Gastrointestinal Organoids: Understanding the Molecular Basis of the Host–Microbe Interface

Cellular and Molecular Gastroenterology and Hepatology

Volumn 3, Issue 2, 2017, Pages 138-149

  Hill, David R ^a   Spence, Jason R ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

Enteroids; Epithelium; Intestine; Model Systems; Pathogenesis; Symbiosis

Indexed keywords

CYTOPLASM; GASTROINTESTINAL TRACT; HELICOBACTER PYLORI; HOST PATHOGEN INTERACTION; HUMAN; MICROBIAL METABOLISM; NEWBORN DISEASE; NONHUMAN; NOROVIRUS; PEPTOCLOSTRIDIUM DIFFICILE; PRIORITY JOURNAL; REVIEW; ROTAVIRUS; SALMONELLA ENTERICA SEROVAR TYPHIMURIUM; SYMBIOSIS;

EID: 85014080556     PISSN: None     EISSN: 2352345X     Source Type: Journal    
DOI: 10.1016/j.jcmgh.2016.11.007     Document Type: Review

References (131)

1. 1 Sato, T., Vries, R.G., Snippert, H.J., et al. Single lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459 (2009), 262–265.
2. 2 Ootani, A., Li, X., Sangiorgi, E., et al. Sustained in vitro intestinal epithelial culture within a wnt-dependent stem cell niche. Nat Med 15 (2009), 701–706.
3. 3 Dedhia, P.H., Bertaux-Skeirik, N., Zavros, Y., et al. Organoid models of human gastrointestinal development and disease. Gastroenterology 150 (2016), 1098–1112.
4. 4 Huch, M., Dorrell, C., Boj, S.F., et al. In vitro expansion of single lgr5+ liver stem cells induced by wnt-driven regeneration. Nature 494 (2013), 247–250.
5. 5 Huch, M., Bonfanti, P., Boj, S.F., et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the lgr5/R-spondin axis. EMBO J 32 (2013), 2708–2721.
6. 6 Huch, M., Gehart, H., van Boxtel, R., et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160 (2015), 299–312.
7. 7 Reichert, M., Takano, S., Heeg, S., et al. Isolation, culture and genetic manipulation of mouse pancreatic ductal cells. Nat Protoc 8 (2013), 1354–1365.
8. 8 Reichert, M., Rhim, A.D., Rustgi, A.K., Culturing primary mouse pancreatic ductal cells. Cold Spring Harb Protoc 2015 (2015), 558–561.
9. 9 Gifford, G.B., Demitrack, E.S., Keeley, T.M., et al. Notch1 and notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut, 2016 Epub ahead of print December 9, 2016. doi: http://dx.doi.org/10.1136/gutjnl-2015-310811.
10. 10 Bartfeld, S., Bayram, T., van de Wetering, M., et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148 (2015), 126–136.e6.
11. 11 Boj, S.F., Hwang, C.I., Baker, L.A., et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160 (2015), 324–338.
12. 12 Sato, T., Stange, D.E., Ferrante, M., et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141 (2011), 1762–1772.
13. 13 Mou, H., Vinarsky, V., Tata, P.R., et al. Dual sMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells. Cell Stem Cell 19 (2016), 217–231.
14. 14 Spence, J.R., Mayhew, C.N., Rankin, S.A., et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470 (2011), 105–109.
15. 15 McCracken, K.W., Catá, E.M., Crawford, C.M., et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516 (2014), 400–404.
16. 16 McCracken, K.W., Howell, J.C., Wells, J.M., et al. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc 6 (2011), 1920–1928.
17. 17 Takebe, T., Sekine, K., Enomura, M., et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499 (2013), 481–484.
18. 18 Hannan, N.R., Fordham, R.P., Syed, Y.A., et al. Generation of multipotent foregut stem cells from human pluripotent stem cells. Stem Cell Reports 1 (2013), 293–306.
19. 19 Hohwieler, M., Illing, A., Hermann, P.C., et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut, 2016 Epub ahead of print September 15, 2016. doi: http://dx.doi.org/10.1136/gutjnl-2016-312423.
20. 20 Schweiger, P.J., Jensen, K.B., Modeling human disease using organotypic cultures. Curr Opin Cell Biol 43 (2016), 22–29.
21. 21 Kretzschmar, K., Clevers, H., Organoids: modeling development and the stem cell niche in a dish. Dev Cell 38 (2016), 590–600.
22. 22 Peterson, L.W., Artis, D., Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14 (2014), 141–153.
