BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Intestinal organoids as advanced modeling platforms to study the role of host-microbiome interaction in homeostasis and disease

  • Ji-Su Ahn (Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University) ;
  • Min-Jung Kang (Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University) ;
  • Yoojin Seo (Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University) ;
  • Hyung-Sik Kim (Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University)
  • Received : 2022.10.20
  • Accepted : 2022.11.14
  • Published : 2023.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

After birth, animals are colonized by a diverse community of microorganisms. The digestive tract is known to contain the largest number of microbiome in the body. With emergence of the gut-brain axis, the importance of gut microbiome and its metabolites in host health has been extensively studied in recent years. The establishment of organoid culture systems has contributed to studying intestinal pathophysiology by replacing current limited models. Owing to their architectural and functional complexity similar to a real organ, co-culture of intestinal organoids with gut microbiome can provide mechanistic insights into the detrimental role of pathobiont and the homeostatic function of commensal symbiont. Here organoid-based bacterial co-culture techniques for modeling host-microbe interactions are reviewed. This review also summarizes representative studies that explore impact of enteric microorganisms on intestinal organoids to provide a better understanding of host-microbe interaction in the context of homeostasis and disease.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (2018-R1A5A2023879, 2019-R1A2C2085876) and the Ministry of Education (2021-R1I1A1A01055654). Korean Fund for Regenerative Medicine (KFRM) grant funded by the Ministry of Science and ICT and the Ministry of Health & Welfare (22A0205L1) also supported this project.

References

  1. Ley RE, Peterson DA and Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837-848  https://doi.org/10.1016/j.cell.2006.02.017
  2. Lynch JB and Hsiao EY (2019) Microbiomes as sources of emergent host phenotypes. Science 365, 1405-1408  https://doi.org/10.1126/science.aay0240
  3. Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y and Andoh A (2018) Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol 11, 1-10  https://doi.org/10.1007/s12328-017-0813-5
  4. Baumler AJ and Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535, 85-93  https://doi.org/10.1038/nature18849
  5. Park EM, Chelvanambi M, Bhutiani N, Kroemer G, Zitvogel L and Wargo JA (2022) Targeting the gut and tumor microbiota in cancer. Nat Med 28, 690-703  https://doi.org/10.1038/s41591-022-01779-2
  6. Nguyen TLA, Vieira-Silva S, Liston A and Raes J (2015) How informative is the mouse for human gut microbiota research? Dis Model Mech 8, 1-16  https://doi.org/10.1242/dmm.017400
  7. Kim J, Koo BK and Knoblich JA (2020) Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 21, 571-584  https://doi.org/10.1038/s41580-020-0259-3
  8. Sato T, Vries RG, Snippert HJ et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262-265  https://doi.org/10.1038/nature07935
  9. Menche C and Farin HF (2021) Strategies for genetic manipulation of adult stem cell-derived organoids. Exp Mol Med 53, 1483-1494  https://doi.org/10.1038/s12276-021-00609-8
  10. Min S, Kim S and Cho SW (2020) Gastrointestinal tract modeling using organoids engineered with cellular and microbiota niches. Exp Mol Med 52, 227-237  https://doi.org/10.1038/s12276-020-0386-0
  11. Leslie JL, Huang S, Opp JS et al (2015) Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun 83, 138-145  https://doi.org/10.1128/IAI.02561-14
