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Impact of enteric bacterial infections at and beyond the epithelial barrier

Nature Reviews Microbiology volume 21, pages 260–274 (2023)Cite this article

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Abstract

The mucosal lining of the gut has co-evolved with a diverse microbiota over millions of years, leading to the development of specialized mechanisms to actively limit the invasion of pathogens. However, some enteric microorganisms have adapted against these measures, developing ways to hijack or overcome epithelial micro-integrity mechanisms. This breach of the gut barrier not only enables the leakage of host factors out of circulation but can also initiate a cascade of detrimental systemic events as microbiota, pathogens and their affiliated secretions passively leak into extra-intestinal sites. Under normal circumstances, gut damage is rapidly repaired by intestinal stem cells. However, with substantial and deep perturbation to the gut lining and the systemic dissemination of gut contents, we now know that some enteric infections can cause the impairment of host regenerative processes. Although these local and systemic aspects of enteric disease are often studied in isolation, they heavily impact one another. In this Review, by examining the journey of enteric infections from initial establishment to systemic sequelae and how, or if, the host can successfully repair damage, we will tie together these complex interactions to provide a holistic overview of the impact of enteric infections at and beyond the epithelial barrier.

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Fig. 1: Commensal maintenance and pathogenic depletion of the mucous gel bilayer.
Fig. 2: Cell contact and polarity cleavage or displacement by enteric pathogens.
Fig. 3: Gut permeability induced by enteric pathogens.
Fig. 4: Effects of bacteria on intestinal stem cells.
Fig. 5: A holistic understanding of enteric infections and host effects.

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References

  1. Karmakar, S., Deng, L., He, X. C. & Li, L. Intestinal epithelial regeneration: active versus reserve stem cells and plasticity mechanisms. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G796–G802 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19–33 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Peck, B. C. E., Shanahan, M. T., Singh, A. P. & Sethupathy, P. Gut microbial influences on the mammalian intestinal stem cell niche. Stem Cell Int. 2017, 5604727 (2017).