23. 23 Mazmanian, S.K., Round, J.L., Kasper, D.L., A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453 (2008), 620–625.
24. 24 Chu, H., Khosravi, A., Kusumawardhani, I.P., et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352 (2016), 1116–1120.
25. 25 Arthur, J.C., Perez-Chanona, E., Mühlbauer, M., et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338 (2012), 120–123.
26. 26 Cox, L.M., Blaser, M.J., Pathways in microbe-induced obesity. Cell Metab 17 (2013), 883–894.
27. 27 Tang, W.H., Wang, Z., Levison, B.S., et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368 (2013), 1575–1584.
28. 28 Koeth, R.A., Wang, Z., Levison, B.S., et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19 (2013), 576–585.
29. 29 Pinkus, H., Organoid nevus. Mod Probl Paediatr 20 (1976), 50–57.
30. 30 Randall, K.J., Turton, J., Foster, J.R., Explant culture of gastrointestinal tissue: a review of methods and applications. Cell Biol Toxicol 27 (2011), 267–284.
31. 31 Wang, X., Yamamoto, Y., Wilson, L.H., et al. Cloning and variation of ground state intestinal stem cells. Nature 522 (2015), 173–178.
32. 32 Li, X., Nadauld, L., Ootani, A., et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med 20 (2014), 769–777.
33. 33 Matano, M., Date, S., Shimokawa, M., et al. Modeling colorectal cancer using cRISPR-cas9-mediated engineering of human intestinal organoids. Nat Med 21 (2015), 256–262.
34. 34 Fujii, M., Shimokawa, M., Date, S., et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18 (2016), 827–838.
35. 35 Drost, J., van Jaarsveld, R.H., Ponsioen, B., et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521 (2015), 43–47.
36. 36 van de Wetering, M., Francies, H.E., Francis, J.M., et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161 (2015), 933–945.
37. 37 Aurora, M., Spence, J.R., HPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 420 (2016), 230–238.
38. 38 Finkbeiner, S.R., Hill, D.R., Altheim, C.H., et al. Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo. Stem Cell Reports, 2015 Epub ahead of print June 3, 2015. doi: http://dx.doi.org/10.1016/j.stemcr.2015.04.010.
39. 39 Dye, B.R., Hill, D.R., Ferguson, M.A., et al. In vitro generation of human pluripotent stem cell derived lung organoids. Elife, 4, 2015.
40. 40 Finkbeiner, S.R., Freeman, J.J., Wieck, M.M., et al. Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol Open 4 (2015), 1462–1472.
41. 41 Watson, C.L., Mahe, M.M., Múnera, J., et al. An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20 (2014), 1310–1314.
42. 42 Balimane, P.V., Chong, S., Cell culture-based models for intestinal permeability: a critique. Drug Discov Today 10 (2005), 335–343.
43. 43 Ahmed, D., Eide, P.W., Eilertsen, I.A., et al. Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis, 2, 2013, e71.
44. 44 Ilyas, M., Tomlinson, I.P., Rowan, A., et al. Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci U S A 94 (1997), 10330–10334.
45. 45 Seok, J., Warren, H.S., Cuenca, A.G., et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110 (2013), 3507–3512.
46. 46 Takao, K., Miyakawa, T., Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 112 (2015), 1167–1172.
47. 47 Ettayebi, K., Crawford, S.E., Murakami, K., et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353 (2016), 1387–1393.
48. 48 VanDussen, K.L., Marinshaw, J.M., Shaikh, N., et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64 (2015), 911–920.
49. 49 Moon, C., VanDussen, K.L., Miyoshi, H., et al. Development of a primary mouse intestinal epithelial cell monolayer culture system to evaluate factors that modulate IgA transcytosis. Mucosal Immunol 7 (2014), 818–828.
50. 50 In, J., Foulke-Abel, J., Zachos, N.C., et al. Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cell Mol Gastroenterol Hepatol 2 (2016), 48–62.e3.
51. 51 Leslie, J.L., Huang, S., Opp, J.S., et al. Persistence and toxin production by clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun 83 (2015), 138–145.
52. 52 Engevik, M.A., Yacyshyn, M.B., Engevik, K.A., et al. Human clostridium difficile infection: altered mucus production and composition. Am J Physiol Gastrointest Liver Physiol 308 (2015), G510–G524.
