Skip to main content

Advertisement

SpringerLink
Log in

Intestinal organoid as an in vitro model in studying host-microbial interactions

  • Review
  • Published:
Frontiers in Biology

Abstract

Background

Organoid is an in vitro three-dimensional organ-bud that shows realistic microanatomy and physiological relevance. The progress in generating organoids that faithfully recapitulate human in vivo tissue composition has extended organoid applications from being just a basic research tool to a translational platform with a wide range of uses. Study of hostmicrobial interactions relies on model systems to mimic the in vivo infection. Researchers have developed various experimental models in vitro and in vivo to examine the dynamic host-microbial interactions. For some infectious pathogens, model systems are lacking whereas some of the used systems are far from optimal.

Objective

In the present work, we will review the brief history and recent findings using organoids for studying hostmicrobial interactions.

Methods

A systematic literature search was performed using the PubMed search engine. We also shared our data and research contribution to the field.

Results

we summarize the brief history of 3D organoids. We discuss the feasibility of using organoids in studying hostmicrobial interactions, focusing on the development of intestinal organoids and gastric organoids. We highlight the advantage and challenges of the new experimental models. Further, we discuss the future direction in using organoids in studying hostmicrobial interactions and its potential application in biomedical studies.

Conclusion

In combination with genetic, transcriptome and proteomic profiling, both murine- and human-derived organoids have revealed crucial aspects of development, homeostasis and diseases. Specifically, human organoids from susceptible host will be used to test their responses to pathogens, probiotics, and drugs. Organoid system is an exciting tool for studying infectious disease, microbiome, and therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aoki-Yoshida A, Saito S, Fukiya S, Aoki R, Takayama Y, Suzuki C, Sonoyama K (2016). Lactobacillus rhamnosus GG increases Toll-like receptor 3 gene expression in murine small intestine ex vivo and in vivo. Benef Microbes, 7(3): 421–429

    Article  CAS  PubMed  Google Scholar 

  • Arnold J W, Roach J, Azcarate-Peril M A (2016). Emerging technologies for gut microbiome research. Trends Microbiol, 24(11): 887–901

    Article  CAS  PubMed  Google Scholar 

  • Barrandon Y, Green H (1987). Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA, 84(8): 2302–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H, Kujala P, Vries R, Peters P J, Clevers H (2015). In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology, 148(1): 126–136.e6

    Google Scholar 

  • Bartfeld S, Clevers H (2015). Organoids as model for infectious diseases: Culture of human and murine stomach organoids and microinjection of Helicobacter pylori. J Vis Exp, 43(105):816–818

    Google Scholar 

  • Bertaux-Skeirik N, Feng R, Schumacher MA, Li J, MaheMM, Engevik A C, Javier J E, Peek RMJr, Ottemann K, Orian-Rousseau V, Boivin G P, Helmrath M A, Zavros Y (2015). CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation. PLoS Pathog, 11(2): e1004663

    Article  PubMed  PubMed Central  Google Scholar 

  • Crosnier C, Stamataki D, Lewis J (2006). Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet, 7(5): 349–359

    Article  CAS  PubMed  Google Scholar 

  • D’Aiuto L, Di Maio R, Heath B, Raimondi G, Milosevic J, Watson A M, Bamne M, Parks WT, Yang L, Lin B, Miki T, Mich-Basso J D, Arav-Boger R, Sibille E, Sabunciyan S, Yolken R, Nimgaonkar V (2012). Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells. PLoS One, 7(11): e49700

    Article  PubMed  PubMed Central  Google Scholar 

  • Dedhia P H, Bertaux-Skeirik N, Zavros Y, Spence J R (2016). Organoid models of human gastrointestinal development and disease. Gastroenterology, 150(5): 1098–1112

    Article  PubMed  Google Scholar 

  • Dingli D, Nowak M A (2006). Cancer biology: infectious tumour cells. Nature, 443(7107): 35–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engevik M A, Aihara E, Montrose M H, Shull G E, Hassett D J, Worrell R T (2013). Loss of NHE3 alters gut microbiota composition and influences Bacteroides thetaiotaomicron growth. Am J Physiol Gastrointest Liver Physiol, 305(10): G697–G711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ettayebi K, Crawford S E, Murakami K, Broughman J R, Karandikar U, Tenge V R, Neill F H, Blutt S E, Zeng X L, Qu L, Kou B, Opekun A R, Burrin D, Graham D Y, Ramani S, Atmar R L, Estes M K (2016). Replication of human noroviruses in stem cell-derived human enteroids. Science, 353(6306): 1387–1393

