Skip to main content
Springer Nature Link
Log in

Enterotoxigenic Escherichia coli Infections

  • Intra-Abdominal Infections, Hepatitis and Gastroenteritis (T. Steiner, Section Editor)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Review recent developments pertaining to the epidemiology, molecular pathogenesis, and sequelae of enterotoxigenic Escherichia coli (ETEC) infections in addition to discussion of challenges for vaccinology.

Recent Findings

ETEC are a major cause of diarrheal illness in resource poor areas of the world where they contribute to unacceptable morbidity and continued mortality particularly among young children; yet, precise epidemiologic estimates of their contribution to death and chronic disease have been difficult to obtain. Although most pathogenesis studies, and consequently vaccine development have focused intensively on canonical antigens, more recently identified molecules unique to the ETEC pathovar may inform our understanding of ETEC virulence, and the approach to broadly protective vaccines.

Summary

ETEC undeniably continue to have a substantial impact on global health; however, further studies are needed to clarify the true impact of these infections, particularly in regions where access to care may be limited. Likewise, our present understanding of the relationship of ETEC infection to non-diarrheal sequelae is presently limited, and additional effort will be required to achieve a mechanistic understanding of these diseases and to fulfill Koch’s postulates on a molecular level. Precise elucidation of the role played by novel virulence factors, the global burden of acute illness, and the contribution of these pathogens and/or their toxins to non-diarrheal morbidity remain important imperatives.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sack RB, Gorbach SL, Banwell JG, Jacobs B, Chatterjee BD, Mitra RC. Enterotoxigenic Escherichia coli isolated from patients with severe cholera-like disease. J Infect Dis. 1971;123(4):378–85.

    Article  CAS  Google Scholar 

  2. Sack RB. The discovery of cholera - like enterotoxins produced by Escherichia coli causing secretory diarrhoea in humans. Indian J Med Res. 2011;133(2):171–80.

    PubMed  PubMed Central  Google Scholar 

  3. Collaborators GBDDD. Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the global burden of disease study 2015. Lancet Infect Dis. 2017;17(9):909–48. https://doi.org/10.1016/S1473-3099(17)30276-1.

    Article  Google Scholar 

  4. Khalil IA, Troeger C, Blacker BF, Rao PC, Brown A, Atherly DE, et al. Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the global burden of disease study 1990-2016. Lancet Infect Dis. 2018;18:1229–40. https://doi.org/10.1016/S1473-3099(18)30475-4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, GEMS): a prospective, case-control study. Lancet. 2013;382(9888):209–22. https://doi.org/10.1016/S0140-6736(13)60844-2.

    Article  PubMed  Google Scholar 

  6. • Liu J, Platts-Mills JA, Juma J, Kabir F, Nkeze J, Okoi C, et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet. 2016;388(10051):1291–301. https://doi.org/10.1016/S0140-6736(16)31529-X ETEC identified more frequently when molecular methods are employed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Qadri F, Saha A, Ahmed T, Al Tarique A, Begum YA, Svennerholm AM. Disease burden due to enterotoxigenic Escherichia coli in the first 2 years of life in an urban community in Bangladesh. Infect Immun. 2007;75(8):3961–8. https://doi.org/10.1128/IAI.00459-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lamberti LM, Bourgeois AL, Fischer Walker CL, Black RE, Sack D. Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa. PLoS Negl Trop Dis. 2014;8(2):e2705. https://doi.org/10.1371/journal.pntd.0002705.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Collaborators GBDDD. 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 2018. https://doi.org/10.1016/S1473-3099(18)30362-1, 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, 18, 1228.

  10. • Reiner RC Jr, Graetz N, Casey DC, Troeger C, Garcia GM, Mosser JF, et al. Variation in Childhood Diarrheal Morbidity and Mortality in Africa, 2000–2015. N Engl J Med. 2018;379(12):1128–38. https://doi.org/10.1056/NEJMoa1716766 Detailed estimates of geographic distribution of diarrheal disease demonstrating that burden is highly concentrated in some regions.

    Article  PubMed  Google Scholar 

  11. •• Lanata CF, Black RE. Estimating the true burden of an enteric pathogen: enterotoxigenic Escherichia coli and Shigella spp. Lancet Infect Dis. 2018;18:1165–6. https://doi.org/10.1016/S1473-3099(18)30546-2 Provides important perspecitives on limitations of current global burden of disease estimates.

    Article  PubMed  Google Scholar 

  12. Gill CJ, Thea DM, Hibberd P. Diarrhoeal disease trends in the GBD 2015 study: optimism tempered by scepticism. Lancet Infect Dis. 2017;17(9):884–5. https://doi.org/10.1016/S1473-3099(17)30336-5.

    Article  PubMed  Google Scholar 

  13. Hosangadi D, Smith PG, Kaslow DC, Giersing BK, Who E, Shigella Vaccine Consultation Expert G. WHO consultation on ETEC and Shigella burden of disease, Geneva, 6-7th April 2017: Meeting report. Vaccine 2018. https://doi.org/10.1016/j.vaccine.2017.10.011.

