P30DK058404. Whole slide imaging was performed in the Digital Histology Shared Resource at Vanderbilt University Medical Center (www.mc.vanderbilt.edu/dhsr). We thank Dr. M. Kay Washington from Vanderbilt University Medical Center for examining intestinal tissue sections from mouse models of colitis.

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Affiliations

  1. Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    • Xi Shen
    • , Liping Liu
    • , Sari A. Acra
    •  & Fang Yan
  2. West China School of Public Health and Healthy Food Evaluation Research Center, Sichuan University, 17 Ren Min South Road, Wuhou District, Chengdu, Sichuan, 610041, China

    • Xi Shen
    •  & Fang He
  3. Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    • Richard M. Peek
    • , Keith T. Wilson
    •  & Fang Yan
  4. Department of Pediatrics, Division of Endocrinology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    • Daniel J. Moore
  5. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37232, USA

    • Keith T. Wilson
  6. Departments of Pediatrics and Biochemistry and Molecular Medicine, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, CA, 90027, USA

    • D. Brent Polk
  7. The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, 90027, USA

    • D. Brent Polk

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Contributions

X.S., L.L., R.M.P., S.A.A., D.J.M., K.T.W., F.H., D.B.P., and F.Y. designed research studies and analyzed data; X.S., L.L., and F.Y. conducted experiments and acquired data. X.S. R.M.P., S.A.A., D.B.P., and F.Y. wrote the manuscript.

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The authors declare no competing interests.

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Correspondence to Fang Yan.

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DOI

https://doi.org/10.1038/s41385-018-0034-3