From Nursery to Nursing Home: Emerging Concepts in Clostridioides difficile Pathogenesis

Abstract

Clostridioides difficile is a Gram-positive, spore-forming, anaerobic bacterium that infects the human gastrointestinal tract, causing a wide range of disorders that vary in severity from mild diarrhea to toxic megacolon and/or death. Over the past decade, incidence, severity, and costs associated with C. difficile infection (CDI) have increased dramatically in both the pediatric and adult populations. The factors driving this rapidly evolving epidemiology remain largely unknown but are likely due in part to previously unappreciated host, microbiota, and environmental factors. In this review, we will cover the risks and challenges of CDI in adult and pediatric populations and examine asymptomatic colonization in infants. We will also discuss the emerging role of diet, pharmaceutical drugs, and pathogen-microbiota interactions in C. difficile pathogenesis, as well as the impact of host-microbiota interactions in the manifestation of C. difficile-associated disease. Finally, we highlight new areas of research and novel strategies that may shed light on this complex infection and provide insights into the future of microbiota-based therapeutics for CDI.

Keywords: Clostridium difficile; infectious disease; microbiota.

FIG 1

Relationship between asymptomatic colonization and disease severity of C. difficile with age. Higher rates of asymptomatic colonization are found in infants and neonates. As the microbiota and immune responses mature throughout development, changes in the bacterial community lead to a drop in colonization rates. In adults, colonization rates are low and increase in the elderly population. This is tightly associated with long-term stays in health facilities. Disease severity is also positively associated with age. While neonates and infants have higher carriage rates, they rarely suffer from infection. Meanwhile, adults and the elderly are the most susceptible population, and this is likely associated with alterations to the microbiota, decreased immune function, and comorbidities.

FIG 2

Factors influencing susceptibility to and severity of C. difficile infection. The factors that act to shape C. difficile susceptibility and infection severity through the tripartite relationship between the host, commensal microbiota, and pathogen are multifactorial. Bystander members of the gut microbiome, as well as their associated metabolites, are known to both positively and negatively modulate C. difficile pathogenesis. This is the basis for the function and activity of fecal microbiota transplant (FMT) as a therapy for C. difficile infection. Dietary factors, which can act directly on C. difficile or mediate interactions through the host, are also known to affect infection severity. Recent studies suggest that common drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) could impact disease progression. Lastly, emerging data suggest that bidirectional transmission of C. difficile strains between humans and animal reservoirs could play an understudied role in C. difficile epidemiology.