  14. •• Hosangadi D, Smith PG, Giersing BK. Considerations for using ETEC and Shigella disease burden estimates to guide vaccine development strategy. Vaccine. 2017. https://doi.org/10.1016/j.vaccine.2017.09.083 Concise summary comparing disease burden estimates.

  15. Kotloff KL. The burden and etiology of diarrheal illness in developing countries. Pediatr Clin N Am. 2017;64(4):799–814. https://doi.org/10.1016/j.pcl.2017.03.006.

    Article  Google Scholar 

  16. International Vaccine Access Center (IVAC) JHSoPH. Pneumonia and Diarrhea Progress Report 2018. 2018.

  17. Petri WA Jr, Miller M, Binder HJ, Levine MM, Dillingham R, Guerrant RL. Enteric infections, diarrhea, and their impact on function and development. J Clin Invest. 2008;118(4):1277–90. https://doi.org/10.1172/JCI34005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Riddle MS, Sanders JW, Putnam SD, Tribble DR. Incidence, etiology, and impact of diarrhea among long-term travelers (US military and similar populations): a systematic review. Am J Trop Med Hyg. 2006;74(5):891–900.

    Article  Google Scholar 

  19. Shah N, DuPont HL, Ramsey DJ. Global etiology of travelers' diarrhea: systematic review from 1973 to the present. Am J Trop Med Hyg. 2009;80(4):609–14.

    Article  Google Scholar 

  20. Hameed JM, McCaffrey RL, McCoy A, Brannock T, Martin GJ, Scouten WT, et al. Incidence, etiology and risk factors for Travelers' diarrhea during a hospital ship-based military humanitarian Mission: continuing promise 2011. PLoS One. 2016;11(5):e0154830. https://doi.org/10.1371/journal.pone.0154830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Steffen R, Hill DR, DuPont HL. Traveler's diarrhea: a clinical review. JAMA. 2015;313(1):71–80. https://doi.org/10.1001/jama.2014.17006.

    Article  CAS  PubMed  Google Scholar 

  22. Jiang ZD, DuPont HL. Etiology of travellers' diarrhea. J Travel Med. 2017;24(suppl_1):S13-S6. https://doi.org/10.1093/jtm/tax003

  23. Tribble DR. Resistant pathogens as causes of traveller's diarrhea globally and impact(s) on treatment failure and recommendations. J Travel Med. 2017;24(suppl_1):S6–S12. https://doi.org/10.1093/jtm/taw090.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Margulieux KR, Srijan A, Ruekit S, Nobthai P, Poramathikul K, Pandey P, et al. Extended-spectrum beta-lactamase prevalence and virulence factor characterization of enterotoxigenic Escherichia coli responsible for acute diarrhea in Nepal from 2001 to 2016. Antimicrob Resist Infect Control. 2018;7:87. https://doi.org/10.1186/s13756-018-0377-2.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Riddle MS, Connor P, Fraser J, Porter CK, Swierczewski B, Hutley EJ, et al. Trial evaluating ambulatory therapy of Travelers' diarrhea (TrEAT TD) study: a randomized controlled trial comparing 3 single-dose antibiotic regimens with Loperamide. Clin Infect Dis. 2017;65(12):2008–17. https://doi.org/10.1093/cid/cix693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruppe E, Armand-Lefevre L, Estellat C, Consigny PH, El Mniai A, Boussadia Y, et al. High rate of acquisition but Short duration of carriage of multidrug-resistant Enterobacteriaceae after travel to the tropics. Clin Infect Dis. 2015;61(4):593–600. https://doi.org/10.1093/cid/civ333.

    Article  PubMed  Google Scholar 

  27. Kennedy K, Collignon P. Colonisation with Escherichia coli resistant to "critically important" antibiotics: a high risk for international travellers. Eur J Clin Microbiol Infect Dis. 2010;29(12):1501–6. https://doi.org/10.1007/s10096-010-1031-y.

    Article  CAS  PubMed  Google Scholar 

  28. Yoder JS, Cesario S, Plotkin V, Ma X, Kelly-Shannon K, Dworkin MS. Outbreak of enterotoxigenic Escherichia coli infection with an unusually long duration of illness. Clin Infect Dis. 2006;42(11):1513–7.

    Article  Google Scholar 

  29. Naimi TS, Wicklund JH, Olsen SJ, Krause G, Wells JG, Bartkus JM, et al. Concurrent outbreaks of Shigella sonnei and enterotoxigenic Escherichia coli infections associated with parsley: implications for surveillance and control of foodborne illness. J Food Prot. 2003;66(4):535–41.

    Article  Google Scholar 

  30. Beatty ME, Bopp CA, Wells JG, Greene KD, Puhr ND, Mintz ED. Enterotoxin-producing Escherichia coli O169:H41. United States Emerg Infect Dis. 2004;10(3):518–21. https://doi.org/10.3201/eid1003.030268.