    Google Scholar 

  4. Leslie, J. L. et al. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect. Immun. 83, 138–145 (2015).

    Article  PubMed  Google Scholar 

  5. Bonfini, A., Liu, X. & Buchon, N. From pathogens to microbiota: how Drosophila intestinal stem cells react to gut microbes. Dev. Comp. Immunol. 64, 22–38 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Hoffmann, W. Regeneration of the gastric mucosa and its glands from stem cells. Curr. Med. Chem. 15, 3133–3144 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Pitsouli, C., Apidianakis, Y. & Perrimon, N. Homeostasis in infected epithelia: stem cells take the lead. Cell Host Microbe 6, 301–307 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Backert, S., Boehm, M., Wessler, S. & Tegtmeyer, N. Transmigration route of Campylobacter jejuni across polarized intestinal epithelial cells: paracellular, transcellular or both? Cell Commun. Signal. 11, 72 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCormick, B. A., Stocker, B. A., Laux, D. C. & Cohen, P. S. Roles of motility, chemotaxis, and penetration through and growth in intestinal mucus in the ability of an avirulent strain of Salmonella Typhimurium to colonize the large intestine of streptomycin-treated mice. Infect. Immun. 56, 2209–2217 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boyle, E. C., Brown, N. F. & Finlay, B. B. Salmonella enterica serovar Typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function. Cell Microbiol. 8, 1946–1957 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Prizont, R. & Reed, W. P. Differences in blood group B-specific mucinase activity between virulent and avirulent Shigella flexneri 2a strains. Microb. Pathog. 11, 129–135 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Silva, A. J., Pham, K. & Benitez, J. A. Haemagglutinin/protease expression and mucin gel penetration in El Tor biotype Vibrio cholerae. Microbiology 149, 1883–1891 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Hoy, B. et al. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 11, 798–804 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mileto, S. J. et al. Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease. Proc. Natl Acad. Sci. USA 117, 8064–8073 (2020). This is an important study demonstrating the direct interaction and impairment of colonic stem cells by a specific enteric pathogen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stanley, R. A., Ram, S. P., Wilkinson, R. K. & Roberton, A. M. Degradation of pig gastric and colonic mucins by bacteria isolated from the pig colon. Appl. Environ. Microbiol. 51, 1104–1119 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lecuit, M. et al. A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier. Science 292, 1722–1725 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Boehm, M. et al. Rapid paracellular transmigration of Campylobacter jejuni across polarized epithelial cells without affecting TER: role of proteolytic-active HtrA cleaving E-cadherin but not fibronectin. Gut Pathog. 4, 3 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wadolkowski, E. A., Laux, D. C. & Cohen, P. S. Colonization of the streptomycin-treated mouse large intestine by a human fecal Escherichia coli strain: role of growth in mucus. Infect. Immun. 56, 1030–1035 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hausmann, A. et al. Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression. Mucosal Immunol. 13, 530–544 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Di Domenico, E. G., Cavallo, I., Pontone, M., Toma, L. & Ensoli, F. Biofilm producing Salmonella Typhi: chronic colonization and development of gallbladder cancer. Int. J. Mol. Sci. 18, 1887 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Johnson, R. et al. Comparison of Salmonella enterica Serovars Typhi and Typhimurium reveals typhoidal serovar-specific responses to bile. Infect. Immun. 86, e00490-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zha, L., Garrett, S. & Sun, J. Salmonella Infection in chronic inflammation and gastrointestinal cancer. Diseases 7, 28 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Carter, G. P. et al. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. mBio 6, e00551 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mimuro, H. et al. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe 2, 250–263 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Costa, A. M., Leite, M., Seruca, R. & Figueiredo, C. Adherens junctions as targets of microorganisms: a focus on Helicobacter pylori. FEBS Lett. 587, 259–265 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jakobsson, H. E. et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE 5, e9836 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tourret, J. et al. Immunosuppressive treatment alters secretion of ileal antimicrobial peptides and gut microbiota, and favors subsequent colonization by uropathogenic Escherichia coli. Transplantation 101, 74–82 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Jones, T. A., Hernandez, D. Z., Wong, Z. C., Wandler, A. M. & Guillemin, K. The bacterial virulence factor CagA induces microbial dysbiosis that contributes to excessive epithelial cell proliferation in the Drosophila gut. PLoS Pathog. 13, e1006631 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ferreyra, J. A. et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe 16, 770–777 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Johansson, M. E. V., Sjövall, H. & Hansson, G. C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361 (2013). A thorough review encompassing the structure and function of mucous within the intestines during health and disease, particularly parasitic and bacterial diseases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wheeler, K. M. et al. Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Nat. Microbiol. 4, 2146–2154 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Furter, M., Sellin, M. E., Hansson, G. C. & Hardt, W. D. Mucus architecture and near-surface swimming affect distinct Salmonella Typhimurium infection patterns along the murine intestinal tract. Cell Rep. 27, 2665–2678.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johansson, M. E. V., Larsson, J. M. H. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions. Proc. Natl Acad. Sci. USA 108, 4659–4665 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Johansson, M. E. V. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).

    Article  PubMed  Google Scholar 

  39. Engevik, M. A. et al. Human Clostridium difficile infection: altered mucus production and composition. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G510–G524 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Johansson, M. E. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS ONE 7, e41009 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Johansson, M. E. V. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feng, Y. et al. Antibiotics induced intestinal tight junction barrier dysfunction is associated with microbiota dysbiosis, activated NLRP3 inflammasome and autophagy. PLoS ONE 14, e0218384 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, S. et al. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development. Gut Microbes 13, 1–20 (2021).

