Microbiota and pathogen 'pas de deux': setting up and breaking down barriers to intestinal infection

Abstract

The gut microbiota plays essential roles in human health and disease. In this review, we focus on the role of the intestinal microbiota in promoting resistance to infection by bacterial pathogens as well as how pathogens overcome this barrier. We discuss how the resident microbiota restricts growth and colonization of invading pathogens by limiting availability of nutrients and through generation of a hostile environment. Additionally, we examine how microbiota-derived signaling molecules interfere with bacterial virulence. In turn, we discuss how pathogens exploit non-competitive metabolites to replicate in vivo as well as to precisely control virulence and cause disease. This bacterial two step of creating and overcoming challenges important in preventing and establishing infection highlights the complexities of elucidating interactions between the commensal bacteria and pathogens. Better understanding of microbiota-pathogen interplay will have significant implications for developing novel therapeutics to treat infectious diseases.

Keywords: competition; metabolites; microbiota; pathogens; signaling; virulence.

Figure 1.

Relative proportions of the microbiota in the gastrointestinal tract. Bacteroidetes and Firmicutes are the most abundant phyla in the gut. Proteobacteria and Actinobacteria species are also frequently represented, but at lower numbers. Relative proportions are compiled as a summary of measurements, and do not represent exact numbers.

Figure 2.

Shifts in the composition of the microbiota allow for pathogen invasion. Diversity in the composition of the microbiota is protective against infection. A loss of diversity, such as that which occurs after antibiotic use, opens up a niche for pathogens to establish infection.

Figure 3.

Microbiota-derived molecules prevent colonization by pathogens. The microbiota produces molecules that contribute to colonization resistance. (A) Members of the microbiota consume complex polysaccharides and produce SCFAs, which prevent proliferation of and colonization by pathogens. (B) The QS molecule, autoinducer-2 (AI-2), helps the microbiota colonize the gut, which also prevents colonization by pathogens. Additionally, AI-2 negatively affects virulence gene regulation.

Figure 4.

Pathogens exploit microbiota-generated metabolites. Bacteroides thetaiotaomicron cleaves host mucin producing monosaccharides, including fucose and sialic acid. (A) Normally, the commensal bacteria consume these nutrients, preventing their consumption by pathogens. (B) If the microbiota is depleted or disturbed, such as after antibiotic use, pathogens are able to utilize these nutrients to establish infection. (C) Pathogens, such as Salmonella, take advantage of molecules generated by the host inflammatory response. Salmonella induces inflammation, which leads to the production of superoxide (O₂⁻) and iNOS, which in turn lead to the formation of tetrathionate (S₄O₆²⁻) and nitrate (NO₃⁻), respectively. Salmonella utilizes tetrathionate and nitrate as electron acceptors during anaerobic respiration.

Figure 5.

Pathogens utilize host- and microbiota-derived molecules to regulate virulence gene expression. Pathogens sense different molecules within different niches of the GI tract (i.e. lumen and mucus layer), and either increase or decrease expression of virulence genes in response. For example, EHEC senses fucose in the lumen of the colon, which inhibits expression of the T3SS, preventing unnecessary expression of virulence genes in the wrong intestinal location. SCFAs in the lumen enhance expression of flagella and motility. In contrast, EHEC senses other metabolites near the epithelial layer, including succinate and the SCFA butyrate, which induce expression of the T3SS and the formation of AE lesions on host epithelial cells. Additionally, the metabolite ethanolamine, a component of host and bacterial cell membranes, induces expression of the T3SS.