    Article  PubMed  Google Scholar 

  31. Beatty ME, Adcock PM, Smith SW, Quinlan K, Kamimoto LA, Rowe SY, et al. Epidemic diarrhea due to enterotoxigenic Escherichia coli. Clin Infect Dis. 2006;42(3):329–34.

    Article  Google Scholar 

  32. Roels TH, Proctor ME, Robinson LC, Hulbert K, Bopp CA, Davis JP. Clinical features of infections due to Escherichia coli producing heat-stable toxin during an outbreak in Wisconsin: a rarely suspected cause of diarrhea in the United States. Clin Infect Dis. 1998;26(4):898–902.

    Article  CAS  Google Scholar 

  33. Devasia RA, Jones TF, Ward J, Stafford L, Hardin H, Bopp C, et al. Endemically acquired foodborne outbreak of enterotoxin-producing Escherichia coli serotype O169:H41. Am J Med. 2006;119(2):168 e7–10.

    Article  Google Scholar 

  34. Jain S, Chen L, Dechet A, Hertz AT, Brus DL, Hanley K, et al. An outbreak of enterotoxigenic Escherichia coli associated with sushi restaurants in Nevada, 2004. Clin Infect Dis. 2008;47(1):1–7.

    Article  Google Scholar 

  35. •• Medus C, Besser JM, Juni BA, Koziol B, Lappi V, Smith KE, et al. Long-Term Sentinel Surveillance for Enterotoxigenic Escherichia coli and Non-O157 Shiga Toxin-Producing E. coli in Minnesota. Open Forum Infect Dis. 2016;3(1):ofw003. https://doi.org/10.1093/ofid/ofw003 In two sites in Minnesota ETEC was surprisingly as common as other enteric pathogens when molcular methods were employed for protection.

  36. So M, Boyer HW, Betlach M, Falkow S. Molecular cloning of an Escherichia coli plasmid determinant than encodes for the production of heat-stable enterotoxin. J Bacteriol. 1976;128(1):463–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. So M, Dallas WS, Falkow S. Characterization of an Escherichia coli plasmid encoding for synthesis of heat-labile toxin: molecular cloning of the toxin determinant. Infect Immun. 1978;21(2):405–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Moseley SL, Samadpour-Motalebi M, Falkow S. Plasmid association and nucleotide sequence relationships of two genes encoding heat-stable enterotoxin production in Escherichia coli H-10407. J Bacteriol. 1983;156(1):441–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gyles C, So M, Falkow S. The enterotoxin plasmids of Escherichia coli. J Infect Dis. 1974;130(1):40–9.

    Article  CAS  Google Scholar 

  40. Dallas WS, Falkow S. Amino acid sequence homology between cholera toxin and Escherichia coli heat-labile toxin. Nature. 1980;288(5790):499–501.

    Article  CAS  Google Scholar 

  41. Simon NC, Aktories K, Barbieri JT. Novel bacterial ADP-ribosylating toxins: structure and function. Nat Rev Microbiol. 2014;12(9):599–611. https://doi.org/10.1038/nrmicro3310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. •• Taxt AM, Diaz Y, Aasland R, Clements JD, Nataro JP, Sommerfelt H, et al. Towards Rational Design of a Toxoid Vaccine against the Heat-Stable Toxin of Escherichia coli. Infect Immun. 2016;84(4):1239–49. https://doi.org/10.1128/IAI.01225-15 Outlines a potential strategy for development of heat-stable toxoids.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen T, Kocinsky HS, Cha B, Murtazina R, Yang J, Tse CM, et al. Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site. J Biol Chem. 2015;290(4):1952–65. https://doi.org/10.1074/jbc.M114.590174.

    Article  CAS  PubMed  Google Scholar 

  44. Tauschek M, Gorrell RJ, Strugnell RA, Robins-Browne RM. Identification of a protein secretory pathway for the secretion of heat-labile enterotoxin by an enterotoxigenic strain of Escherichia coli. Proc Natl Acad Sci U S A. 2002;99(10):7066–71.

    Article  CAS  Google Scholar 

  45. Yamanaka H, Nomura T, Fujii Y, Okamoto K. Need for TolC, an Escherichia coli outer membrane protein, in the secretion of heat-stable enterotoxin I across the outer membrane. Microb Pathog. 1998;25(3):111–20. https://doi.org/10.1006/mpat.1998.0211.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu Y, Luo Q, Davis SM, Westra C, Vickers TJ, Fleckenstein JM. Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery. Infect Immun. 2018;86(11). https://doi.org/10.1128/IAI.00526-18.

  47. Evans DG, Silver RP, Evans DJ Jr, Chase DG, Gorbach SL. Plasmid-controlled colonization factor associated with virulence in Escherichia coli enterotoxigenic for humans. Infect Immun. 1975;12(3):656–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Evans DG, Evans DJ Jr, Clegg S, Pauley JA. Purification and characterization of the CFA/I antigen of enterotoxigenic Escherichia coli. Infect Immun. 1979;25(2):738–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mentzer AV, Tobias J, Wiklund G, Nordqvist S, Aslett M, Dougan G, et al. Identification and characterization of the novel colonization factor CS30 based on whole genome sequencing in enterotoxigenic Escherichia coli (ETEC). Sci Rep. 2017;7(1):12514. https://doi.org/10.1038/s41598-017-12743-3.

