Microbiota-mediated colonization resistance against intestinal pathogens

Abstract

Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium, Gram-negative Enterobacteriaceae and Clostridium difficile. In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.

Figure 1. Intestinal bacteria confer indirect (immune-mediated) and direct colonization resistance against enteric pathogens

The intestinal microbiota enhances colonization resistance to intestinal pathogens by both direct and indirect (immune-mediated) mechanisms of action. Commensal bacterial species and microbial products (green) protect against infection indirectly by activating immune responses that in turn target pathogenic bacteria (red) (parts a–c); for example, Bacteroides thetaiotaomicron enhances expression of the peptidoglycan-binding C-type lectin regenerating islet-derived protein IIIγ (REGIIIγ), which is an antimicrobial peptide that primarily targets and kills Gram-positive bacteria. Microbial products such as lipopolysaccharide (LPS) and flagellin stimulate Toll-like receptor 4 (TLR4)⁺ stromal cells and TLR5⁺CD103⁺ dendritic cells (DCs) to enhance epithelial expression of REGIIIγ, which impairs colonization by Gram-positive vancomycin-resistant Enterococcus spp. (VRE) (part a). Segmented filamentous bacteria (SFB) closely associate with the intestinal epithelium and enhance IgA production by B cells, serum amyloid A (SAA)-dependent T helper 17 (T_H17) cell differentiation, pro-inflammatory cytokine production and epithelial production of antimicrobial peptides. These processes confer protection against Citrobacter rodentium (part b). Undefined microbial populations and products activate immune defences, including nucleotide-binding oligomerization domain 2 (NOD2)- dependent cryptdin expression by Paneth cells’ myeloid differentiation primary-response protein 88 (MYD88)-dependent production of antimicrobial peptides and extension of transepithelial dendrites by phagocytic DC populations in the lamina propria. These processes enhance resistance to Salmonella enterica subsp. enterica serovar Typhimurium infection (part c). Other bacteria directly inhibit intestinal pathogens by competing for nutrients or by inducing the production of inhibitory substances (parts d–g); for example, B. thetaiotaomicron consumes carbohydrates used by C. rodentium, which contributes to the competitive exclusion of the pathogen from the intestinal lumen (part d). Bacteroides thuringiensis secretes a bacteriocin that directly targets spore-forming Bacilli and Clostridia, including Clostridium difficile, through an unknown mechanism of action (part e). Gram-negative bacteria, such as Vibrio cholerae, deliver toxic effector proteins directly to Escherichia coli through type VI secretion systems (part f). A variety of Bifidobacterium spp. produce organic acids and peptides that impair growth and adhesion of pathogenic E. coli to enterocytes (part g). Some bacterial populations may inhibit colonization by pathogens through a combination of direct and indirect mechanisms (for example, B. thetaiotaomicron (parts a and d)), or may require other bacteria to carry out antagonistic effects, which complicates the identification and the interpretation of bacterial species that enhance colonization resistance. CX₃CR1, CX₃C-chemokine receptor 1; IL, interleukin; ILC, innate lymphoid cell.

Figure 2. Phylogenetic relationships of intestinal bacteria that influence host immunity and colonization resistance to pathogens

Individual bacterial species that influence host immune-mediated and/or direct colonization resistance against antibiotic-resistant intestinal pathogens have been identified among the four phyla that comprise the majority of the intestinal microbiota (that is, Actinobacteria, Firmicutes, Bacteroidetes and Proteobacteria). A phylogenetically diverse group of commensal bacteria can restrain immune responses (blue), which often facilitates the colonization of intestinal niches and sometimes mitigates inflammatory disease such as colitis (blue cells). A distinct but phylogenetically related group of commensal bacteria activate mucosal immune responses (red). A subset of these pro-inflammatory bacteria are associated with the development of colitis (red cells), whereas others enhance immunity to intestinal pathogens (yellow cells). Other commensal bacteria secrete antimicrobial factors or otherwise impair the growth and pathogenesis of intestinal pathogens in vitro, which suggests that these commensal bacteria directly antagonize pathogens (green cells). Additional commensal bacteria inhibit infection with pathogens in vivo, but the dependence of this inhibition on immunity or other host factors remains unclear (purple cells). Reference numbers are indicated in table cells. SFB, segmented filamentous bacteria; VRE, vancomycin-resistant Enterococcus spp.