Enterotoxigenic Escherichia coli: intestinal pathogenesis mechanisms and colonization resistance by gut microbiota

Abstract

Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in children and travelers in developing countries. ETEC is characterized by the ability to produce major virulence factors including colonization factors (CFs) and enterotoxins, that bind to specific receptors on epithelial cells and induce diarrhea. The gut microbiota is a stable and sophisticated ecosystem that performs a range of beneficial functions for the host, including protection against pathogen colonization. Understanding the pathogenic mechanisms of ETEC and the interaction between the gut microbiota and ETEC represents not only a research need but also an opportunity and challenge to develop precautions for ETEC infection. Herein, this review focuses on recent discoveries about ETEC etiology, pathogenesis and clinical manifestation, and discusses the colonization resistances mediated by gut microbiota, as well as preventative strategies against ETEC with an aim to provide novel insights that can reduce the adverse effect on human health.

Keywords: Enterotoxigenic Escherichia coli; colonization resistance; enterotoxin; gut microbiota; pathogenesis.

Figure 1.

Characteristics of the ETEC infection. ETEC is the major enteric pathogen that account for the diarrhea that occurs in travelers and children in developing countries. ETEC infection is caused by ingestion of contaminated food and water, ETEC through the gastrointestinal tract, and eventually colonization in the small intestine. When ETEC is exposed in the small intestine, it colonizes intestinal epithelial cells via CFs, and ETEC proliferates on the intestinal epithelial after colonization. ETEC produces and delivers heat-labile (LT) and/or heat-stable (ST) enterotoxins to exert toxic effect. Image created with BioRender.

Figure 2.

The structure of LT, STa, STb, uroguanylin, and guanylin. (a), (b) Three-dimensional structure of the LT (PDB accession no. 1LTB). (c) Three-dimensional structure of the STa (PDB accession no. 1ETN). (d) Three-dimensional structure of the STb (PDB accession no. 1EHS). (e) Three-dimensional structure of the uroguanylin (PDB accession no. 1UYA). (f) Three-dimensional structure of the guanylin (PDB accession no. 1GNA). Image created with BioRender software.

Figure 3.

The mechanisms of disease caused by ETEC. Once ETEC established in the small intestinal epithelia via CFs, subsequent efficient enterotoxins delivery activity begins. The ST and LT of ETEC activate adenylyl and guanylate cyclase lead to high level of cAMP and cGMP, which stimulates water and electrolytes secretion in the intestinal lumen.

Figure 4.

Direct and indirect inhibition mediated by gut microbiota against ETEC infections. On the left, an illustration depicts the direct inhibition against ETEC mediated by gut bacteria. Gut bacteria directly impede ETEC colonization and proliferation. Certain antibacterial compounds, such as bacteriocins, SCFAs, and secondary bile acid, generated by the gut microbiota have been shown to directly inhibit ETEC. Additionally, gut microbiota can compete with ETEC for nutrients, which could limit the growth of ETEC. On the right, indirect methods of competition between gut microbiota and ETEC are depicted. The antimicrobial molecules produced by gut microbiota, such as SCFAs and bacteriocins, which could release into inner mucus layer and stimulate the barrier function. The commensal microbiota induces the differentiation of CD4 T cells into Th17 cells, which contribute to colonization resistance against ETEC by the release of cytokines such as IL-22. Under the stimulation of gut microbiota, intestinal epithelia secrete inflammatory factors, AMPs and sIgA into the mucus, which inhibits the colonization of ETEC. Image created with BioRender.