  12. Zhang Y and Yu LC (2008) Microinjection as a tool of mechanical delivery. Curr Opin Biotechnol 19, 506-510  https://doi.org/10.1016/j.copbio.2008.07.005
  13. Poletti M, Arnauts K, Ferrante M and Korcsmaros T (2021) Organoid-based models to study the role of host-micrbiota Interactions in IBD. J Crohns Colitis 15, 1222-1235  https://doi.org/10.1093/ecco-jcc/jjaa257
  14. Ginga NJ, Slyman R, Kim GA et al (2022) Perfusion system for modification of luminal contents of human intestinal organoids and realtime imaging analysis of microbial populations. Micromachines (Basel) 13, 131 
  15. Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A et al (2021) Intestinal organoid cocultures with microbes. Nat Protoc 16, 4633-4649  https://doi.org/10.1038/s41596-021-00589-z
  16. Williamson IA, Arnold JW, Samsa LA et al (2018) A high-throughput organoid microinjection platform to study gastrointestinal microbiota and luminal physiology. Cell Mol Gastroenterol Hepatol 6, 301-319  https://doi.org/10.1016/j.jcmgh.2018.05.004
  17. Chen Y, Cao K, Liu H et al (2021) Heat killed Salmonella typhimurium protects intestine against radiation injury through wnt signaling pathway. J Oncol 2021, 5550956 
  18. Fischer S, Uckert AK, Landenberger M et al (2020) Human peptide alpha-defensin-1 interferes with Clostridioides difficile toxins TcdA, TcdB, and CDT. FASEB J 34, 6244-6261  https://doi.org/10.1096/fj.201902816R
  19. Liu R, Moriggl R, Zhang D et al (2019) Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis. Life Sci Alliance 2, e201900296 
  20. Huang J, Zhou C, Zhou G, Li H and Ye K (2021) Effect of Listeria monocytogenes on intestinal stem cells in the coculture model of small intestinal organoids. Microb Pathog 153, 104776 
  21. Iftekhar A, Berger H, Bouznad N et al (2021) Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells. Nat Commun 12, 1003 
  22. Sato T, Stange DE, Ferrante M et al (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141, 1762-1772  https://doi.org/10.1053/j.gastro.2011.07.050
  23. Thorne CA, Chen IW, Sanman LE, Cobb MH, Wu LF and Altschuler SJ (2018) Enteroid monolayers reveal an autonomous WNT and BMP circuit controlling intestinal epithelial growth and organization. Dev Cell 44, 624-633 e624 
  24. Nickerson KP, Llanos-Chea A, Ingano L et al (2021) A versatile human intestinal organoid-derived epithelial monolayer model for the study of enteric pathogens. Microbiol Spectr 9, e0000321 
  25. Zhang J, Hernandez-Gordillo V, Trapecar M et al (2021) Coculture of primary human colon monolayer with human gut bacteria. Nat Protoc 16, 3874-3900  https://doi.org/10.1038/s41596-021-00562-w
  26. Nossol C, Diesing AK, Walk N et al (2011) Air-liquid interface cultures enhance the oxygen supply and trigger the structural and functional differentiation of intestinal porcine epithelial cells (IPEC). Histochem Cell Biol 136, 103-115  https://doi.org/10.1007/s00418-011-0826-y
  27. Sachs N, Papaspyropoulos A, Zomer-van Ommen DD et al (2019) Long-term expanding human airway organoids for disease modeling. EMBO J 38, e100300 
  28. Kim R, Attayek PJ, Wang Y et al (2019) An in vitro intestinal platform with a self-sustaining oxygen gradient to study the human gut/microbiome interface. Biofabrication 12, 015006 
  29. Sasaki N, Miyamoto K, Maslowski KM, Ohno H, Kanai T and Sato T (2020) Development of a scalable coculture system for gut anaerobes and human colon epithelium. Gastroenterology 159, 388-390 https://doi.org/10.1053/j.gastro.2020.03.021
  30. Co JY, Margalef-Catala M, Li X et al (2019) Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep 26, 2509-2520 https://doi.org/10.1016/j.celrep.2019.01.108
  31. Troeger C, Blacker BF, Khalil IA et al (2018) Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 18, 1211-1228  https://doi.org/10.1016/S1473-3099(18)30362-1