    Article  PubMed  Google Scholar 

  44. Wrzosek, L. et al. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent. BMC Biol. 11, 61 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Valeri, M. et al. Pathogenic E. coli exploits SslE mucinase activity to translocate through the mucosal barrier and get access to host cells. PLoS ONE 10, e0117486 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Luo, Q. et al. Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. Infect. Immun. 82, 509–521 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wilson, K. H. & Perini, F. Role of competition for nutrients in suppression of Clostridium difficile by the colonic microflora. Infect. Immun. 56, 2610–2614 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Farquhar, M. G. & Palade, G. E. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Drolia, R. & Bhunia, A. K. Crossing the intestinal barrier via Listeria adhesion protein and internalin A. Trends Microbiol. 27, 408–425 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Drolia, R., Tenguria, S., Durkes, A. C., Turner, J. R. & Bhunia, A. K. Listeria adhesion protein induces intestinal epithelial barrier dysfunction for bacterial translocation. Cell Host Microbe 23, 470–484.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fattinger, S. A. et al. Salmonella Typhimurium discreet-invasion of the murine gut absorptive epithelium. PLoS Pathog. 16, e1008503 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meza-Segura, M. et al. SepA enhances Shigella invasion of epithelial cells by degrading alpha-1 antitrypsin and producing a neutrophil chemoattractant. mBio 12, e0283321 (2021).

    Article  PubMed  Google Scholar 

  53. Das, S. et al. Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis. Proc. Natl Acad. Sci. USA 119, e2110166119 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Guttman, J. A. & Finlay, B. B. Tight junctions as targets of infectious agents. Biochim. Biophys. Acta 1788, 832–841 (2009). An extensive review highlighting the profound effect pathogen-induced breakdown of tight junctions has on human health and disease.

    Article  CAS  PubMed  Google Scholar 

  55. Grosheva, I. et al. High-throughput screen identifies host and microbiota regulators of intestinal barrier function. Gastroenterology 159, 1807–1823 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Wine, E., Chan, V. L. & Sherman, P. M. Campylobacter jejuni mediated disruption of polarized epithelial monolayers is cell-type specific, time dependent, and correlates with bacterial invasion. Pediatr. Res. 64, 599–604 (2008).

    Article  PubMed  Google Scholar 

  57. Kazmierczak, B. I., Mostov, K. & Engel, J. N. Interaction of bacterial pathogens with polarized epithelium. Annu. Rev. Microbiol. 55, 407–435 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Sears, C. L. Molecular physiology and pathophysiology of tight junctions V. assault of the tight junction by enteric pathogens. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1129–G1134 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Hoy, B. et al. Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin. J. Biol. Chem. 287, 10115–10120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wu, S., Lim, K. C., Huang, J., Saidi, R. F. & Sears, C. L. Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc. Natl Acad. Sci. USA 95, 14979–14984 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Steck, N. et al. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology 141, 959–971 (2011). A study delineating the ability of bacterial enzymes to compromise epithelial barrier integrity contributing to chronic intestinal inflammation.

    Article  CAS  PubMed  Google Scholar 

  62. Inoshima, I. et al. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17, 1310–1314 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Viswanathan, V. K. et al. Comparative analysis of EspF from enteropathogenic and enterohemorrhagic Escherichia coli in alteration of epithelial barrier function. Infect. Immun. 72, 3218–3227 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Matsuzawa, T., Kuwae, A. & Abe, A. Enteropathogenic Escherichia coli type III effectors EspG and EspG2 alter epithelial paracellular permeability. Infect. Immun. 73, 6283–6289 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dean, P. & Kenny, B. Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein. Mol. Microbiol. 54, 665–675 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Runswick, S., Mitchell, T., Davies, P., Robinson, C. & Garrod, D. R. Pollen proteolytic enzymes degrade tight junctions. Respirology 12, 834–842 (2007).

    Article  PubMed  Google Scholar 

  67. Saitoh, Y. et al. Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science 347, 775–778 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Chen, M. L., Ge, Z., Fox, J. G. & Schauer, D. B. Disruption of tight junctions and induction of proinflammatory cytokine responses in colonic epithelial cells by Campylobacter jejuni. Infect. Immun. 74, 6581–6589 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lobo de Sá, F. D. et al. Resveratrol prevents Campylobacter jejuni-induced leaky gut by restoring occludin and claudin-5 in the paracellular leak pathway. Front. Pharmacol. 12, 640572 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Simonovic, I., Arpin, M., Koutsouris, A., Falk-Krzesinski, H. J. & Hecht, G. Enteropathogenic Escherichia coli activates ezrin, which participates in disruption of tight junction barrier function. Infect. Immun. 69, 5679–5688 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, Q. et al. Enteropathogenic Escherichia coli changes distribution of occludin and ZO-1 in tight junction membrane microdomains in vivo. Microb. Pathog. 48, 28–34 (2010).