    Article  PubMed  PubMed Central  Google Scholar 

  • Fang S B, Schüller S, Phillips A D (2013). Human intestinal in vitro organ culture as a model for investigation of Bacteriae-host interactions. J Exp Clin Med, 5(2): 43–50

    Article  Google Scholar 

  • Fatehullah A, Tan S H, Barker N (2016). Organoids as an in vitro model of human development and disease. Nat Cell Biol, 18(3): 246–254

    Article  PubMed  Google Scholar 

  • Finkbeiner S R, Zeng X L, Utama B, Atmar R L, Shroyer N F, Estes MK (2012). Stem cell-derived human intestinal organoids as an infection model for rotaviruses. MBio, 3(4): e00159–e12

    Google Scholar 

  • Forbester J L, Goulding D, et al (2014). Intestinal organoids are a novel system to study Salmonella enterica Serovar Typhimurium interaction with the intestinal epithelial barrier. Immunology, 143: 111–112

    Google Scholar 

  • Forbester J L, Goulding D, Vallier L, Hannan N, Hale C, Pickard D, Mukhopadhyay S, Dougan G (2015). Interaction of Salmonella enterica Serovar Typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun, 83(7): 2926–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foulke-Abel J, In J, Kovbasnjuk O, Zachos N C, Ettayebi K, Blutt S E, Hyser J M, Zeng X L, Crawford S E, Broughman J R, Estes M K, Donowitz M (2014). Human enteroids as an ex-vivo model of hostpathogen interactions in the gastrointestinal tract. Exp Biol Med (Maywood), 239(9): 1124–1134

    Article  Google Scholar 

  • Garcez P P, Loiola E C, Madeiro da Costa R, Higa L M, Trindade P, Delvecchio R, Nascimento J M, Brindeiro R, Tanuri A, Rehen S K (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science, 352(6287): 816–818

    Article  CAS  PubMed  Google Scholar 

  • Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina M E, Ordóñez-Morán P, Clevers H, Lutolf M P (2016). Designer matrices for intestinal stem cell and organoid culture. Nature, 539(7630): 560–564

    Article  CAS  PubMed  Google Scholar 

  • Harrison R G (1907). Observations on the living developing fiber. Proc Soc Exp Biol Med, 4(1): 140–143

    Article  Google Scholar 

  • Heuberger J, Kosel F, Qi J, Grossmann K S, Rajewsky K, Birchmeier W (2014). Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine. Proc Natl Acad Sci USA, 111(9): 3472–3477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hilleman M R (1990). History, precedent, and progress in the development of mammalian cell culture systems for preparing vaccines: safety considerations revisited. J Med Virol, 31(1): 5–12

    Article  CAS  PubMed  Google Scholar 

  • Huang G, Ye S, Zhou X, Liu D, Ying Q L (2015a). Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network. Cell Mol Life Sci, 72(9): 1741–1757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J Y, Sweeney E G, Sigal M, Zhang H C, Remington S J, Cantrell M A, Kuo C J, Guillemin K, Amieva M R (2015b). Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Cell Host Microbe, 18(2): 147–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huch M, Koo B K (2015). Modeling mouse and human development using organoid cultures. Development, 142(18): 3113–3125

    Article  CAS  PubMed  Google Scholar 

  • In J G, Foulke-Abel J, Estes MK, Zachos N C, Kovbasnjuk O, Donowitz M (2016). Human mini-guts: new insights into intestinal physiology and host-pathogen interactions. Nat Rev Gastroenterol Hepatol, 13(11): 633–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung P, Sato T, Merlos-Suárez A, Barriga F M, Iglesias M, Rossell D, Auer H, Gallardo M, Blasco M A, Sancho E, Clevers H, Batlle E (2011). Isolation and in vitro expansion of human colonic stem cells. Nat Med, 17(10): 1225–1227

    Article  CAS  PubMed  Google Scholar 

  • Klotz C, Aebischer T, Seeber F (2012). Stem cell-derived cell cultures and organoids for protozoan parasite propagation and studying hostparasite interaction. Int J Med Microbiol, 302(4–5): 203–209