  32. Hazen TH, Michalski J, Nagaraj S, Okeke IN and Rasko DA (2017) Characterization of a large antibiotic resistance plasmid found in enteropathogenic escherichia coli strain B171 and its relatedness to plasmids of diverse E. coli and shigella strains. Antimicrob Agents Chemother 61, e00995-17 
  33. Livio S, Strockbine NA, Panchalingam S et al (2014) Shigella isolates from the global enteric multicenter study inform vaccine development. Clin Infect Dis 59, 933-941  https://doi.org/10.1093/cid/ciu468
  34. Llanos-Chea A, Citorik RJ, Nickerson KP et al (2019) Bacteriophage therapy testing against shigella flexneri in a novel human intestinal organoid-derived infection model. J Pediatr Gastroenterol Nutr 68, 509-516  https://doi.org/10.1097/MPG.0000000000002203
  35. Ranganathan S, Doucet M, Grassel CL, Delaine-Elias B, Zachos NC and Barry EM (2019) Evaluating shigella flexneri pathogenesis in the human enteroid model. Infect Immun 87, e00740-18 
  36. Koestler BJ, Ward CM, Fisher CR, Rajan A, Maresso AW and Payne SM (2019) Human intestinal enteroids as a model system of shigella pathogenesis. Infect Immun 87, e00733-18 
  37. Jajere SM (2019) A review of Salmonella enterica with particular focus on the pathogenicity and virulence factors, host specificity and antimicrobial resistance including multidrug resistance. Vet World 12, 504-521  https://doi.org/10.14202/vetworld.2019.504-521
  38. Zhang YG, Wu S, Xia Y and Sun J (2014) Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol Rep 2, e12147 
  39. Geiser P, Di Martino ML, Samperio Ventayol P et al (2021) Salmonella enterica serovar typhimurium exploits cycling through epithelial cells to colonize human and murine enteroids. mBio 12, e02684-20 
  40. Forbester JL, Goulding D, Vallier L et al (2015) Interaction of Salmonella enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun 83, 2926-2934  https://doi.org/10.1128/IAI.00161-15
  41. Lawrence AE, Abuaita BH, Berger RP et al (2021) Salmonella enterica serovar typhimurium SPI-1 and SPI-2 shape the global transcriptional landscape in a human intestinal organoid model system. mBio 12, e00399-21 
  42. Verma S, Prescott RA, Ingano L et al (2020) The YrbE phospholipid transporter of Salmonella enterica serovar Typhi regulates the expression of flagellin and influences motility, adhesion and induction of epithelial inflammatory responses. Gut Microbes 11, 526-538  https://doi.org/10.1080/19490976.2019.1697593
  43. Blount ZD (2015) The unexhausted potential of E. coli. Elife 4, e05826 
  44. Kaper JB, Nataro JP and Mobley HL (2004) Pathogenic Escherichia coli. Nat Rev Microbiol 2, 123-140  https://doi.org/10.1038/nrmicro818
  45. Takeda Y (1997) Enterohaemorrhagic Escherichia coli. World Health Stat Q 50, 74-80 
  46. In J, Foulke-Abel J, Zachos NC et al (2016) Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cell Mol Gastroenterol Hepatol 2, 48-62 e43 
  47. Tse CM, In JG, Yin J et al (2018) Enterohemorrhagic E. coli (EHEC)-secreted serine protease EspP stimulates electrogenic ion transport in human colonoid monolayers. Toxins (Basel) 10, 351 
  48. Kotloff KL, Nataro JP, Blackwelder WC et al (2013) Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multi-center Study, GEMS): a prospective, case-control study. Lancet 382, 209-222  https://doi.org/10.1016/S0140-6736(13)60844-2
  49. Evans DJ Jr and Evans DG (1973) Three characteristics associated with enterotoxigenic Escherichia coli isolated from man. Infect Immun 8, 322-328  https://doi.org/10.1128/iai.8.3.322-328.1973
  50. Foulke-Abel J, Yu H, Sunuwar L et al (2020) Phosphodiesterase 5 (PDE5) restricts intracellular cGMP accumulation during enterotoxigenic Escherichia coli infection. Gut Microbes 12, 1752125 
