Control of pathogens and pathobionts by the gut microbiota

Abstract

A dense resident microbial community in the gut, referred as the commensal microbiota, coevolved with the host and is essential for many host physiological processes that include enhancement of the intestinal epithelial barrier, development of the immune system and acquisition of nutrients. A major function of the microbiota is protection against colonization by pathogens and overgrowth of indigenous pathobionts that can result from the disruption of the healthy microbial community. The mechanisms that regulate the ability of the microbiota to restrain pathogen growth are complex and include competitive metabolic interactions, localization to intestinal niches and induction of host immune responses. Pathogens, in turn, have evolved strategies to escape from commensal-mediated resistance to colonization. Thus, the interplay between commensals and pathogens or indigenous pathobionts is critical for controlling infection and disease. Understanding pathogen-commensal interactions may lead to new therapeutic approaches to treating infectious diseases.

Figure 1. Localization of dominant bacterial groups within the intestine

The small intestine is rich in nutrients utilized by both the host and microbe for growth. Proteobacteria (mainly enterobacteria), Lactobacillales and Erysipelotrichales (especially Turicibacter) are dominant in the small intestine. In contrast, the large intestine is poor in such nutrients and therefore harbor much fewer numbers of these bacteria, while Bacteroidetes and Clostridia which can utilize host indigestible fibers as energy sources are enriched.

Figure 2. Commensal microbiota prevents colonization by exogenous pathogens and pathobionts

In the healthy gut, the resident bacteria occupy intestinal colonization niches. Commensal microbiota suppresses the proliferation and colonization of incoming enteric pathogens as well as opportunistic pathobionts through multiple mechanisms. Microbiota produces bacteriocins and short-chain fatty acids, which directly inhibit the growth of pathogen and pathobiont. Commensals can also modify virulence factor expression in pathogens by consuming residual oxygen or suppressing growth by their metabolites. Commensal microbiota facilitates host barrier function through up-regulation of the mucus layer, induction of antimicrobial molecules, such as RegIIIβ and γ, and regulating secretion of IgA. Commensal bacteria also prime intestinal macrophages by upregulating pro-IL-1β. Pathogen infection results in the conversion of pro-IL-1β into the enzymatically active mature form of IL-1β, which promotes neutrophil recruitment and pathogen eradication. Antibiotic treatment or other environmental factors that disrupt the commensal microbial community results in diminished colonization resistance against pathogens (e.g. Salmonella, Shigella) and allow the outgrowth of indigenous pathobionts (e.g. Clostridium difficile, vancomycin-resistant Enterococcus) that have the potential to disseminate systemically and induce septic shock and/or systemic organ infection.

Figure 3. Pathogen overcome commensal-mediated resistance through multiple strategies

a| Pathogenic Escherichia coli: Pathogenic E. coli is capable of utilizing carbohydrates and other resources, such as ethanolamine distinct from that scavenged by commensals. Pathogenic E. coli can also localize to the intestinal epithelial surface that is devoid of commensal microbiota through expression of adhesion molecules, such as intimin. Pathogen-induced gut inflammation confers a growth advantage to the pathogen through the generation of molecules such as inducible nitric oxide synthase (iNOS) expression by host innate immune cells leading to the release of nitrate (NO₃-) that can be utilized as an electron acceptor by E. coli to generate energy through nitrate respiration. Commensal obligate anaerobes, such as Bacteroidetes or Firmicutes lack this ability. b| Salmonella spp.: Lipocalin-2 derived from host cells block commensal bacterial iron uptake by binding to the bacterial siderophore, enterobactin. Salmonella, however, has a distinct siderophore, salmochelin, for iron uptake, which is not blocked by lipocalin-2. Salmonella-induced gut inflammation also promotes migration of neutrophils that produce reactive oxygen species (ROS), which facilitate conversion of thiosulphate (S₂O₃^2-), generated by commensal bacteria, into tetrathionate (S₄O₆^2-). Salmonella, but not commensals, is capable of utilizing tetrathionate as an electron acceptor for anaerobic respiration.