Diarrheagenic E. coli

Diarrheagenic Escherichia coli are a diverse group of E. coli that are classified into 5 major pathotypes which can cause intestinal infection and diarrhea. Transmission is often through the fecal–oral route via the consumption of contaminated food or water. Pathogenesis varies based on the strain, but it can include toxin production, invasion of the mucosal surface, and adhesion with alteration of enterocyte structure. Noninvasive disease tends to present with watery diarrhea, while invasive infections cause bloody diarrhea. The diagnosis can be established with PCR. Management generally consists of supportive therapy (fluids and electrolytes). Antibiotics are reserved for severe or persistent infections and are contraindicated with enterohemorrhagic E. coli because of the risk of hemolytic uremic syndrome.

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Overview

Microbiology

  • Escherichia coli is a gram-negative bacillus bacterium.
  • Family: Enterobacteriaceae
  • Characteristics: 
    • Ferments lactose
    • Facultatively anaerobic
    • Oxidase-negative
    • Catalase-positive
  • Most strains are harmless and: 
    • Aid in the synthesis of vitamins K and B12
    • Protect against colonization by pathogenic organisms
Scanning electron microscope image of enterotoxigenic escherichia coli

Scanning electron microscope image of enterotoxigenic Escherichia coli

Image: “Under an extremely high magnification of 44, 818X, twice that of PHIL 10574 and 10575, this scanning electron microscopic (SEM) image revealed some of the morphologic details displayed by a single Gram-negative, rod-shaped, Escherichia coli bacterium.” by Janice Haney Carr. License: Public Domain

Pathogenic strains of E. coli

The following strains of E. coli are diarrheagenic: 

  • Enterotoxigenic E. coli (ETEC)
  • Enteropathogenic E. coli (EPEC)
  • Enteroaggregative E. coli (EAEC)
  • Enteroinvasive E. coli (EIEC)
  • Enterohemorrhagic E. coli (EHEC)/Shiga toxin-producing E. coli (STEC)

Transmission

  • Fecal–oral route
  • Contaminated meat or produce (E. coli  serotype O157:H7 and other STEC have a bovine reservoir)
  • Contaminated water
Table: Comparison of E. coli strains
Pathogen Invasive? Toxin? Type of diarrhea
ETEC No
  • LT
  • ST
  • Noninflammatory
  • Watery
EPEC No No
  • Mild inflammatory
  • Watery
EAEC No
  • Some have ST.
  • Alpha-hemolysin
  • Mild inflammatory
  • Watery
EIEC Yes
  • Enterotoxins
  • Cytotoxins
  • Inflammatory
  • Bloody
EHEC Yes Shiga toxin
  • Inflammatory
  • Bloody
LT: heat-labile enterotoxin
ST: heat-stable enterotoxin
ETEC: Enterotoxigenic E. coli
EPEC: Enteropathogenic E. coli
EAEC: Enteroaggregative E. coli
EIEC: Enteroinvasive E. coli
EHEC: Enterohemorrhagic E. coli

Enterotoxigenic E. coli

Epidemiology

  • Most common cause of traveler’s diarrhea
  • > 200 million cases/year

Pathophysiology

Enterotoxigenic E. coli is a noninvasive pathogen. It uses fimbrial adhesins to bind enterocytes in the small intestine and produces the following enterotoxins:

  • Heat-stable enterotoxin (ST): 
    • Activates guanylate cyclase → ↑ intracellular cyclic guanosine monophosphate (cGMP) 
    • ↑ Chloride secretion and ↓ NaCl absorption → water efflux into the intestinal lumen → watery diarrhea
  • Heat-labile enterotoxin (LT): 
    • Activates adenylate cyclase → ↑ intracellular cAMP 
    • ↑ Chloride secretion and ↓ NaCl absorption → water efflux into the intestinal lumen → watery diarrhea
    • Similar to cholera toxin (less severe)
Etec pathogenesis

Enterotoxigenic Escherichia coli (ETEC) pathogenesis:
ETEC attaches to enterocytes via colonization factor antigen (CFA; fimbrial adhesin). The heat-stable (ST) enterotoxin causes cyclic guanosine monophosphate (cGMP) accumulation in cells and secretion of fluid and electrolytes into the intestinal lumen. The heat-labile (LT) enterotoxin acts like cholera toxin, which increases cyclic adenosine monophosphate (cAMP) by activating adenylyl cyclase (AC). The general effect is water and chloride hypersecretion and inhibited sodium reabsorption. Noninvasive enterotoxins remain within the intestinal lumen and do not invade the epithelial cells.
GC: guanylyl cyclase
LTA: A subunit of the heat-labile enterotoxin

Image by Lecturio.