    Article  CAS  Google Scholar 

  50. Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine. 2011;29(37):6167–78. https://doi.org/10.1016/j.vaccine.2011.06.084.

    Article  CAS  PubMed  Google Scholar 

  51. Qadri F, Das SK, Faruque ASG, Fuchs GJ, Albert MJ, Sack RB, et al. Prevalence of toxin types and colonization factors in Enterotoxigenic Escherichia coli isolated during a 2-year period from diarrheal patients in Bangladesh. J Clin Microbiol. 2000;38(1):27–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sahl JW, Sistrunk JR, Baby NI, Begum Y, Luo Q, Sheikh A, et al. Insights into enterotoxigenic Escherichia coli diversity in Bangladesh utilizing genomic epidemiology. Sci Rep. 2017;7(1):3402. https://doi.org/10.1038/s41598-017-03631-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Satterwhite TK, Evans DG, DuPont HL, Evans DJ Jr. Role of Escherichia coli colonisation factor antigen in acute diarrhoea. Lancet. 1978;2(8082):181–4.

    Article  CAS  Google Scholar 

  54. Patel SK, Dotson J, Allen KP, Fleckenstein JM. Identification and molecular characterization of EatA, an autotransporter protein of enterotoxigenic Escherichia coli. Infect Immun. 2004;72(3):1786–94.

    Article  CAS  Google Scholar 

  55. Fleckenstein JM, Roy K, Fischer JF, Burkitt M. Identification of a two-partner secretion locus of enterotoxigenic Escherichia coli. Infect Immun. 2006;74(4):2245–58.

    Article  CAS  Google Scholar 

  56. Kumar P, Luo Q, Vickers TJ, Sheikh A, Lewis WG, Fleckenstein JM. EatA, an immunogenic protective antigen of Enterotoxigenic Escherichia coli. Degrades Intestinal Mucin Infect Immun. 2014;82(2):500–8. https://doi.org/10.1128/IAI.01078-13.

    Article  CAS  PubMed  Google Scholar 

  57. Roy K, Kansal R, Bartels SR, Hamilton DJ, Shaaban S, Fleckenstein JM. Adhesin degradation accelerates delivery of heat-labile toxin by Enterotoxigenic Escherichia coli. J Biol Chem. 2011;286(34):29771–9. https://doi.org/10.1074/jbc.M111.251546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Roy K, Hilliard GM, Hamilton DJ, Luo J, Ostmann MM, Fleckenstein JM. Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells. Nature. 2009;457(7229):594–8. https://doi.org/10.1038/nature07568.

    Article  CAS  PubMed  Google Scholar 

  59. Kumar P, Kuhlmann FM, Bhullar K, Yang H, Vallance BA, Xia L, et al. Dynamic interactions of a conserved Enterotoxigenic Escherichia coli Adhesin with intestinal mucins govern epithelium engagement and toxin delivery. Infect Immun. 2016;84(12):3608–17. https://doi.org/10.1128/IAI.00692-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Arike L, Holmen-Larsson J, Hansson GC. Intestinal Muc2 mucin O-glycosylation is affected by microbiota and regulated by differential expression of glycosyltranferases. Glycobiology. 2017;27(4):318–28. https://doi.org/10.1093/glycob/cww134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kumar P, Kuhlmann FM, Chakroborty S, Bourgeois AL, Foulke-Abel J, Tumala B, et al. Enterotoxigenic Escherichia coli blood group a interactions intensify diarrheal severity. J Clin Invest. 2018;128:3298–311. https://doi.org/10.1172/JCI97659.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kansal R, Rasko DA, Sahl JW, Munson GP, Roy K, Luo Q, et al. Transcriptional modulation of enterotoxigenic Escherichia coli virulence genes in response to epithelial cell interactions. Infect Immun. 2013;81(1):259–70. https://doi.org/10.1128/IAI.00919-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sheikh A, Rashu R, Begum YA, Kuhlman FM, Ciorba MA, Hultgren SJ, et al. Highly conserved type 1 pili promote enterotoxigenic E. coli pathogen-host interactions. PLoS Negl Trop Dis. 2017;11(5):e0005586. https://doi.org/10.1371/journal.pntd.0005586.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sheikh A, Luo Q, Roy K, Shabaan S, Kumar P, Qadri F, et al. Contribution of the highly conserved EaeH surface protein to enterotoxigenic Escherichia coli pathogenesis. Infect Immun. 2014;82(9):3657–66. https://doi.org/10.1128/IAI.01890-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Harris JA, Roy K, Woo-Rasberry V, Hamilton DJ, Kansal R, Qadri F, et al. Directed evaluation of enterotoxigenic Escherichia coli autotransporter proteins as putative vaccine candidates. PLoS Negl Trop Dis. 2011;5(12):e1428. https://doi.org/10.1371/journal.pntd.0001428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Luo Q, Kumar P, Vickers TJ, Sheikh A, Lewis WG, Rasko DA, et al. Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. Infect Immun. 2014;82(2):509–21. https://doi.org/10.1128/IAI.01106-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dorsey FC, Fischer JF, Fleckenstein JM. Directed delivery of heat-labile enterotoxin by enterotoxigenic Escherichia coli. Cell Microbiol. 2006;8(9):1516–27. https://doi.org/10.1111/j.1462-5822.2006.00736.x.

