Taming the Beast: Interplay between Gut Small Molecules and Enteric Pathogens

Abstract

The overuse of antibiotics has led to the evolution of drug-resistant bacteria that are becoming increasingly dangerous to human health. According to the Centers for Disease Control and Prevention, antibiotic-resistant bacteria cause at least 2 million illnesses and 23,000 deaths in the United States annually. Traditionally, antibiotics are bactericidal or bacteriostatic agents that place selective pressure on bacteria, leading to the expansion of antibiotic-resistant strains. In addition, antibiotics that are effective against some pathogens can also exacerbate their pathogenesis and may lead to severe progression of the disease. Therefore, alternative strategies are needed to treat antibiotic-resistant bacterial infections. One novel approach is to target bacterial virulence to prevent or limit pathogen colonization, while also minimizing tissue damage and disease comorbidities in the host. This review focuses on the interactions between enteric pathogens and naturally occurring small molecules in the human gut as potential therapeutic targets for antivirulence strategies. Individual small molecules in the intestines modulate enteric pathogen virulence and subsequent intestinal fitness and colonization. Targeted interruption of pathogen sensing of these small molecules could therefore attenuate their virulence. This review highlights the paths of discovery for new classes of antimicrobials that could potentially mitigate the urgent problem of antibiotic resistance.

Keywords: Clostridium difficile; Escherichia coli; Salmonella; enteropathogens; microbiota.

FIG 1

Dysbiosis is associated with enteric pathogen expansion in the gut. Antibiotic treatment causes the depletion of the gut microbiota and a reduction in microbial metabolites. Opportunistic pathogens like Salmonella and C. difficile thrive in such an environment and cause disease. Acute dietary interventions change the metabolic landscape and help to reduce the pathogen load as well as overall pathogenesis of the disease, leading to restored homeostasis. Commensal bacteria are indicated in green, gut pathogens are indicated in red, and purple dots represent gut small molecules like acetate, butyrate, and propionate.

FIG 2

EHEC senses gut metabolites to regulate gene expression. In the healthy gut, small molecules/metabolites accumulate through microbial/host metabolic processes. These small molecules are present in abundance in the gut and are important for maintaining homeostasis. For successful infection, an intestinal pathogen like EHEC needs to sense these signals to coordinately regulate its gene expression, especially those involved in virulence and colonization. Small molecules in the gut can affect the virulence of enteric pathogens either by directly sensing a cytoplasmic transcription factor (e.g., CutR and EutR for cysteine and ethanolamine, respectively) or by sensing through bacterial two-component systems. Small molecules like epinephrine, norepinephrine, autoinducer-3, and fucose are sensed by histidine kinases like QseC. QseE, and FusK, respectively. These histidine kinases then transmit the message to their cognate response regulators that directly mediate different aspects of bacterial gene expression, including regulation of the virulence gene program.