Mechanism of the Gut Microbiota Colonization Resistance and Enteric Pathogen Infection

Abstract

The mammalian gut microbial community, known as the gut microbiota, comprises trillions of bacteria, which co-evolved with the host and has an important role in a variety of host functions that include nutrient acquisition, metabolism, and immunity development, and more importantly, it plays a critical role in the protection of the host from enteric infections associated with exogenous pathogens or indigenous pathobiont outgrowth that may result from healthy gut microbial community disruption. Microbiota evolves complex mechanisms to restrain pathogen growth, which included nutrient competition, competitive metabolic interactions, niche exclusion, and induction of host immune response, which are collectively termed colonization resistance. On the other hand, pathogens have also developed counterstrategies to expand their population and enhance their virulence to cope with the gut microbiota colonization resistance and cause infection. This review summarizes the available literature on the complex relationship occurring between the intestinal microbiota and enteric pathogens, describing how the gut microbiota can mediate colonization resistance against bacterial enteric infections and how bacterial enteropathogens can overcome this resistance as well as how the understanding of this complex interaction can inform future therapies against infectious diseases.

Keywords: colonization resistance; commensals; enteric infections; gut microbiota; microbial interaction; pathogens.

Figure 1

A triangular form of the gut microbial community interactions. 1) Commensal–pathogen interactions; 2) commensal–host interactions; and 3) pathogen–host interactions.

Figure 2

Outline of the gut commensal and pathogen mechanisms. (A) Commensal colonization resistance mechanisms. (B) Pathogen expansion mechanisms to overcome commensals. C, commensal; P, pathogen.

Figure 3

The gut microbiota during health and disease and their mechanisms. (A) A diverse and non-disturbed microbiota confers resistance to colonization by enteric pathogens in the intestinal epithelium. (B) Treatment with antibiotics decreases the diversity of the microbiota and leads to the expansion of the pathogen population. (C) The mechanisms of intestinal microbiota-mediated colonization resistance: in the healthy state, the resident commensal bacteria occupy the entire intestinal colonization niches and mediate colonization resistance through several direct and indirect mechanisms, thereby suppressing the proliferation and colonization by exogenous enteric pathogens and resident opportunistic pathobionts. Examples of gut microbiota-mediated direct inhibition of pathogens from intestinal colonization include the following: 1) competition for nutrients and production of toxic substances such as bacteriocin, secondary bile acids, and fermentation products such as short-chain fatty acids; these microbiota-derived products directly inhibit the growth of pathogens and pathobionts. 2) Commensals can also modify virulence factor expression in pathogens by consuming residual oxygen or suppressing growth by their metabolites. Specific commensals reduce pathogen adherence to the intestinal mucosa due to having high diversity or possessing unique adhesion molecules, and the process is termed as niche or adhesion exclusion. Similarly, gut commensals mediate colonization resistance via a variety of indirect means. 3) Gut microbiota enhances the gut barrier function through upregulation of the mucus through the release of antimicrobial peptides, such as Regγ, and regulating IgA secretion. Similarly, microbiota activates host immune response and provides colonization resistance. Gut microbiota stimulates the priming of intestinal macrophages through IL-1β, which promotes the recruitment of neutrophils to the site of infection and eradicates pathogens. Commensal microbiota promotes differentiation and/or activation of Th17 cells and innate lymphoid cells (ILCs), which control both commensals and pathogens through secreted cytokines, such as IL-22- and IL-22-dependent antimicrobial peptides. Thus, commensals boost both innate and adaptive mucosa immunity and prevent pathogen colonization. Disruptions of the commensal gut microbial community by antibiotics or other environmental incursions result in increased colonization by pathogens. As a result, pathogens may potentially disseminate systemically and induce septic shock and/or systemic organ infection. (D) The mechanisms of pathogens to overcome commensal-mediated resistance: pathogens resist commensals through multiple strategies. 1) Pathogenic bacteria/enteric pathogens overcome commensals via specific alternate nutrients such as carbohydrates and ethanolamine. 2) Pathogens adhere to a pathogenic specific niche on the intestinal epithelial surface that is devoid of commensal microbiota through the expression of adhesion molecules, such as intimin. 3) Pathogens induce intestinal inflammation, which alters the gut nutritional and physiological environment and inhibits the growth of commensal bacteria, thus conferring an advantage to enteric pathogens. Pathogens trigger intestinal inflammation and use its virulent factors such as T3SS-1 and T3SS-2 (S. Typhimurium) or toxins (C. difficile), which results in the release of antimicrobial molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), e.g., inducible nitric oxide synthase (iNOS), from host epithelial cells, converted into nitrate (NO³⁻), which can be utilized by pathogenic bacteria as an energy source through nitrate respiration, while commensals lack this ability, thus having a growth advantage over commensals. Similarly, a high influx of neutrophils during inflammation to the site of infection produces ROS, which enable the conversion of $S_2{O}_3^{2-},$ generated by commensal bacteria, into $S_4{O}_6^{2-},$ which can be used by pathogens through anaerobic respiration but cannot be used by commensals as an electron acceptor to extract energy that further boosts the growth of pathogenic bacteria such as S. Typhimurium. Similarly, lipocalin-2 is an anti-siderophore molecule, produced by the host cell during pathogen infection, which prohibits iron uptake by commensal bacteria by binding to the bacterial siderophore, enterobactin, which can block the growth of commensals such as Enterobacteriaceae that rely on the siderophore enterobactin for the acquisition of iron (Fe³⁺). However, pathogens such as Salmonella spp. have a distinct siderophore, salmochelin, for iron uptake, so it does not bind to the S. Typhimurium siderophore salmochelin, which is resistant to lipocalin-2-mediated inhibition.