    Article  CAS  PubMed  Google Scholar 

  68. Vicente AC, Teixeira LF, Iniguez-Rojas L, Luna MG, Silva L, Andrade JR, et al. Outbreaks of cholera-like diarrhoea caused by enterotoxigenic Escherichia coli in the Brazilian Amazon rainforest. Trans R Soc Trop Med Hyg. 2005;99(9):669–74.

    Article  CAS  Google Scholar 

  69. Dutta S, Pazhani GP, Nataro JP, Ramamurthy T. Heterogenic virulence in a diarrheagenic Escherichia coli: evidence for an EPEC expressing heat-labile toxin of ETEC. Int J Med Microbiol. 2015;305(1):47–54. https://doi.org/10.1016/j.ijmm.2014.10.006.

    Article  CAS  PubMed  Google Scholar 

  70. Nyholm O, Halkilahti J, Wiklund G, Okeke U, Paulin L, Auvinen P, et al. Comparative genomics and characterization of hybrid Shigatoxigenic and Enterotoxigenic Escherichia coli (STEC/ETEC) strains. PLoS One. 2015;10(8):e0135936. https://doi.org/10.1371/journal.pone.0135936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Investigators M-EN. The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments. Clin Infect Dis. 2014;59(Suppl 4):S193–206. https://doi.org/10.1093/cid/ciu653.

    Article  CAS  Google Scholar 

  72. Kosek MN, Investigators M-EN. Causal pathways from Enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study. EBioMedicine. 2017;18:109–17. https://doi.org/10.1016/j.ebiom.2017.02.024.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Connor BA. Sequelae of traveler's diarrhea: focus on postinfectious irritable bowel syndrome. Clin Infect Dis. 2005;41(Suppl 8):S577–86. https://doi.org/10.1086/432956.

    Article  PubMed  Google Scholar 

  74. DuPont AW. Postinfectious irritable bowel syndrome. Clin Infect Dis. 2008;46(4):594–9. https://doi.org/10.1086/526774.

    Article  PubMed  Google Scholar 

  75. Ghoshal UC, Gwee KA. Post-infectious IBS, tropical sprue and small intestinal bacterial overgrowth: the missing link. Nat Rev Gastroenterol Hepatol. 2017;14(7):435–41. https://doi.org/10.1038/nrgastro.2017.37.

    Article  PubMed  Google Scholar 

  76. Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in north American travelers to Mexico. Am J Gastroenterol. 2004;99(9):1774–8. https://doi.org/10.1111/j.1572-0241.2004.30435.x.

    Article  PubMed  Google Scholar 

  77. Klem F, Wadhwa A, Prokop LJ, Sundt WJ, Farrugia G, Camilleri M, et al. Prevalence, risk factors, and outcomes of irritable bowel syndrome after infectious enteritis: a systematic review and meta-analysis. Gastroenterology. 2017;152(5):1042–54. https://doi.org/10.1053/j.gastro.2016.12.039.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Schwille-Kiuntke J, Mazurak N, Enck P. Systematic review with meta-analysis: post-infectious irritable bowel syndrome after travellers' diarrhoea. Aliment Pharmacol Ther. 2015;41(11):1029–37. https://doi.org/10.1111/apt.13199.

    Article  CAS  PubMed  Google Scholar 

  79. Stermer E, Lubezky A, Potasman I, Paster E, Lavy A. Is traveler's diarrhea a significant risk factor for the development of irritable bowel syndrome? A prospective study. Clin Infect Dis. 2006;43(7):898–901. https://doi.org/10.1086/507540.

    Article  PubMed  Google Scholar 

  80. Nair P, Okhuysen PC, Jiang ZD, Carlin LG, Belkind-Gerson J, Flores J, et al. Persistent abdominal symptoms in US adults after short-term stay in Mexico. J Travel Med. 2014;21(3):153–8. https://doi.org/10.1111/jtm.12114.

    Article  PubMed  Google Scholar 

  81. Dupont HL. Gastrointestinal infections and the development of irritable bowel syndrome. Curr Opin Infect Dis. 2011;24(5):503–8. https://doi.org/10.1097/QCO.0b013e32834a962d.

    Article  PubMed  Google Scholar 

  82. Harvey RF, Mauad EC, Brown AM. Prognosis in the irritable bowel syndrome: a 5-year prospective study. Lancet. 1987;1(8539):963–5.

