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Human mini-guts: new insights into intestinal physiology and host–pathogen interactions

Nature Reviews Gastroenterology & Hepatology volume 13, pages 633–642 (2016)Cite this article

Subjects

Key Points

  • Human 'mini-guts' generated from crypt-based or induced pluripotent stem (iPS) cells functionally recapitulate normal intestinal transport physiology and model pathophysiologic changes following interactions with enteric pathogens

  • iPS-cell-derived intestinal organoids can be used to model intestinal development and engrafted in vivo to differentiate the epithelium along a crypt–villus axis supported by subepithelial and smooth muscle layers

  • 3D enteroids and colonoids derived from intestinal stem cells can be used to measure ion, nutrient and water absorption or secretion as part of normal intestinal transport function

  • Both human intestinal organoids and enteroids or colonoids can be used as models to study enteric bacterial and viral pathogenesis

  • Enteroids and colonoids can be grown on 2D permeable supports to enable apical access to study host–pathogen interactions as well as drug absorption and/or metabolism

  • Stem cell or iPS-cell-derived gastrointestinal organoids from the stomach, pancreas and liver are also being developed as models to study development, infection and regenerative medicine

Abstract

The development of indefinitely propagating human 'mini-guts' has led to a rapid advance in gastrointestinal research related to transport physiology, developmental biology, pharmacology, and pathophysiology. These mini-guts, also called enteroids or colonoids, are derived from LGR5+ intestinal stem cells isolated from the small intestine or colon. Addition of WNT3A and other growth factors promotes stemness and results in viable, physiologically functional human intestinal or colonic cultures that develop a crypt–villus axis and can be differentiated into all intestinal epithelial cell types. The success of research using human enteroids has highlighted the limitations of using animals or in vitro, cancer-derived cell lines to model transport physiology and pathophysiology. For example, curative or preventive therapies for acute enteric infections have been limited, mostly due to the lack of a physiological human intestinal model. However, the human enteroid model enables specific functional studies of secretion and absorption in each intestinal segment as well as observations of the earliest molecular events that occur during enteric infections. This Review describes studies characterizing these human mini-guts as a physiological model to investigate intestinal transport and host–pathogen interactions.

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Figure 1: Human intestinal enteroids represent human intestinal tissue.
Figure 2: Enteroids can model transport physiology.
Figure 3: Small intestinal and colonic enteroids can form a 2D monolayer and present a novel model to study intestinal–enteric pathogen interactions.

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Acknowledgements

The authors' research is supported by NIH grants K01DK106323 (J.G.I.), R01DK026523 (M.D.), R01DK061765 (M.D.), P30DK089502 (M.D.), T32DK007632 (M.D.), UH3TR000503 (M.D.), UH3TR000504 (M.D.), U01DK10316 (M.K.E.), and the Bill and Melinda Gates Foundation: Grand Challenges (M.D., O.K., M.K.E.).

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  1. Department of Medicine, Division of Gastroenterology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, 21205, Maryland, USA

    Julie G. In, Jennifer Foulke-Abel, Nicholas C. Zachos, Olga Kovbasnjuk & Mark Donowitz

  2. Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Mary K. Estes

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M.D. and J.G.I. researched data, contributed to discussion of content and writing, and reviewed/edited the manuscript before submission. J.F.-A. researched data for the article and contributed to writing. M.K.E. reviewed/edited the manuscript before submission. N.C.Z. and O.K. researched data for the article and contributed to discussion of content and writing.

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In, J., Foulke-Abel, J., Estes, M. et al. Human mini-guts: new insights into intestinal physiology and host–pathogen interactions. Nat Rev Gastroenterol Hepatol 13, 633–642 (2016). https://doi.org/10.1038/nrgastro.2016.142

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