Microbiota-mediated protection against antibiotic-resistant pathogens

Abstract

Colonization by the microbiota provides one of our most effective barriers against infection by pathogenic microbes. The microbiota protects against infection by priming immune defenses, by metabolic exclusion of pathogens from their preferred niches, and through direct antimicrobial antagonism. Disruption of the microbiota, especially by antibiotics, is a major risk factor for bacterial pathogen colonization. Restoration of the microbiota through microbiota transplantation has been shown to be an effective way to reduce pathogen burden in the intestine but comes with a number of drawbacks, including the possibility of transferring other pathogens into the host, lack of standardization, and potential disruption to host metabolism. More refined methods to exploit the power of the microbiota would allow us to utilize its protective power without the drawbacks of fecal microbiota transplantation. To achieve this requires detailed understanding of which members of the microbiota protect against specific pathogens and the mechanistic basis for their effects. In this review, we will discuss the clinical and experimental evidence that has begun to reveal which members of the microbiota protect against some of the most troublesome antibiotic-resistant pathogens: Klebsiella pneumoniae, vancomycin-resistant enterococci, and Clostridioides difficile.

Fig. 1. Mechanisms of microbiota-mediated colonization resistance against pathogens within the gastrointestinal tract.

Representation of pathways involving components of the immune system and microbiota that help suppress gastrointestinal tract colonization by Clostridioides difficile, Klebsiella pneumoniae, and vancomycin-resistant enterococci (VRE). Suppressive mechanisms involve a variety of important pathways that can be broadly classified into four interconnected categories. Cellular interaction: microbiota activating intestinal epithelia (1) or immune cells (2) induce production of proinflammatory cytokines such as IL-22 and IL-17. These cytokines promote clearance of C. difficile through the regulation of important innate cells such as neutrophils (3). Important phyla such as Bacteroidetes induce the production of IL-36 that promotes macrophage-mediated clearing of K. pneumoniae (4). Antimicrobial production: pattern recognition receptor (PRR) detection of the microbiota induces the production of antimicrobial peptides (AMP) such as REGIIIγ that is protective against VRE (5). Members of the microbiota can also produce their own AMPS such as bacteriocins. For example, Blautia producta produce lantibiotics that inhibit VRE (6). Metabolic: metabolic products from the microbiota, including short-chain fatty acids (SCFA), can be antagonistic to pathogens reducing the fitness of C. difficile and acidifying K. pneumoniae intracellularly (7). Enzymes produced by the microbiota can also metabolize host compounds into products that are disruptive to pathogens. The bile acid taurocholic acid (TCA) is deconjugated by microbiota bile acid hydrolases into cholic acid (CA) and subsequently into deoxycholic acid (DCA) that is inhibitory to C. difficile growth (8). Nutritional immunity: nutrients are limited resources and so utilization by the microbiota diminishes availability to incoming pathogens. IL-22-induced N-glycosylation promotes microbiota that utilize sialic acid and succinate reducing their abundance preventing the expansion of C. difficile (9). Similarly, IL-22 induction of glycan fucosylation promotes anaerobic commensals competing with VRE limiting its expansion (10). These examples demonstrate how the microbiota provide resistance to three pathogens by engaging with a multitude of mechanisms that are antagonistic to the success of the pathogens in the gastrointestinal tract. DC dendritic cell, ILC innate lymphoid cell. Created with BioRender.com.