    Article  CAS  Google Scholar 

  83. Neal KR, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a six year follow up study. Gut. 2002;51(3):410–3.

    Article  CAS  Google Scholar 

  84. Hillary W, Hillary W. Observations on the changes of the air and the concomitant epidemical diseases, in the island of Barbados. To which is added A treatise on the putrid bilious fever, commonly called the yellow fever; and such other diseases as are indigenous or endemial, in the West India Islands, or in the Torrid Zone. London,: C. Hitch and L. Hawes; 1759. 8 , 360, 4 p. p.

  85. Manson P. Imperial Maritime Customs II-special series 2. Medical reports for the first half year ended 31st March 188–0. 19th issue. Shanghai: Statistical department of the Inspectorate General 1880. 1880.

  86. Cook GC. Aetiology and pathogenesis of postinfective tropical malabsorption (tropical sprue). Lancet. 1984;1(8379):721–3.

    Article  CAS  Google Scholar 

  87. Ghitis J, Tripathy K, Mayoral G. Malabsorption in the tropics. 2. Tropical sprue versus primary protein malnutrition: vitamin B12 and folic acid studies. Am J Clin Nutr. 1967;20(11):1206–11. https://doi.org/10.1093/ajcn/20.11.1206.

    Article  CAS  PubMed  Google Scholar 

  88. Klipstein FA. Tropical sprue in travelers and expatriates living abroad. Gastroenterology. 1981;80(3):590–600.

    CAS  PubMed  Google Scholar 

  89. Klipstein FA, Falaiye JM. Tropical sprue in expatriates from the tropics living in the continental United States. Medicine (Baltimore). 1969;48(6):475–91.

    Article  CAS  Google Scholar 

  90. Lindenbaum J, Gerson CD, Kent TH. Recovery of small-intestinal structure and function after residence in the tropics. I. Studies in peace corps volunteers. Ann Intern Med. 1971;74(2):218–22.

    Article  CAS  Google Scholar 

  91. Klipstein FA, Holdeman LV, Corcino JJ, Moore WE. Enterotoxigenic intestinal bacteria in tropical sprue. Ann Intern Med. 1973;79(5):632–41.

    Article  CAS  Google Scholar 

  92. Klipstein FA, Samloff IM, Schenk EA. Tropical sprue in Haiti. Ann Intern Med. 1966;64(3):575–94.

    Article  CAS  Google Scholar 

  93. Klipstein FA, Engert RF, Short HB. Enterotoxigenicity of colonising coliform bacteria in tropical sprue and blind-loop syndrome. Lancet. 1978;2(8085):342–4.

    Article  CAS  Google Scholar 

  94. Sharma P, Baloda V, Gahlot GP, Singh A, Mehta R, Vishnubathla S, et al. Clinical, endoscopic, and histological differentiation between celiac disease and tropical sprue: a systematic review. J Gastroenterol Hepatol. 2018. https://doi.org/10.1111/jgh.14403.

  95. Falkow S. Molecular Koch's postulates applied to bacterial pathogenicity--a personal recollection 15 years later. Nat Rev Microbiol. 2004;2(1):67–72. https://doi.org/10.1038/nrmicro799.

    Article  CAS  PubMed  Google Scholar 

  96. Walker MM. What is tropical sprue? J Gastroenterol Hepatol. 2003;18(8):887–90.

    Article  Google Scholar 

  97. Mathan VI. Tropical sprue in southern India. Trans R Soc Trop Med Hyg. 1988;82(1):10–4.

    Article  CAS  Google Scholar 

  98. Naylor C, Lu M, Haque R, Mondal D, Buonomo E, Nayak U, et al. Environmental enteropathy, Oral vaccine failure and growth faltering in infants in Bangladesh. EBioMedicine. 2015;2(11):1759–66. https://doi.org/10.1016/j.ebiom.2015.09.036.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Keusch GT, Denno DM, Black RE, Duggan C, Guerrant RL, Lavery JV, et al. Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences. Clin Infect Dis. 2014;59(Suppl 4):S207–12. https://doi.org/10.1093/cid/ciu485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Church JA, Parker EP, Kosek MN, Kang G, Grassly NC, Kelly P, et al. Exploring the relationship between environmental enteric dysfunction and oral vaccine responses. Future Microbiol. 2018;13:1055–70. https://doi.org/10.2217/fmb-2018-0016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Watanabe K, Petri WA Jr. Environmental enteropathy: elusive but significant subclinical abnormalities in developing countries. EBioMedicine. 2016;10:25–32. https://doi.org/10.1016/j.ebiom.2016.07.030.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Niehaus MD, Moore SR, Patrick PD, Derr LL, Lorntz B, Lima AA, et al. Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown. Am J Trop Med Hyg. 2002;66(5):590–3.

    Article  Google Scholar 

  103. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and infection. Monogr Ser World Health Organ. 1968;57:3–329.

    CAS  PubMed  Google Scholar 

  104. Black RE, Brown KH, Becker S. Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh. Am J Clin Nutr. 1984;39(1):87–94. https://doi.org/10.1093/ajcn/39.1.87.