    Article  CAS  PubMed  Google Scholar 

  • Kristin W, Weitz J, et al (2016). Organoids as model systems for gastrointestinal diseases: tissue engineering meets. Curr Pathobiol Rep, 4(1): 1–9

    Article  Google Scholar 

  • Leslie J L, Huang S, Opp J S, Nagy M S, Kobayashi M, Young V B, Spence J R (2015). Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun, 83(1): 138–145

    Article  PubMed  Google Scholar 

  • Mahe M M, Aihara E, Schumacher M A, Zavros Y, Montrose M H, Helmrath M A, Sato T, Shroyer N F (2013). Establishment of gastrointestinal epithelial organoids. Curr Protoc Mouse Biol, 3(4): 217–240

    Article  PubMed  PubMed Central  Google Scholar 

  • Mahe M M, Sundaram N, Watson C L, Shroyer N F, Helmrath M A (2015). Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy. J Vis Exp, (97): e52483-e52483

  • McCracken K W, Catá E M, Crawford C M, Sinagoga K L, Schumacher M, Rockich B E, Tsai Y H, Mayhew C N, Spence J R, Zavros Y, Wells J M (2014). Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature, 516(7531): 400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyoshi H, Stappenbeck T S (2013). In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc, 8(12): 2471–2482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng S, Schwartz R E, March S, Galstian A, Gural N, Shan J, Prabhu M, Mota M M, Bhatia S N (2015). Human iPSC-derived hepatocyte-like cells support Plasmodium liver-stage infection in vitro. Stem Cell Rep, 4(3): 348–359

    Article  CAS  Google Scholar 

  • Ootani A, Li X, Sangiorgi E, Ho Q T, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman I L, Capecchi MR, Kuo C J (2009). Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med, 15(6): 701–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penkert R R, Kalejta R F (2013). Human embryonic stem cell lines model experimental human cytomegalovirus latency. MBio, 4(3): e00298–e13

    Google Scholar 

  • Roelandt P, Obeid S, Paeshuyse J, Vanhove J, Van Lommel A, Nahmias Y, Nevens F, Neyts J, Verfaillie CM (2012). Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus. J Hepatol, 57(2): 246–251

    Article  CAS  PubMed  Google Scholar 

  • Salama N R, Hartung ML, Müller A (2013). Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol, 11(6): 385–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato T, Stange D E, Ferrante M, Vries R G, Van Es J H, Van den Brink S, Van Houdt W J, Pronk A, Van Gorp J, Siersema P D, Clevers H (2011a). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 141(5): 1762–1772

    Article  CAS  PubMed  Google Scholar 

  • Sato T, van Es J H, Snippert H J, Stange D E, Vries R G, van den Born M, Barker N, Shroyer N F, van de Wetering M, Clevers H (2011b). Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature, 469(7330): 415–418

    Article  CAS  PubMed  Google Scholar 

  • Sato T, Vries R G, Snippert H J, van de Wetering M, Barker N, Stange D E, van Es J H, Abo A, Kujala P, Peters P J, Clevers H (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459(7244): 262–265

    Article  CAS  PubMed  Google Scholar 

  • Saxena K, Blutt S E, Ettayebi K, Zeng X L, Broughman J R, Crawford S E, Karandikar U C, Sastri N P, Conner M E, Opekun A R, Graham D Y, Qureshi W, Sherman V, Foulke-Abel J, In J, Kovbasnjuk O, Zachos N C, Donowitz M, Estes M K (2015). Human intestinal enteroids: a new model to study human rotavirus infection, host restriction, and pathophysiology. J Virol, 90(1): 43–56

    Article  PubMed  PubMed Central  Google Scholar 

  • Schlaermann P, Toelle B, Berger H, Schmidt S C, Glanemann M, Ordemann J, Bartfeld S, Mollenkopf H J, Meyer T F (2016). A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. Gut, 65(2): 202–213

    Article  CAS  PubMed  Google Scholar 

  • Schumacher M A, Feng R, Aihara E, Engevik A C, Montrose M H, Ottemann K M, Zavros Y (2015). Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NFkB pathway activation: the use of a novel in vitro model to study epithelial response to infection. Helicobacter, 20(1): 19–28

