Multifaceted Interactions of Bacterial Toxins With the Gastrointestinal Mucosa

MR Popoff


Future Microbiol. 2011;6(7):763-797. 

In This Article

Overview of Bacterial Enteropathogens & Enterotoxins

Among the large number of bacteria from the environment, that can be found in the digestive tract, or those of the resident intestinal microflora, only a low proportion produce virulence factors responsible for gastrointestinal or food-borne diseases. However, this results in a large number of diverse bacteria being able to interact with the digestive mucosa, either directly or indirectly (Figure 1). Enteropathogenic or enterotoxigenic bacteria have developed multiple strategies to counteract the natural or acquired host defenses, and to cause disease, either from accidental introduction of environmental bacteria into the host or from a long-term adaptation of an environmental bacteria to the new survival conditions of the digestive tract. Among the diverse virulence factors, toxins represent the most powerful and fast-acting ways to affect target cells. Toxigenic bacteria, which produce enterotoxins or toxins able to cross the intestinal mucosa, can be found in three situations. The natural habitat of most of toxigenic bacteria is the environment, and some of them can grow and secrete their toxin(s) in particular environments, such as food. Ingestion of preformed toxin in food causes food intoxication, for example, Staphylococcus aureus, Bacillus cereus food poisoning and botulism. Other toxigenic bacteria can enter the digestive tract and grow in the intestinal lumen under certain conditions, permitting them to overcome the inhibitory effects of the resident microflora. This is the case of Clostridium difficile (responsible for antibiotic-associated diarrhea, which can colonize the intestine when the inhibitory microflora has been unbalanced by antibiotics), Clostridium botulinum (the agent of infant botulism, which, when ingested in large numbers, can grow in the digestive tract of young babies with undeveloped or not yet functional microflora) or enterotoxigenic Clostridium perfringens (which, when ingested in large number, can grow and sporulate in the intestinal lumen despite the resident microflora). A third class of toxigenic bacteria are those that are also colonizing bacteria. These enteropathogens express adherence factors (e.g., pili and fimbriae), which mediate the attachment of the bacteria to the brush border, thus permitting evasion of inhibitory microflora and, thus, favoring the colonization of the intestinal mucosal surface. For example, Vibrio cholerae and some Escherichia coli strains are adherent and enterotoxigenic bacteria. Invasive bacteria use different strategies to enter target intestinal cells or to pass through the intestinal barrier by injecting virulence factors directly into target cells through a specialized secretion system, such as type III or IV secretion system, but not by secreting toxins. Some invasive bacteria synthesize toxins, but they have no essential role in the invasion process. An overview of the different strategies of toxigenic and enteroinvasive bacteria is shown in Figure 1.

Figure 1.

Main classes of toxigenic bacteria responsible for gastrointestinal or food-borne diseases and main sites of toxin production.

The numerous enterotoxins and toxins interacting with the gastrointestinal barrier display a great diversity in size, structure and mode of action (Table 1). They are single proteins, ranging from 2 to 250–300 kDa, or are organized in complexes of two (binary toxins) or three (tripartite toxins) protein chains, or are assembled in a more composite structure, such as the AB5 structure with one enzymatic subunit and five binding subunits. Whatever the structural organization, the essential steps of activity are controlled by specific toxin domains or subunits. All the toxins first recognize and interact with a specific receptor on the surface of target cells through a distinct domain or subunit called the binding domain or binding subunit. Certain toxins are active from the cell membrane, others enter the cytosol and interfere with an intracellular target. Toxins active on cell surface use additional domains for their activity steps, such as oligomerization, pore formation or enzymatic activity (Table 2). The intracellularly active toxins contain at least one receptor-binding domain and two additional domains involved in translocation of the active domain from endosomes to the cytosol, and in intracellular activity supported by the enzymatic domain (Table 3). Figure 2 shows a summarized view of the main effects of toxins on the intestinal mucosa.

Figure 2.

Main effects of bacterial toxins interacting with the gastrointestinal mucosa.
Enterotoxins can alter intestinal cell homeostasis leading to efflux of water and electrolytes by interaction with a cell surface receptor (e.g., guanylate cyclase) and transduction of a signal, causing an increase in intracellular secondary messengers (e.g., cGMP) and activation of Cl channels, pore formation through the plasma membrane permitting the leakage of fluid and electrolytes, interaction with an intracellular target (e.g., regulatory heterotrimeric G-proteins of adenyl cyclase) also leading to an increase in intracellular secondary messenger (cAMP) and activation of Cl channels. Other toxins alter the actin cytoskeleton, subsequently disorganize the intercellular junctions and increase intestinal barrier permeability by proteolytic cleavage of the extracellular domain of E-cadherin, inactivate (clostridial glucosylating toxins) or activate (deamidase toxins) of regulatory proteins (Rho GTPases) of actin filament polymerization and modify through ADP ribosylation monomeric actin and thus impair actin filament polymerization. Some toxins alter the cell viability by pore formation and cell necrosis, inactivation or cleavage of an intracellular target (elongation factor 2, rRNA, Ras protein or DNA) critical for protein synthesis, cell cycle progression or transduction of an apoptotic signal. Emetic toxins activate the release of serotonin (5-HT) or directly stimulate afferent vagal neurons in the intestinal mucosa. Stars represent intracellular active toxin.
CFTR: Cystic fibrosis transmembrane conductance regulator.