  51. Vermeire B, Gonzalez LM, Jansens RJJ, Cox E and Devriendt B (2021) Porcine small intestinal organoids as a model to explore ETEC-host interactions in the gut. Vet Res 52, 94 
  52. Dejea CM, Fathi P, Craig JM et al (2018) Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592-597  https://doi.org/10.1126/science.aah3648
  53. Escobar-Paramo P, Le Menac'h A, Le Gall T et al (2006) Identification of forces shaping the commensal Escherichia coli genetic structure by comparing animal and human isolates. Environ Microbiol 8, 1975-1984  https://doi.org/10.1111/j.1462-2920.2006.01077.x
  54. Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A et al (2020) Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli. Nature 580, 269-273  https://doi.org/10.1038/s41586-020-2080-8
  55. Chandrasekaran R and Lacy DB (2017) The role of toxins in Clostridium difficile infection. FEMS Microbiol Rev 41, 723-750  https://doi.org/10.1093/femsre/fux048
  56. Engevik MA, Engevik KA, Yacyshyn MB et al (2015) Human Clostridium difficile infection: inhibition of NHE3 and microbiota profile. Am J Physiol Gastrointest Liver Physiol 308, G497-G509  https://doi.org/10.1152/ajpgi.00090.2014
  57. Mileto SJ, Jarde T, Childress KO et al (2020) Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease. Proc Natl Acad Sci U S A 117, 8064-8073  https://doi.org/10.1073/pnas.1915255117
  58. Engevik MA, Danhof HA, Chang-Graham AL et al (2020) Human intestinal enteroids as a model of Clostridioides difficile-induced enteritis. Am J Physiol Gastrointest Liver Physiol 318, G870-G888  https://doi.org/10.1152/ajpgi.00045.2020
  59. di Masi A, Leboffe L, Polticelli F et al (2018) Human serum albumin is an essential component of the host defense mechanism against clostridium difficile intoxication. J Infect Dis 218, 1424-1435  https://doi.org/10.1093/infdis/jiy338
  60. Zhu Z, Schnell L, Muller B, Muller M, Papatheodorou P and Barth H (2019) The antibiotic bacitracin protects human intestinal epithelial cells and stem cell-derived intestinal organoids from clostridium difficile toxin TcdB. Stem Cells Int 2019, 4149762 
  61. Sigman M and Luchette FA (2012) Cholera: something old, something new. Surg Infect (Larchmt) 13, 216-222  https://doi.org/10.1089/sur.2012.127
  62. Foulke-Abel J, In J, Yin J et al (2016) Human enteroids as a model of upper small intestinal ion transport physiology and pathophysiology. Gastroenterology 150, 638-649 e638 
  63. Zomer-van Ommen DD, Pukin AV, Fu O et al (2016) Functional characterization of cholera toxin inhibitors using human intestinal organoids. J Med Chem 59, 6968-6972  https://doi.org/10.1021/acs.jmedchem.6b00770
  64. Kuhlmann FM, Santhanam S, Kumar P, Luo Q, Ciorba MA and Fleckenstein JM (2016) Blood group O-dependent cellular responses to cholera toxin: parallel clinical and epidemiological links to severe cholera. Am J Trop Med Hyg 95, 440-443  https://doi.org/10.4269/ajtmh.16-0161
  65. Radoshevich L and Cossart P (2018) Listeria monocytogenes: towards a complete picture of its physiology and pathogenesis. Nat Rev Microbiol 16, 32-46  https://doi.org/10.1038/nrmicro.2017.126
  66. Zhou C, Zhang Y, Bassey A, Huang J, Zou Y and Ye K (2022) Expansion of intestinal secretory cell population induced by listeria monocytogenes infection: accompanied with the inhibition of NOTCH pathway. Front Cell Infect Microbiol 12, 793335 
  67. Zhou C, Zou Y, Zhang Y, Teng S and Ye K (2022) Involvement of CCN1 protein and TLR2/4 signaling pathways in intestinal epithelial cells response to listeria monocytogenes. Int J Mol Sci 23, 2739 
  68. Kim M, Fevre C, Lavina M, Disson O and Lecuit M (2021) Live imaging reveals listeria hijacking of E-cadherin recycling as it crosses the intestinal barrier. Curr Biol 31, 1037-1047 e4 
