The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens

Abstract

The human gastrointestinal tract hosts a diverse network of microorganisms, collectively known as the microbiota that plays an important role in health and disease. For instance, the intestinal microbiota can prevent invading microbes from colonizing the gastrointestinal tract, a phenomenon known as colonization resistance. Perturbations to the microbiota, such as antibiotic administration, can alter microbial composition and result in the loss of colonization resistance. Consequently, the host may be rendered susceptible to colonization by a pathogen. This is a particularly relevant concern in the hospital setting, where antibiotic use and antibiotic-resistant pathogen exposure are more frequent. Many nosocomial infections arise from gastrointestinal colonization. Due to their resistance to antibiotics, treatment is often very challenging. However, recent studies have demonstrated that manipulating the commensal microbiota can prevent and treat various infections in the intestine. In this review, we discuss the members of the microbiota, as well as the mechanisms, that govern colonization resistance against specific pathogens. We also review the effects of antibiotics on the microbiota, as well as the unique epidemiology of immunocompromised patients that renders them a particularly high-risk population to intestinal nosocomial infections.

Keywords: antibiotic; colonization resistance; gut; infection; microbiota.

FIGURE 1

The intestinal microbiota mediates colonization resistance against pathogens by both direct and indirect mechanisms of action. Commensal bacterial species and their products interact with host factors to provide indirect colonization resistance by producing antimicrobial peptides, maintaining the epithelial barrier, and modulating bile acids (A-C). Regenerating islet-derived protein IIIγ (RegIIIγ) and angiogenin-4 (ANG4) are antimicrobial proteins produced by the host that are regulated by the microbiota (A). The microbiota can enhance expression of RegIIIγ by stimulating Toll-like receptors (TLRs). Lipopolysaccharide (LPS) stimulates TLR-4, most likely on intestinal epithelial cells, which results n RegIIIγ production by Paneth cells. Flagellin stimulates TLR-5 on TLR5⁺CD103⁺ dendritic cells (DCs), and the TLR-7 agonist resiquimod (R484) stimulates TLR-7 on TLR7⁺CD11c⁺ DCs. Activated DCs release IL-23 that stimulates group 3 innate lymphoid cells (ILC3) to secrete IL-22, which subsequently results in Paneth cells producing RegIIIγ. The microbial metabolite, taurine, can signal though an inflammasome complex n the intestinal epithelial cell. The inflammasome contains the nucleotide-binding oligomerization domain (NOD), leucine-rich-repeat (LRR)-containing protein (NLR) family member NLRP6, and caspase-1. Signaling through the inflammasome results in the downstream production of proinflammatory cytokines including IL-18. IL-18 enhances the production of antimicrobial peptides, including ANG4. Certain commensal bacteria, like Clostridium scindens, can dehydroxylate primary bile acids into secondary bile acids using the enzyme 7α-hydroxysteroid deyhydrogenase, which inhibits the vegetative growth of C. difficile (B). The microbiota also maintains the epithelial barrier by inducing mucus production, and transcriptional activation of the nuclear factor-κB (NF-κB) within epithelial cells to delay apoptosis and repair tissue. Pathogens are restricted at sites of epithelial damage by the epithelial cell’s downstream expression of the chemokine CXCL1 that recruits neutrophils, as well as expression of IL-12 that activates ILC1s to release IFNγ for phagocyte recruitment (C). Direct mechanisms of colonization resistance include bacteriocin production, nutrient depletion, and type VI secretion systems (D-F). Several commensal bacteria have been identified to produce bacteriocins with a narrow spectrum of activity that inhibit specific pathogens with minimal impact to the indigenous microbiota (D). Additionally, the microbiota competes with pathogens for various nutrients, including dietary and host-derived carbohydrates, as well as microbial metabolites like succinate, which drives a reduction in pathogen colonization (E). Gram-negative bacteria in the microbiota, like the Bacteroidales order, can deliver toxins to pathogens in a contact-dependent manner via the type VI secretion system. IL, interleukin