Pathogen Colonization Resistance in the Gut and Its Manipulation for Improved Health

Abstract

Mammals have coevolved with a large community of symbiotic, commensal, and some potentially pathogenic microbes. The trillions of bacteria and hundreds of species in our guts form a relatively stable community that resists invasion by outsiders, including pathogens. This powerful protective force is referred to as colonization resistance. We discuss the variety of proposed or demonstrated mechanisms that can mediate colonization resistance and some potential ways to manipulate them for improved human health. Instances in which certain bacterial pathogens can overcome colonization resistance are also discussed.

Figure 1

Direct mechanisms. Anaerobic symbionts (top left) digest host mucus and dietary polysaccharides, releasing monosaccharides for another symbiont to take up, excreting short-chain fatty acids (SCFAs), and acidifying the environment, which suppresses growth of a pathogen. Bacteria deconjugate bile acids (top right), and others produce 7α-dehydroxylases that convert them to secondary bile acids, which also inhibit the pathogen. A symbiont produces bacteriocins (green), which form pores in the pathogen, allowing leakage of cellular contents (gray). Symbionts could also theoretically target pathogens with contact-dependent mechanisms, like the type 6 secretion system (T6SS; blue) or contact-dependent inhibition (CDI; red).

Figure 2

Indirect mechanisms. Dimeric IgA, produced by a B cell in the lamina propria, is transcytosed by the poly-Ig receptor into the lumen, where it binds a bacterium's flagella. Farnesoid X receptor (FXR) and TGR5 on epithelial cells and macrophages up-regulate defenses or modulate inflammation, respectively, in response to bile acids. The short-chain fatty acid butyrate, produced by anaerobic Clostridia, promotes oxygen respiration in an epithelial cell, reducing the oxygen concentration at the epithelial surface. Toll-like receptors (TLRs) on epithelial cells, macrophages, and dendritic cells (DCs) can sense microbial molecules and signal through myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) adaptors. Macrophages make IL-1β and DCs make IL-23 cytokines in response to TLR stimulation, which induces type 17 helper T cells (Th17s) and innate-like lymphocytes (ILCs) to secrete IL-22. This acts on epithelial cells, causing them to produce regenerating islet-derived protein 3β (Reg3β) (red) and lipocalin-2 (green), which attack a pathogen in the lumen and sequester iron (red circles) from it, respectively. On the right side, protective symbionts, like Clostridia, have been depleted (eg, by antibiotics), resulting in increased oxygen in the lumen. Salmonella enterica serovar Typhimurium (S. typhimurium) is resistant to Reg3β and can capture iron from lipocalin-2. Meanwhile Citrobacter rodentium uses its type 3 secretion system to inject effectors into an epithelial cell and cause hyperplasia, further increasing oxygen levels and supporting its replication.