Clinical presentation

  • Time course:
    • Incubation period: 1–3 days
    • Symptom duration: 1–5 days
  • Clinical characteristics:
    • Acute secretory diarrhea:
      • Watery
      •  Occasionally severe
    • Abdominal cramping
    • Nausea (vomiting is less common)

Diagnosis

This disease is self-limited; therefore, a diagnostic workup is not usually needed. However, ETEC can be diagnosed by identifying LT or ST genes on PCR for individuals with severe disease.

Management

  • Supportive therapy:
    • Rehydration and electrolyte replenishment
    • Antimotility agents (e.g., loperamide)
  • Antibiotics are generally not required for most cases because of the disease’s self-limited nature.

Enteropathogenic E. coli

Epidemiology

  • A common cause of diarrhea in infants or young children (< 2 years of age)
  • Most common in resource-limited areas

Pathophysiology

  • Bundle-forming pilus: necessary for attaching to intestinal cells
  • Intimin adhesin:
    • Outer membrane protein
    • Also used in adherence to enterocytes
  • Attachment → cell deformation 
  • Results in:
    • Effacement of microvilli
    • ↑ Tight junction permeability
    • Altered water and electrolyte secretion and absorption
Epec pathogenesis

Enteropathogenic Escherichia coli (EPEC) pathogenesis:
EPEC uses intimin adhesion molecules to adhere to the intestinal cells. Binding causes cell deformation (brush border degeneration and loss of microvilli). The characteristic effect of attachment and effacement is thought to be the primary cause of diarrhea.

Image by Lecturio.

Clinical presentation

  • Watery diarrhea 
  • Nausea and vomiting
  • Low-grade fever
  • Malnutrition is a potential complication of persistent diarrhea.

Diagnosis

Enteropathogenic E. coli can be diagnosed by identifying specific genes using PCR.

Management

  • Supportive therapy
  • Most individuals do not require antibiotic therapy.

Enteroaggregative E. coli

Epidemiology

Enteroaggregative E. coli is most commonly associated with persistent diarrhea in:

  • Children
  • Immunocompromised individuals (e.g., those with HIV/AIDS)

Pathophysiology

  • Aggregative adherence fimbriae (AAF) help bacteria adhere to intestinal mucosa.
  • Aggregation of bacteria → forms a biofilm
  • Toxins produced:
    • Alpha-hemolysin
    • Some possess ST, similar to ETEC

Clinical presentation

  • Acute and chronic watery diarrhea
  • Fever
  • Abdominal pain
  • Vomiting

Diagnosis

The diagnosis of EAEC can be made by identifying specific genes using PCR.

Management

  • Supportive therapy
  • Antibiotic therapy (e.g., fluoroquinolones) may be indicated for persistent disease.

Enteroinvasive E. coli

Pathophysiology

  • Pathophysiology is closely related to Shigella.
  • Bacteria penetrate through the epithelial wall of the intestine.
  • Intracellular multiplication → spread into adjacent epithelial cells
  • Additionally, produce:
    • Enterotoxins
    • Cytotoxins  
  • Inflammatory response → necrosis (can produce ulceration) → dysentery

Clinical presentation

Enteroinvasive E. coli presents very similarly to shigellosis and can be severe.

  • Watery and/or bloody diarrhea (with or without mucus)
  • Fever
  • Malaise
  • Abdominal cramps
  • Nausea and vomiting

Diagnosis

The diagnosis of EIEC can be made by identifying specific genes using PCR.

Management

  • Supportive therapy 
  • Antimotility agents are contraindicated.
  • Antibiotics (e.g., fluoroquinolones, macrolides) may be used in severe cases.

Enterohemorrhagic E. coli

Pathophysiology

Enterohemorrhagic E. coli results in clinical manifestations through the production of shiga toxin: 

  • Localized effect: inhibits enterocyte protein synthesis → enterocyte death → inflammation
  • Systemic effect: vascular endothelial injury in glomeruli → microthrombi and renal dysfunction (hemolytic uremic syndrome (HUS))

Clinical presentation

  • Incubation period: 2–10 days
  • Hemorrhagic colitis:
    • Bloody diarrhea
    • Abdominal pain and cramping
  • Serotype O157:H7 is commonly associated with HUS:
    • Microangiopathic hemolytic anemia
    • Thrombocytopenia
    • Acute renal failure

Diagnosis

The diagnosis of EHEC is made by identifying:

  • Shiga toxin via enzyme immunoassay
  • The gene that encodes shiga toxin using PCR

Management

  • Supportive therapy
  • Antimotility agents are contraindicated.
  • Antibiotics are contraindicated because of ↑ risk of HUS. 