53. 53 Bertaux-Skeirik, N., Feng, R., Schumacher, M.A., et al. CD44 plays a functional role in helicobacter pylori-induced epithelial cell proliferation. PLoS Pathog, 11, 2015, e1004663.
54. 54 Renz, H., Brandtzaeg, P., Hornef, M., The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol 12 (2012), 9–23.
55. 55 Palmer, C., Bik, E.M., DiGiulio, D.B., et al. Development of the human infant intestinal microbiota. PLoS Biol, 5, 2007, e177.
56. 56 Koenig, J.E., Spor, A., Scalfone, N., et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A 108:Suppl 1 (2011), 4578–4585.
57. 57 Newburg, D.S., Morelli, L., Human milk and infant intestinal mucosal glycans guide succession of the neonatal intestinal microbiota. Pediatr Res 77 (2015), 115–120.
58. 58 Pacheco, A.R., Barile, D., Underwood, M.A., et al. The impact of the milk glycobiome on the neonate gut microbiota. Annu Rev Anim Biosci 3 (2015), 419–445.
59. 59 Salzman, N.H., Hung, K., Haribhai, D., et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11 (2010), 76–83.
60. 60 Schluter, J., Foster, K.R., The evolution of mutualism in gut microbiota via host epithelial selection. PLoS Biol, 10, 2012, e1001424.
61. 61 Marcobal, A., Southwick, A.M., Earle, K.A., et al. A refined palate: bacterial consumption of host glycans in the gut. Glycobiology 23 (2013), 1038–1046.
62. 62 Cho, I., Yamanishi, S., Cox, L., et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488 (2012), 621–626.
63. 63 Erkosar, B., Storelli, G., Mitchell, M., et al. Pathogen virulence impedes mutualist-mediated enhancement of host juvenile growth via inhibition of protein digestion. Cell Host Microbe 18 (2015), 445–455.
64. 64 Diaz Heijtz, R., Wang, S., Anuar, F., et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108 (2011), 3047–3052.
65. 65 Desbonnet, L., Clarke, G., Shanahan, F., et al. Microbiota is essential for social development in the mouse. Mol Psychiatry 19 (2014), 146–148.
66. 66 Shaw, S.Y., Blanchard, J.F., Bernstein, C.N., Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol 105 (2010), 2687–2692.
67. 67 Hviid, A., Svanström, H., Frisch, M., Antibiotic use and inflammatory bowel diseases in childhood. Gut 60 (2011), 49–54.
68. 68 Abrahamsson, T.R., Jakobsson, H.E., Andersson, A.F., et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy 44 (2014), 842–850.
69. 69 Arrieta, M.C., Stiemsma, L.T., Dimitriu, P.A., et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med, 7, 2015, 307ra152.
70. 70 Holman, R.C., Stoll, B.J., Curns, A.T., et al. Necrotising enterocolitis hospitalisations among neonates in the united states. Paediatr Perinat Epidemiol 20 (2006), 498–506.
71. 71 Lin, P.W., Stoll, B.J., Necrotising enterocolitis. Lancet 368 (2006), 1271–1283.
72. 72 Sankaran, K., Puckett, B., Lee, D.S., et al., Canadian Neonatal Network. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J Pediatr Gastroenterol Nutr 39 (2004), 366–372.
73. 73 Neu, J., Walker, W.A., Necrotizing enterocolitis. N Engl J Med 364 (2011), 255–264.
74. 74 Morrow, A.L., Lagomarcino, A.J., Schibler, K.R., et al. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome, 1, 2013, 13.
75. 75 Torrazza, R.M., Ukhanova, M., Wang, X., et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One, 8, 2013, e83304.
76. 76 Neu, J., Probiotics and necrotizing enterocolitis. Clin Perinatol 41 (2014), 967–978.
77. 77 Boccia, D., Stolfi, I., Lana, S., et al. Nosocomial necrotising enterocolitis outbreaks: epidemiology and control measures. Eur J Pediatr 160 (2001), 385–391.
78. 78 Schullinger, J.N., Mollitt, D.L., Vinocur, C.D., et al. Neonatal necrotizing enterocolitis. survival, management, and complications: a 25-year study. Am J Dis Child 135 (1981), 612–614.
79. 79 Tanner, S.M., Berryhill, T.F., Ellenburg, J.L., et al. Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. Am J Pathol 185 (2015), 4–16.
80. 80 Wroblewski, L.E., Piazuelo, M.B., Chaturvedi, R., et al. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64 (2015), 720–730.