    Article  PubMed  Google Scholar 

  72. Köhler, H. et al. Salmonella enterica serovar Typhimurium regulates intercellular junction proteins and facilitates transepithelial neutrophil and bacterial passage. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G178–G187 (2007).

    Article  PubMed  Google Scholar 

  73. Sakaguchi, T., Köhler, H., Gu, X., McCormick, B. A. & Reinecker, H. C. Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Cell Microbiol. 4, 367–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Vikström, E., Bui, L., Konradsson, P. & Magnusson, K. E. The junctional integrity of epithelial cells is modulated by Pseudomonas aeruginosa quorum sensing molecule through phosphorylation-dependent mechanisms. Exp. Cell Res. 315, 313–326 (2009).

    Article  PubMed  Google Scholar 

  75. Peralta-Ramírez, J. et al. EspF interacts with nucleation-promoting factors to recruit junctional proteins into pedestals for pedestal maturation and disruption of paracellular permeability. Infect. Immun. 76, 3854–3868 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Shifflett, D. E., Clayburgh, D. R., Koutsouris, A., Turner, J. R. & Hecht, G. A. Enteropathogenic E. coli disrupts tight junction barrier function and structure in vivo. Lab. Invest. 85, 1308–1324 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Fasano, A. et al. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J. Clin. Investig. 96, 710–720 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Maldonado-Contreras, A. et al. Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation. Gut Microbes 8, 544–560 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, F. et al. Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am. J. Pathol. 166, 409–419 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Odenwald, M. A. & Turner, J. R. The intestinal epithelial barrier: a therapeutic target? Nat. Rev. Gastroenterol. Hepatol. 14, 9–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Wotzka, S. Y. et al. Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice. Nat. Microbiol. 4, 2164–2174 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sun, Y. et al. Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages. PLoS Biol. 17, e3000044 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fasciano, A. C. et al. Yersinia pseudotuberculosis YopE prevents uptake by M cells and instigates M cell extrusion in human ileal enteroid-derived monolayers. Gut Microbes 13, 1988390 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Zhang, K. et al. Minimal SPI1-T3SS effector requirement for Salmonella enterocyte invasion and intracellular proliferation in vivo. PLoS Pathog. 14, e1006925 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Crowley, S. M. et al. Intestinal restriction of Salmonella Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes. PLoS Pathog. 16, e1008498 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Fehon, R. G., McClatchey, A. I. & Bretscher, A. Organizing the cell cortex: the role of ERM proteins. Nat. Rev. Mol. Cell Biol. 11, 276–287 (2010). A thorough review of the structure and function of polarity-determining proteins within the body.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tapia, R., Kralicek, S. E. & Hecht, G. A. Enteropathogenic Escherichia coli (EPEC) recruitment of PAR polarity protein atypical PKCζ to pedestals and cell-cell contacts precedes disruption of tight junctions in intestinal epithelial cells. Int. J. Mol. Sci. 21, 527 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Aktories, K., Schwan, C. & Jank, T. Clostridium difficile toxin biology. Annu. Rev. Microbiol. 71, 281–307 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Robert, A. & Wiels, J. Shiga toxins as antitumor tools. Toxins 13, 690 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Navarro, M. A., McClane, B. A. & Uzal, F. A. Mechanisms of action and cell death associated with Clostridium perfringens toxins. Toxins 10, 212 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Chen, P. et al. Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection. Nat. Commun. 12, 3748–3748 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Holly, M. K. et al. Salmonella enterica infection of murine and human enteroid-derived monolayers elicits differential activation of epithelium-intrinsic inflammasomes. Infect. Immun. 88, e00017-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Balk, R. A. Systemic inflammatory response syndrome (SIRS): where did it come from and is it still relevant today? Virulence 5, 20–26 (2014).

    Article  PubMed  Google Scholar 

  95. Ho, J. T. K., Chan, G. C. F. & Li, J. C. B. Systemic effects of gut microbiota and its relationship with disease and modulation. BMC Immunol. 16, 21 (2015). A review discussing the relationship between a balanced or dysbiotic gut microbiota and systemic health or disease.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Tao, L. et al. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538, 350–355 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dobson, G., Hickey, C. & Trinder, J. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Intensive Care Med. 29, 1030 (2003).