  69. Zhou C, Zou Y, Huang J et al (2022) TMT-based quantitative proteomic analysis of intestinal organoids infected by listeria monocytogenes strains with different virulence. Int J Mol Sci 23, 6231 
  70. Wu N, Yang X, Zhang R et al (2013) Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol 66, 462-470  https://doi.org/10.1007/s00248-013-0245-9
  71. Phongsisay V (2016) The immunobiology of Campylobacter jejuni: innate immunity and autoimmune diseases. Immunobiology 221, 535-543  https://doi.org/10.1016/j.imbio.2015.12.005
  72. He Z, Gharaibeh RZ, Newsome RC et al (2019) Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 68, 289-300  https://doi.org/10.1136/gutjnl-2018-317200
  73. Shang FM and Liu HL (2018) Fusobacterium nucleatum and colorectal cancer: a review. World J Gastrointest Oncol 10, 71-81  https://doi.org/10.4251/wjgo.v10.i3.71
  74. Engevik MA, Danhof HA, Ruan W et al (2021) Fusobacterium nucleatum secretes outer membrane vesicles and promotes intestinal inflammation. mBio 12, e02706-20  https://doi.org/10.1128/mBio.02706-20
  75. Seo Y, Oh SJ, Ahn JS, Shin YY, Yang JW and Kim HS (2019) Implication of Porphyromonas gingivalis in colitis and homeostasis of intestinal epithelium. Lab Anim Res 35, 26 
  76. Khan R, Petersen FC and Shekhar S (2019) Commensal bacteria: an emerging player in defense against respiratory pathogens. Front Immunol 10, 1203 
  77. Lordan C, Thapa D, Ross RP and Cotter PD (2020) Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components. Gut Microbes 11, 1-20  https://doi.org/10.1080/19490976.2019.1613124
  78. Park NY and Koh A (2022) From the dish to the real world: modeling interactions between the gut and microorganisms in gut organoids by tailoring the gut milieu. Int J Stem Cells 15, 70-84  https://doi.org/10.15283/ijsc21243
  79. Wu H, Xie S, Miao J et al (2020) Lactobacillus reuteri maintains intestinal epithelial regeneration and repairs damaged intestinal mucosa. Gut Microbes 11, 997-1014  https://doi.org/10.1080/19490976.2020.1734423
  80. Hou QH, Ye LL, Liu HF et al (2018) Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 25, 1657-1670  https://doi.org/10.1038/s41418-018-0070-2
  81. Engevik MA, Ruan W, Esparza M et al (2021) Immunomodulation of dendritic cells by Lactobacillus reuteri surface components and metabolites. Physiol Rep 9, e14719 
  82. Aoki-Yoshida A, Saito S, Fukiya S et al (2016) Lactobacillus rhamnosus GG increases Toll-like receptor 3 gene expression in murine small intestine ex vivo and in vivo. Benef Microbes 7, 421-429  https://doi.org/10.3920/BM2015.0169
  83. Han X, Lee A, Huang S, Gao J, Spence JR and Owyang C (2019) Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes 10, 59-76  https://doi.org/10.1080/19490976.2018.1479625
  84. Lu X, Xie S, Ye L, Zhu L and Yu Q (2020) Lactobacillus protects against S. typhimurium-induced intestinal inflammation by determining the fate of epithelial proliferation and differentiation. Mol Nutr Food Res 64, e1900655 
  85. Sittipo P, Pham HQ, Park CE et al (2020) Irradiation-induced intestinal damage is recovered by the indigenous gut bacteria lactobacillus acidophilus. Front Cell Infect Microbiol 10, 415 
  86. Pino A, Benkaddour B, Inturri R et al (2022) Characterization of Bifidobacterium asteroides Isolates. Microorganisms 10, 655 
  87. Pradhan S and Weiss AA (2020) Probiotic properties of escherichia coli nissle in human intestinal organoids. mBio 11, e01470-20 
  88. Hill DR, Huang S, Nagy MS et al (2017) Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium. Elife 6, e29132 
  89. Kim J, Koo BK and Knoblich JA (2020) Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 21, 571-584  https://doi.org/10.1038/s41580-020-0259-3
  90. Lee JY, Tsolis RM and Baumler AJ (2022) The microbiome and gut homeostasis. Science 377, eabp9960