81. 81 Forbester, J.L., Goulding, D., Vallier, L., et al. Interaction of salmonella enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun 83 (2015), 2926–2934.
82. 82 Yin, Y., Bijvelds, M., Dang, W., et al. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antiviral Res 123 (2015), 120–131.
83. 83 Leslie, J.L., Young, V.B., A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions. Anaerobe 37 (2016), 25–28.
84. 84 Chaaban, H., Stonestreet, B.S., Intestinal hemodynamics and oxygenation in the perinatal period. Semin Perinatol 36 (2012), 260–268.
85. 85 Jenny, M., Uhl, C., Roche, C., et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21 (2002), 6338–6347.
86. 86 López-Díaz, L., Jain, R.N., Keeley, T.M., et al. Intestinal neurogenin 3 directs differentiation of a bipotential secretory progenitor to endocrine cell rather than goblet cell fate. Dev Biol 309 (2007), 298–305.
87. 87 Wang, J., Cortina, G., Wu, S.V., et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med 355 (2006), 270–280.
88. 88 Ward, D.V., Scholz, M., Zolfo, M., et al. Metagenomic sequencing with strain-level resolution implicates uropathogenic E. coli in necrotizing enterocolitis and mortality in preterm infants. Cell Rep 14 (2016), 2912–2924.
89. 89 Bäckhed, F., Roswall, J., Peng, Y., et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe, 17, 2015, 852.
90. 90 Yassour, M., Vatanen, T., Siljander, H., et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med, 8, 2016, 343ra81.
91. 91 Oude Munnink, B.B., van der Hoek, L., Viruses causing gastroenteritis: the known, the new and those beyond. Viruses, 8, 2016, 2.
92. 92 Kosek, M., Bern, C., Guerrant, R.L., The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 81 (2003), 197–204.
93. 93 Estes, M.K., Kang, G., Zeng, C.Q., et al. Pathogenesis of rotavirus gastroenteritis. Novartis Found Symp 238 (2001), 82–100.
94. 94 Finkbeiner, S.R., Zeng, X.L., Utama, B., et al. Stem cell-derived human intestinal organoids as an infection model for rotaviruses. MBio, 3, 2012 e00159–12.
95. 95 Saxena, K., Blutt, S.E., Ettayebi, K., et al. Human intestinal enteroids: a new model to study human rotavirus infection, host restriction, and pathophysiology. J Virol 90 (2016), 43–56.
96. 96 Duizer, E., Schwab, K.J., Neill, F.H., et al. Laboratory efforts to cultivate noroviruses. J Gen Virol 85 (2004), 79–87.
97. 97 Herbst-Kralovetz, M.M., Radtke, A.L., Lay, M.K., et al. Lack of norovirus replication and histo-blood group antigen expression in 3-dimensional intestinal epithelial cells. Emerg Infect Dis 19 (2013), 431–438.
98. 98 Ha, S., Choi, I.S., Choi, C., et al. Infection models of human norovirus: challenges and recent progress. Arch Virol 161 (2016), 779–788.
99. 99 Jones, M.K., Watanabe, M., Zhu, S., et al. Enteric bacteria promote human and mouse norovirus infection of b cells. Science 346 (2014), 755–759.
100. 100 Deng, X., Desai, P.T., den Bakker, H.C., et al. Genomic epidemiology of salmonella enterica serotype enteritidis based on population structure of prevalent lineages. Emerg Infect Dis 20 (2014), 1481–1489.
101. 101 Zhang, Y.G., Wu, S., Xia, Y., et al. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol Rep, 2, 2014, 9.
102. 102 Wilson, S.S., Tocchi, A., Holly, M.K., et al. A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol 8 (2015), 352–361.
103. 103 Rupnik, M., Wilcox, M.H., Gerding, D.N., Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7 (2009), 526–536.
104. 104 Lessa, F.C., Gould, C.V., McDonald, L.C., Current status of clostridium difficile infection epidemiology. Clin Infect Dis 55:Suppl 2 (2012), S65–S70.
105. 105 McFarland, L.V., Surawicz, C.M., Rubin, M., et al. Recurrent clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 20 (1999), 43–50.
106. 106 Seekatz, A.M., Rao, A.M., Santhosh, K., et al. Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent clostridium difficile infection. Genome Med, 8, 2016, 47.