    Article  PubMed  Google Scholar 

  98. Steele, J. et al. Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models. J. Infect. Dis. 205, 384–391 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Yu, H. et al. Identification of toxemia in patients with Clostridium difficile infection. PLoS ONE 10, e0124235 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Sae-Khow, K. et al. Pathogen-associated molecules from gut translocation enhance severity of cecal ligation and puncture sepsis in iron-overload β-thalassemia mice. J. Inflamm. Res. 13, 719–735 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Thim-Uam, A. et al. Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus. Sci. Rep. 10, 777 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Li, J., Moturi, K. R., Wang, L., Zhang, K. & Yu, C. Gut derived-endotoxin contributes to inflammation in severe ischemic acute kidney injury. BMC Nephrol. 20, 16 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Karmali, M. A. et al. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J. Infect. Dis. 151, 775–782 (1985).

    Article  CAS  PubMed  Google Scholar 

  104. Banatvala, N. et al. The United States National Prospective Hemolytic Uremic Syndrome Study: microbiologic, serologic, clinical, and epidemiologic findings. J. Infect. Dis. 183, 1063–1070 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Lill, J. K. et al. Tissue-resident macrophages mediate neutrophil recruitment and kidney injury in shiga toxin-induced hemolytic uremic syndrome. Kidney Int. 100, 349–363 (2021).

    Article  CAS  PubMed  Google Scholar 

  106. Karpman, D. et al. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection. J. Infect. Dis. 175, 611–620 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Szeto, C. C., McIntyre, C. W. & Li, P. K. Circulating bacterial fragments as cardiovascular risk factors in CKD. J. Am. Soc. Nephrol. 29, 1601–1608 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Awad, M. M. et al. Human plasminogen exacerbates Clostridioides difficile enteric disease and alters the spore surface. Gastroenterology 159, 1431–1443.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Menzel, K. et al. Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition in vivo. Clin. Exp. Immunol. 146, 169–180 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tarlton, J. F. et al. The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis. Am. J. Pathol. 157, 1927–1935 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Palmieri, V. et al. Interleukin-33 signaling exacerbates experimental infectious colitis by enhancing gut permeability and inhibiting protective Th17 immunity. Mucosal Immunol. 14, 923–936 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cebra, J. J. Influences of microbiota on intestinal immune system development. Am. J. Clin. Nutr. 69, 1046s–1051s (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Vĕtvicka, V., Tlaskalová-Hogenová, H. & Stĕpánková, R. Effects of microflora antigens on lymphocyte migration patterns in germfree and conventional rats. Folia Biol. 29, 412–418 (1983).

    Google Scholar 

  114. Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rea, M. C. et al. Bioavailability of the anti-clostridial bacteriocin thuricin CD in gastrointestinal tract. Microbiology 160, 439–445 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lu, X., Xie, S., Ye, L., Zhu, L. & Yu, Q. Lactobacillus protects against S. Typhimurium-induced intestinal inflammation by determining the fate of epithelial proliferation and differentiation. Mol. Nutr. Food Res. 64, e1900655 (2020). An important study demonstrating the links between microbiota, enteric pathogens, host immune responses, and colonocyte proliferation and differentiation during enteric disease.

    Article  PubMed  Google Scholar 

  118. Velazquez, E. M. et al. Endogenous Enterobacteriaceae underlie variation in susceptibility to Salmonella infection. Nat. Microbiol. 4, 1057–1064 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Drolia, R. et al. Receptor-targeted engineered probiotics mitigate lethal Listeria infection. Nat. Commun. 11, 6344 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Taha-Abdelaziz, K. et al. In vitro assessment of immunomodulatory and anti-Campylobacter activities of probiotic lactobacilli. Sci. Rep. 9, 17903 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Nattramilarasu, P. K., Lobo de Sá, F. D., Schulzke, J. D. & Bücker, R. Immune-mediated aggravation of the Campylobacter concisus-induced epithelial barrier dysfunction. Int. J. Mol. Sci. 22, 2043 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sakaue, M. et al. Type A fulminant Clostridium perfringens sepsis indicated RBC/Hb discrepancy; a case report. BMC Infect. Dis. 19, 719 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Shibata, W. et al. Helicobacter-induced gastric inflammation alters the properties of gastric tissue stem/progenitor cells. BMC Gastroenterol. 17, 145 (2017). This study establishes the link between enteric bacterial pathogens, the inflammation and host immune responses they induce and, in turn, the effects they can elicit on stem or progenitor cells during infection.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Beumer, J. & Clevers, H. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development 143, 3639–3649 (2016). A review encompassing the stem cell populations and regeneration mechanisms within the intestines during health and repair from injury.