    Article  CAS  PubMed  Google Scholar 

  • Schwank G, Koo B K, Sasselli V, Dekkers J F, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent C K, Nieuwenhuis E E, Beekman J M, Clevers H (2013). Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell, 13(6): 653–658

    Article  CAS  PubMed  Google Scholar 

  • Schwartz R E, Trehan K, Andrus L, Sheahan T P, Ploss A, Duncan S A, Rice C M, Bhatia S N (2012). Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc Natl Acad Sci USA, 109(7): 2544–2548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shlomai A, Schwartz R E, Ramanan V, Bhatta A, de Jong Y P, Bhatia S N, Rice C M (2014). Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc Natl Acad Sci USA, 111(33): 12193–12198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sigal M, RothenbergME, Logan C Y, Lee J Y, Honaker R W, Cooper R L, Passarelli B, Camorlinga M, Bouley D M, Alvarez G, Nusse R, Torres J, Amieva M R (2015). Helicobacter pylori activates and expands Lgr5(+) stem cells through direct colonization of the gastric glands. Gastroenterology, 148(7): 1392–404.e21

    Google Scholar 

  • Spence J R, Mayhew C N, Rankin S A, Kuhar M F, Vallance J E, Tolle K, Hoskins E E, Kalinichenko V V, Wells S I, Zorn A M, Shroyer N F, Wells J M (2011). Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature, 470(7332): 105–109

    Article  PubMed  Google Scholar 

  • Unsworth B R, Lelkes P I (1998). Growing tissues in microgravity. Nat Med, 4(8): 901–907

    Article  CAS  PubMed  Google Scholar 

  • Van Dussen K L, Marinshaw J M, Shaikh N, Miyoshi H, Moon C, Tarr P I, Ciorba M A, Stappenbeck T S (2015). Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut, 64(6): 911–920

    Article  Google Scholar 

  • Wang X, Yamamoto Y, Wilson L H, Zhang T, Howitt B E, Farrow M A, Kern F, Ning G, Hong Y, Khor C C, Chevalier B, Bertrand D, Wu L, Nagarajan N, Sylvester F A, Hyams J S, Devers T, Bronson R, Lacy D B, Ho K Y, Crum C P, McKeon F, Xian W (2015). Cloning and variation of ground state intestinal stem cells. Nature, 522(7555): 173–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson S S, Tocchi A, Holly MK, Parks WC, Smith J G (2015). A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol, 8(2): 352–361

    Article  CAS  PubMed  Google Scholar 

  • Wroblewski L E, Peek R M Jr, Wilson K T (2010). Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev, 23(4): 713–739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Robotham J M, Lee E, Dalton S, Kneteman N M, Gilbert D M, Tang H (2012). Productive hepatitis C virus infection of stem cellderived hepatocytes reveals a critical transition to viral permissiveness during differentiation. PLoS Pathog, 8(4): e1002617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin Y, Bijvelds M, Dang W, Xu L, van der Eijk A A, Knipping K, Tuysuz N, Dekkers J F, Wang Y, de Jonge J, Sprengers D, van der Laan L J, Beekman J M, Ten Berge D, Metselaar H J, de Jonge H, Koopmans M P, Peppelenbosch M P, Pan Q (2015). Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antiviral Res, 123: 120–131

    Article  CAS  PubMed  Google Scholar 

  • Yoshida T, Takayama K, Kondoh M, Sakurai F, Tani H, Sakamoto N, Matsuura Y, Mizuguchi H, Yagi K (2011). Use of human hepatocytelike cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection. Biochem Biophys Res Commun, 416(1–2): 119–124

    Article  CAS  PubMed  Google Scholar 

  • Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, Ichinose S, Nagaishi T, Okamoto R, Tsuchiya K, Clevers H, Watanabe M (2012). Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat Med, 18(4): 618–623

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y G, Wu S, Xia Y, Sun J (2014). Salmonella-infected cryptderived intestinal organoid culture system for host-bacterial interactions. Physiol Rep, 2(9): e12147

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIDDK 1R01DK105118-01 and the UIC Cancer Center to Jun Sun.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S Wood Street, Chicago, IL, 60612, USA

    Jun Sun

Authors
  1. Jun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Sun.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, J. Intestinal organoid as an in vitro model in studying host-microbial interactions. Front. Biol. 12, 94–102 (2017). https://doi.org/10.1007/s11515-017-1444-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-017-1444-4

Keywords

Search

Navigation