107. 107 Hall, A.J., Curns, A.T., McDonald, L.C., et al. The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999-2007. Clin Infect Dis 55 (2012), 216–223.
108. 108 Theriot, C.M., Koumpouras, C.C., Carlson, P.E., et al. Cefoperazone-treated mice as an experimental platform to assess differential virulence of clostridium difficile strains. Gut Microbes 2 (2011), 326–334.
109. 109 Reeves, A.E., Theriot, C.M., Bergin, I.L., et al. The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile infection. Gut Microbes 2 (2011), 145–158.
110. 110 Engevik, M.A., Engevik, K.A., Yacyshyn, M.B., et al. Human clostridium difficile infection: inhibition of nHE3 and microbiota profile. Am J Physiol Gastrointest Liver Physiol 308 (2015), G497–G509.
111. 111 Theriot, C.M., Koenigsknecht, M.J., Carlson, P.E. Jr., et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun, 5, 2014, 3114.
112. 112 Stokely, J.N., Niendorf, S., Taube, S., et al. Prevalence of human norovirus and Clostridium difficile coinfections in adult hospitalized patients. Clin Epidemiol 8 (2016), 253–260.
113. 113 Nguyen, G.C., Kaplan, G.G., Harris, M.L., et al. A national survey of the prevalence and impact of clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 103 (2008), 1443–1450.
114. 114 Backert, S., Neddermann, M., Maubach, G., et al. Pathogenesis of Helicobacter pylori infection. Helicobacter 21:Suppl 1 (2016), 19–25.
115. 115 Leja, M., Axon, A., Brenner, H., Epidemiology of helicobacter pylori infection. Helicobacter 21:Suppl 1 (2016), 3–7.
116. 116 Barker, N., Huch, M., Kujala, P., et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6 (2010), 25–36.
117. 117 Karam, S.M., Leblond, C.P., Dynamics of epithelial cells in the corpus of the mouse stomach. I. identification of proliferative cell types and pinpointing of the stem cell. Anat Rec 236 (1993), 259–279.
118. 118 Sigal, M., Rothenberg, M.E., Logan, C.Y., et al. Helicobacter pylori activates and expands lgr5(+) stem cells through direct colonization of the gastric glands. Gastroenterology 148 (2015), 1392–1404.e21.
119. 119 Huang, J.Y., Sweeney, E.G., Sigal, M., et al. Chemodetection and destruction of host urea allows helicobacter pylori to locate the epithelium. Cell Host Microbe 18 (2015), 147–156.
120. 120 Abreu, M.T., Fukata, M., Arditi, M., TLR signaling in the gut in health and disease. J Immunol 174 (2005), 4453–4460.
121. 121 Magalhães, A., Rossez, Y., Robbe-Masselot, C., et al. Muc5ac gastric mucin glycosylation is shaped by fUT2 activity and functionally impacts Helicobacter pylori binding. Sci Rep, 6, 2016, 25575.
122. 122 Bessède, E., Dubus, P., Mégraud, F., et al. Helicobacter pylori infection and stem cells at the origin of gastric cancer. Oncogene 34 (2015), 2547–2555.
123. 123 Sharon, G., Garg, N., Debelius, J., et al. Specialized metabolites from the microbiome in health and disease. Cell Metab 20 (2014), 719–730.
124. 124 Wu, G.D., Chen, J., Hoffmann, C., et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334 (2011), 105–108.
125. 125 Ridaura, V.K., Faith, J.J., Rey, F.E., et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341, 2013, 1241214.
126. 126 Sanderson, I.R., Short chain fatty acid regulation of signaling genes expressed by the intestinal epithelium. J Nutr 134 (2004), 2450S–2454S.
127. 127 Derrien, M., Collado, M.C., Ben-Amor, K., et al. The mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol 74 (2008), 1646–1648.
128. 128 Lukovac, S., Belzer, C., Pellis, L., et al. Differential modulation by Akkermansia muciniphila and faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. MBio, 5, 2014.
129. 129 Kaiko, G.E., Ryu, S.H., Koues, O.I., et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165 (2016), 1708–1720.
130. 130 Zachos, N.C., Kovbasnjuk, O., Foulke-Abel, J., et al. Human enteroids/colonoids and intestinal organoids functionally recapitulate normal intestinal physiology and pathophysiology. J Biol Chem 291 (2016), 3759–3766.
131. 131 Hamburg, M.A., Collins, F.S., The path to personalized medicine. N Engl J Med 363 (2010), 301–304.