The Nexus of Gut Microbiome, Microbial Metabolites, and Colonization Resistance Against Enteric Pathogens

The gut microbiome is a complex ecological system crucial to human physiology. Commensal microbes in the gut provide resistance against pathogenic colonization, mainly due to their metabolites. Though studies have revealed a few mechanisms of microbial metabolite-mediated colonization resistance, various commensal microbes in the gut produce versatile metabolites and confront different pathogens. To pave the way for microbial metabolite-based treatment, clarification of what microbes and derived metabolites contribute to colonization resistance is a central topic. This focused review addressed the nexus of the gut microbiome, microbial metabolites, and colonization resistance against three representative pathogens, namely Clostridioides difficile, Salmonella enterica subspecies enterica serovar Typhimurium, and vancomycin-resistant Enterococcus. Different microbes and microbial metabolites involved in colonization resistance against these pathogens are discussed. Microbial metabolites, mainly short-chain fatty acids, secondary bile acids, and bacteriocins, were included. The emerging role of signal molecules in combating pathogenic infections is also addressed. In contrast to others, we further discussed different strategies that can enhance microbial metabolite-mediated colonization resistance, such as precise microbial preparation, targeted proliferation of a protective metabolite-producing microbiome, regulation of dietary patterns to optimize metabolic homeostasis, enhancing the local concentration of metabolites in the gut, and host-matched intervention.