Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them

Abstract

The communities of bacteria that reside in the intestinal tract are in constant competition within this dynamic and densely colonized environment. At homeostasis, the equilibrium that exists between these species and strains is shaped by their metabolism and also by pathways of active antagonism, which drive competition with related and unrelated strains. Importantly, these normal activities contribute to colonization resistance by the healthy microbiota, which includes the ability to prevent the expansion of potential pathogens. Disruption of the microbiota, resulting from, for example, inflammation or antibiotic use, can reduce colonization resistance. Pathogens that engraft following disruption of the microbiota are often adapted to expand into newly created niches and compete in an altered gut environment. In this review, we examine both the interbacterial mechanisms of colonization resistance and the strategies of pathogenic strains to exploit gaps in colonization resistance.

Fig. 1

Microbiota metabolism contributes to colonization resistance. a Members of the microbiota, such as C. scindens, convert primary bile salts (blue stars) into secondary bile salts (red stars) that inhibit the vegetative growth of C. difficile. b The healthy microbiota ferments diet-derived simple sugars (purple/pink circles), complex polysaccharides (blue lines), and microbiota-liberated metabolites from the mucous layer (brown circles) to produce inhibitory SCFA. c In the absence of competing strains, E. coli and C. rodentium utilize the increased availability of simple sugars for replication

Fig. 2

Mechanisms of active antagonism contribute to colonization resistance: a Constituents of the microbiota can express contact-dependent secretion systems that deliver antagonistic effector proteins. In Gram-negatives, such as Bacteroides, delivery is driven by the T6SS, while the Esx system has recently been identified as having an analogous role in Gram-positive bacteria. b In Bacteroides, the GAI-1 and GAI-2 variants of the T6SS are encoded on conjugative plasmids enabling horizontal gene transfer to other strains in the microbiota. c Short peptide antimicrobials, termed bacteriocins, are secreted by the microbiota and have activity against both related non-immune commensal strains and exogenous species

Fig. 3

Expansion and engraftment strategies of invading species. a Some pathogens, such as Salmonella and P. aeruginosa, target either the microbiota or other opportunistic species through using T6SS’s and bacteriocin production. b Pathogens can drive host inflamma-tory responses (yellow stars) in order to trigger the release of nitrates or oxygen into the lumen of the gut (shaded gradient), and the formation of an oxidative environment. Together with novel metabolites formed by oxidation, such as tetrathionate, O₂ and NO₃ are used in anaerobic and aerobic respiration pathways by pathogens able to use these electron acceptors