    Article  CAS  PubMed  Google Scholar 

  125. van der Wath, R. C., Gardiner, B. S., Burgess, A. W. & Smith, D. W. Cell organisation in the colonic crypt: a theoretical comparison of the pedigree and niche concepts. PLoS ONE 8, e73204 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Hua, T. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  Google Scholar 

  127. Liu, X., Lu, R., Wu, S. & Sun, J. Salmonella regulation of intestinal stem cells through the Wnt/beta-catenin pathway. FEBS Lett. 584, 911–916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huan, Y. W. et al. Lawsonia intracellularis exploits beta-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation. PLoS ONE 12, e0173782 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Flanagan, D. J. et al. Frizzled7 functions as a wnt receptor in intestinal epithelial Lgr5+ stem cells. Stem Cell Rep. 4, 759–767 (2015).

    Article  CAS  Google Scholar 

  130. Holmberg, J. et al. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125, 1151–1163 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Gregorieff, A. et al. Expression pattern of wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Gonzalez, L. M. et al. Preservation of reserve intestinal epithelial stem cells following severe ischemic injury. Am. J. Physiol. Gastrointest. Liver Physiol. 316, G482–G494 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Potten, C. S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Merlos-Suárez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511–524 (2011).

    Article  PubMed  Google Scholar 

  136. Bankaitis, E. D., Ha, A., Kuo, C. J. & Magness, S. T. Reserve stem cells in intestinal homeostasis and injury. Gastroenterology 155, 1348–1361 (2018).

    Article  PubMed  Google Scholar 

  137. Chatzivasileiou, K., Kriebel, K., Steinhoff, G., Kreikemeyer, B. & Lang, H. Do oral bacteria alter the regenerative potential of stem cells? A concise review. J. Cell Mol. Med. 19, 2067–2074 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  138. O’Rourke, F. & Kempf, V. A. J. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol. Rev. 43, 162–180 (2019). A review presenting current knowledge on the diverse interactions between bacteria and stem cells throughout the body in regulating stem cell renewal and homeostasis as well as targets for bacterial pathogenicity strategies.

    Article  PubMed  Google Scholar 

  139. Sellin, J. H., Wang, Y., Singh, P. & Umar, S. beta-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia. Exp. Cell Res. 315, 97–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. van der Post, S., Birchenough, G. M. H. & Held, J. M. NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation. Cell Rep. 35, 108949 (2021).