Differential Diagnosis

  • Viral gastroenteritis: inflammation of the stomach and intestines, caused by a variety of viruses. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. The majority of cases of gastroenteritis are self-limited; therefore, the diagnosis is generally clinical and the only required treatment is supportive therapy.
  • Shigellosis: caused by Shigella species. S. dysenteriae produces shiga toxin. Individuals may experience fever, abdominal cramping, and inflammatory diarrhea (with mucus, pus, and blood). Hemolytic uremic syndrome is a potential complication. The diagnosis is confirmed with a stool culture. Management includes supportive therapy and antibiotics (for moderate to severe disease).
  • Giardiasis: caused by Giardia lamblia, a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling diarrhea (steatorrhea). Individuals who develop chronic infections may suffer from weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. The diagnosis is made through detection of Giardia organisms, antigens, or DNA in the stool. Management includes supportive treatment and antimicrobial therapy.
  • Pseudomembranous colitis: infection caused by Clostridioides difficile. This species is commonly found in the normal gut microbiome, but pathogenesis occurs when there is an overabundance of C. difficile. Common symptoms include foul-smelling, nonbloody diarrhea, abdominal pain, and nausea with vomiting. Diagnosis is made with stool PCR or enzyme assays. Treatment generally consists of discontinuing the offending antibiotic and administering oral vancomycin.
  • Colonic ischemia: hypoperfusion to areas of the colon (often in regions without redundant sources of arterial blood). This hypoperfusion can be due to thrombosis, embolism, or hypotension. The acute phase of colonic ischemia is characterized by a classic triad of severe abdominal pain, vomiting, and diarrhea that may be bloody. Individuals may have a history of cardiovascular disease. Diagnosis is generally made with laboratory studies and CTA. Treatment includes fluid replacement, antibiotics, systemic anticoagulation, and often surgery.
  • Diverticulitis: inflammation of diverticula (small outpouching regions of the colon) often due to obstruction with fecal matter. Diverticulitis presents with abdominal pain (most frequently in the LLQ), nausea, and diarrhea that may be bloody. The definitive diagnosis is usually made with a CT scan. Treatment involves bowel rest, IV fluids, and antibiotics.

References

  1. Nataro, J. P. (2020). Pathogenic Escherichia coli associated with diarrhea. UpToDate. Retrieved October 3, 2021, from https://www.uptodate.com/contents/pathogenic-escherichia-coli-associated-with-diarrhea
  2. Holtz, L. R., Tarr, P. I. (2021). Shiga toxin-producing Escherichia coli: microbiology, pathogenesis, epidemiology, and prevention. UpToDate. Retrieved October 3, 2021, from https://www.uptodate.com/contents/shiga-toxin-producing-escherichia-coli-microbiology-pathogenesis-epidemiology-and-prevention
  3. Mueller, M., Tainter, C. R. (2021). Escherichia coli. StatPearls. Retrieved October 3, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK564298/
  4. Centers for Disease Control and Prevention (2014). Enterotoxigenic E. coli (ETEC). Retrieved October 3, 2021, from https://www.cdc.gov/ecoli/etec.html
  5. Nguyen, Y., Sperandio, V. (2012). Enterohemorrhagic E. coli (EHEC) pathogenesis. Frontiers in Cellular and Infection Microbiology 2:90. Retrieved October 3, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417627/
  6. Gomes, T. A. T., et al. (2016). Diarrheagenic Escherichia coli. Brazilian Journal of Microbiology 47:3–30. Retrieved October 3, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156508/
  7. Bush, L. M. (2020). Escherichia coli infections. MSD Manual Professional Version. Retrieved October 3, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/gram-negative-bacilli/escherichia-coli-infections
  8. Bush, L. M., Vazquez-Pertejo, M. T. (2020). Infection by Escherichia coli O157:H7 and other enterohemorrhagic E. coli (EHEC). MSD Manual Professional Version. Retrieved October 3, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/gram-negative-bacilli/infection-by-escherichia-coli-o157-h7-and-other-enterohemorrhagic-e-coli-ehec
  9. Wong, C. S., Jelacic, S., Habeeb, R. L., et al. (2000). The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 342:1930–1936. Retrieved October 3, 2021, from reference.medscape.com/medline/abstract/10874060

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