    Article  CAS  PubMed  Google Scholar 

  105. Mondal D, Haque R, Sack RB, Kirkpatrick BD, Petri WA Jr. Attribution of malnutrition to cause-specific diarrheal illness: evidence from a prospective study of preschool children in Mirpur, Dhaka. Bangladesh Am J Trop Med Hyg. 2009;80(5):824–6.

    Article  Google Scholar 

  106. •• Platts-Mills JA, Taniuchi M, Uddin MJ, Sobuz SU, Mahfuz M, Gaffar SA, et al. Association between enteropathogens and malnutrition in children aged 6–23 mo in Bangladesh: a case-control study. Am J Clin Nutr. 2017;105(5):1132–8. https://doi.org/10.3945/ajcn.116.138800 Association of LT-ETEC and malnutrition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Rogawski ET, Liu J, Platts-Mills JA, Kabir F, Lertsethtakarn P, Siguas M, et al. Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study. Lancet Glob Health. 2018;6(12):e1319–e28. https://doi.org/10.1016/S2214-109X(18)30351-6.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Investigators M-EN. Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study. BMJ Glob Health. 2018;3(4):e000752. https://doi.org/10.1136/bmjgh-2018-000752.

    Article  Google Scholar 

  109. Vonaesch P, Morien E, Andrianonimiadana L, Sanke H, Mbecko JR, Huus KE, et al. Stunted childhood growth is associated with decompartmentalization of the gastrointestinal tract and overgrowth of oropharyngeal taxa. Proc Natl Acad Sci U S A. 2018;115:E8489–98. https://doi.org/10.1073/pnas.1806573115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. • Bourgeois AL, Wierzba TF, Walker RI. Status of vaccine research and development for enterotoxigenic Escherichia coli. Vaccine. 2016;34(26):2880–6. https://doi.org/10.1016/j.vaccine.2016.02.076 Summary of current state of ETEC vaccine research.

    Article  CAS  PubMed  Google Scholar 

  111. Ahmed T, Bhuiyan TR, Zaman K, Sinclair D, Qadri F. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013;7:CD009029. https://doi.org/10.1002/14651858.CD009029.pub2.

    Article  Google Scholar 

  112. Walker RI, Wierzba TF, Mani S, Bourgeois AL. Vaccines against Shigella and enterotoxigenic Escherichia coli: A summary of the 2016 VASE Conference. Vaccine. 2017;35(49 Pt A):6775–82. https://doi.org/10.1016/j.vaccine.2017.09.045.

    Article  PubMed  Google Scholar 

  113. Clemens JD, Sack DA, Harris JR, Chakraborty J, Neogy PK, Stanton B, et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J Infect Dis. 1988;158(2):372–7.

    Article  CAS  Google Scholar 

  114. Scerpella EG, Sanchez JL, Mathewson IJ, Torres-Cordero JV, Sadoff JC, Svennerholm AM, et al. Safety, immunogenicity, and protective efficacy of the whole-cell/recombinant B subunit (WC/rBS) Oral cholera vaccine against Travelers' diarrhea. J Travel Med. 1995;2(1):22–7.

    Article  CAS  Google Scholar 

  115. Lopez-Gigosos R, Campins M, Calvo MJ, Perez-Hoyos S, Diez-Domingo J, Salleras L, et al. Effectiveness of the WC/rBS oral cholera vaccine in the prevention of traveler's diarrhea: a prospective cohort study. Hum Vaccin Immunother. 2013;9(3):692–8.

    Article  Google Scholar 

  116. Peltola H, Siitonen A, Kyronseppa H, Simula I, Mattila L, Oksanen P, et al. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet. 1991;338(8778):1285–9.

    Article  CAS  Google Scholar 

  117. Rasko DA, Rosovitz MJ, Myers GS, Mongodin EF, Fricke WF, Gajer P, et al. The pangenome structure of Escherichia coli: comparative genomic analysis of E. coli commensal and pathogenic isolates. J Bacteriol. 2008;190(20):6881–93. https://doi.org/10.1128/JB.00619-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. von Mentzer A, Tobias J, Wiklund G, Nordqvist S, Aslett M, Dougan G, et al. Identification and characterization of the novel colonization factor CS30 based on whole genome sequencing in enterotoxigenic Escherichia coli (ETEC). Sci Rep. 2017;7(1):12514. https://doi.org/10.1038/s41598-017-12743-3.

    Article  CAS  Google Scholar 

  119. Lundgren A, Bourgeois L, Carlin N, Clements J, Gustafsson B, Hartford M, et al. Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled phase I study. Vaccine. 2014;32(52):7077–84. https://doi.org/10.1016/j.vaccine.2014.10.069.

    Article  CAS  PubMed  Google Scholar 

  120. Darsley MJ, Chakraborty S, Denearing B, Sack DA, Feller A, Buchwaldt C, et al. ACE527 Oral, live attenuated ETEC vaccine reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease. Clin Vaccine Immunol. 2012;19:1921–31. https://doi.org/10.1128/CVI.00364-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sahl JW, Steinsland H, Redman JC, Angiuoli SV, Nataro JP, Sommerfelt H, et al. A comparative genomic analysis of diverse clonal types of enterotoxigenic Escherichia coli reveals pathovar-specific conservation. Infect Immun. 2011;79(2):950–60. https://doi.org/10.1128/IAI.00932-10.