    Article  PubMed  Google Scholar 

  141. Lee, Y. S. et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe 24, 833–846.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  142. Reedy, A. R., Luo, L., Neish, A. S. & Jones, R. M. Commensal microbiota-induced redox signaling activates proliferative signals in the intestinal stem cell microenvironment. Development 146, dev171520 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Sellin, M. E. et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237–248 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Fast, D., Duggal, A. & Foley, E. Monoassociation with Lactobacillus plantarum disrupts intestinal homeostasis in adult Drosophila melanogaster. mBio 9, e01114-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Kuo, W. T. et al. the tight junction protein ZO-1 is dispensable for barrier function but critical for effective mucosal repair. Gastroenterology 161, 1924–1939 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Samba-Louaka, A., Nougayrède, J. P., Watrin, C., Oswald, E. & Taieb, F. The enteropathogenic Escherichia coli effector Cif induces delayed apoptosis in epithelial cells. Infect. Immun. 77, 5471–5477 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Iwai, H. et al. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell 130, 611–623 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Glotfelty, L. G. et al. Enteropathogenic E. coli effectors EspG1/G2 disrupt microtubules, contribute to tight junction perturbation and inhibit restoration. Cell Microbiol. 16, 1767–1783 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Pearson, J. S. et al. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature 501, 247–251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li, S. et al. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 501, 242–246 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Parigi, S. M. et al. The spatial transcriptomic landscape of the healing mouse intestine following damage. Nat. Commun. 13, 828 (2022). This study utilizes an exciting new technology that combines spatial biology with transcriptomics to assess intestinal repair in an approach dubbed by Nature Methods as ‘method of the year’ for 2020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Leblond, F., Davis, S. C., Valdés, P. A. & Pogue, B. W. Pre-clinical whole-body fluorescence imaging: review of instruments, methods and applications. J. Photochem. Photobiol. B 98, 77–94 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Engel, R. M. et al. Patient-derived colorectal cancer organoids upregulate revival stem cell marker genes following chemotherapeutic treatment. J. Clin. Med. 9, 128 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Nusse, Y. M. et al. Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113 (2018). An important study demonstrating the ability of parasitic helminths, and in turn microorganisms, to affect intestinal stem cell function and microenvironment for their own gain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhang, J., Liang, Y., Bradford, W. H. & Sheikh, F. Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease. Biophys. Rev. 13, 697–706 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tsukita, S., Furuse, M. & Itoh, M. Multifunctional strands in tight junctions. Nat. Rev. Mol. Cell Biol. 2, 285–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Nitta, T. et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell Biol. 161, 653–660 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Balda, M. S. & Matter, K. Tight junctions at a glance. J. Cell Sci. 121, 3677–3682 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Guillemot, L., Paschoud, S., Pulimeno, P., Foglia, A. & Citi, S. The cytoplasmic plaque of tight junctions: a scaffolding and signalling center. Biochim. Biophys. Acta Biomembr. 1778, 601–613 (2008).

    Article  CAS  Google Scholar 

  160. Krause, G. et al. Structure and function of claudins. Biochim. Biophys. Acta Biomembr. 1778, 631–645 (2008).

    Article  CAS  Google Scholar 

  161. Ayyaz, A. et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569, 121–125 (2019). A pioneering study defining a unique stem cell population that is activated by damage to regenerate the injured intestinal epithelium separate to homeostatic intestinal stem cell populations.

    Article  CAS  PubMed  Google Scholar 

  162. Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  163. Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl Acad. Sci. USA 109, 466–471 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Harnack, C. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat. Commun. 10, 4368 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Davidson, L. A. et al. Alteration of colonic stem cell gene signatures during the regenerative response to injury. Biochim. Biophys. Acta 1822, 1600–1607 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the referees for their helpful comments on this work. The authors also thank H. Abud for stimulating discussions about intestinal stem cells. The authors would also like to acknowledge that, due to space limitations, many important studies and citations could not be included.

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Authors and Affiliations

  1. Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

    Ashleigh P. Rogers, Steven J. Mileto & Dena Lyras

  2. Department of Microbiology, Monash University, Melbourne, Victoria, Australia

    Ashleigh P. Rogers, Steven J. Mileto & Dena Lyras

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A.P.R., S.J.M. and D.L. researched data for the article. All authors substantially contributed to the discussion of content. A.P.R. wrote the manuscript. S.J.M. and D.L. reviewed or edited the manuscript before submission.

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Correspondence to Dena Lyras.

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Glossary

Goblet cells

Intestinal epithelial cells with the primary function to synthesize and secrete mucous.

Bacteraemia

An infection of the bloodstream.

Sepsis

An overactivation of the immune response following infection that causes inflammation throughout the body and can be life threatening.

Haemolytic uraemic syndrome

A syndrome most commonly caused by infection, which leads to kidney damage, blood cell lysis and retention of kidney filtrates.

Paneth cells

Specialized epithelial cells located at the small intestinal crypt base that secrete stem cell-supporting factors.

Stem cell niche

Specific microenvironment at the base of the intestinal crypt that promotes an undifferentiated, self-renewable state.

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Rogers, A.P., Mileto, S.J. & Lyras, D. Impact of enteric bacterial infections at and beyond the epithelial barrier. Nat Rev Microbiol 21, 260–274 (2023). https://doi.org/10.1038/s41579-022-00794-x

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