    Article  CAS  PubMed  Google Scholar 

  122. Luo Q, Qadri F, Kansal R, Rasko DA, Sheikh A, Fleckenstein JM. Conservation and immunogenicity of novel antigens in diverse isolates of enterotoxigenic Escherichia coli. PLoS Negl Trop Dis. 2015;9(1):e0003446. https://doi.org/10.1371/journal.pntd.0003446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chakraborty S, Randall A, Vickers TJ, Molina D, Harro CD, DeNearing B, et al. Human experimental challenge with enterotoxigenic Escherichia coli elicits immune responses to canonical and novel antigens relevant to vaccine development. J Infect Dis. 2018;218:1436–46. https://doi.org/10.1093/infdis/jiy312.

    Article  PubMed  Google Scholar 

  124. Ward JI, Cherry JD, Chang SJ, Partridge S, Lee H, Treanor J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med. 2005;353(15):1555–63. https://doi.org/10.1056/NEJMoa050824.

    Article  CAS  PubMed  Google Scholar 

  125. Taranger J, Trollfors B, Bergfors E, Knutsson N, Lagergard T, Schneerson R, et al. Immunologic and epidemiologic experience of vaccination with a monocomponent pertussis toxoid vaccine. Pediatrics. 2001;108(6):E115.

    Article  CAS  Google Scholar 

  126. Clements JD, Norton EB. The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT. mSphere. 2018;3(4). https://doi.org/10.1128/mSphere.00215-18.

  127. Fleckenstein J, Sheikh A, Qadri F. Novel antigens for enterotoxigenic Escherichia coli vaccines. Expert Rev Vaccines. 2014;13(5):631–9. https://doi.org/10.1586/14760584.2014.905745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fleckenstein JM. Providing structure to Enterotoxigenic Escherichia coli vaccine development. J Infect Dis. 2017;216(1):1–3. https://doi.org/10.1093/infdis/jix146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Holmgren J, Bourgeois L, Carlin N, Clements J, Gustafsson B, Lundgren A, et al. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant. Vaccine. 2013;31(20):2457–64. https://doi.org/10.1016/j.vaccine.2013.03.027.

    Article  CAS  PubMed  Google Scholar 

  130. Behrens RH, Cramer JP, Jelinek T, Shaw H, von Sonnenburg F, Wilbraham D, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis. 2013;14:197–204. https://doi.org/10.1016/S1473-3099(13)70297-4.

    Article  CAS  PubMed  Google Scholar 

  131. Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine. 2017;35(49 Pt A):6790–2. https://doi.org/10.1016/j.vaccine.2017.06.076.

    Article  PubMed  Google Scholar 

  132. Laird RM, Ma Z, Dorabawila N, Pequegnat B, Omari E, Liu Y, et al. Evaluation of a conjugate vaccine platform against enterotoxigenic Escherichia coli (ETEC), campylobacter jejuni and Shigella. Vaccine. 2018;36(45):6695–702. https://doi.org/10.1016/j.vaccine.2018.09.052.

    Article  CAS  PubMed  Google Scholar 

  133. Barry EM, Altboum Z, Losonsky G, Levine MM. Immune responses elicited against multiple enterotoxigenic Escherichia coli fimbriae and mutant LT expressed in attenuated Shigella vaccine strains. Vaccine. 2003;21(5–6):333–40.

    Article  CAS  Google Scholar 

  134. Barry EM, Wang J, Wu T, Davis T, Levine MM. Immunogenicity of multivalent Shigella-ETEC candidate vaccine strains in a Guinea pig model. Vaccine. 2006;24(18):3727–34. https://doi.org/10.1016/j.vaccine.2005.07.013.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Work reported in this publication was supported by PATH; funding from National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers R01AI089894 (jmf), R01AI126887 (jmf), K23 AI130389 (fmk), the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the NIH, and the Department of Veterans Affairs (5I01BX001469, jmf). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NIAID, NCATS, the Department of Veterans Affairs, or PATH.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA

    James M. Fleckenstein & F. Matthew Kuhlmann

  2. Medicine Service, Veterans Affairs Medical Center, Saint Louis, MO, USA

    James M. Fleckenstein

Authors
  1. James M. Fleckenstein
    View author publications

    Search author on:PubMed Google Scholar

  2. F. Matthew Kuhlmann
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to James M. Fleckenstein.

Ethics declarations

Conflict of Interest

James M. Fleckenstein and F. Matthew Kuhlmann declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors. Informed consent was taken from patients prior to enrollment.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Intra-Abdominal Infections, Hepatitis and Gastroenteritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fleckenstein, J.M., Kuhlmann, F.M. Enterotoxigenic Escherichia coli Infections. Curr Infect Dis Rep 21, 9 (2019). https://doi.org/10.1007/s11908-019-0665-x

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11908-019-0665-x

Keywords

Profiles

  1. James M. Fleckenstein View author profile