Genomic Delineation of Zoonotic Origins of Clostridium difficile

Abstract

Clostridium difficile is toxin-producing antimicrobial resistant (AMR) enteropathogen historically associated with diarrhea and pseudomembranous colitis in hospitalized patients. In recent years, there have been dramatic increases in the incidence and severity of C. difficile infection (CDI), and associated morbidity and mortality, in both healthcare and community settings. C. difficile is an ancient and diverse species that displays a sympatric lifestyle, establishing itself in a range of ecological niches external to the healthcare system. These sources/reservoirs include food, water, soil, and over a dozen animal species, in particular, livestock such as pigs and cattle. In a manner analogous to human infection, excessive antimicrobial exposure, particularly to cephalosporins, is driving the expansion of C. difficile in livestock populations worldwide. Subsequent spore contamination of meat, vegetables grown in soil containing animal feces, agricultural by-products such as compost and manure, and the environment in general (households, lawns, and public spaces) is contributing to a persistent community source/reservoir of C. difficile and the insidious rise of CDI in the community. The whole-genome sequencing era continues to redefine our view of this complex pathogen. The application of high-resolution microbial genomics in a One Health framework (encompassing clinical, veterinary, and environment derived datasets) is the optimal paradigm for advancing our understanding of CDI in humans and animals. This approach has begun to yield critical insights into the genetic diversity, evolution, AMR, and zoonotic potential of C. difficile . In Europe, North America, and Australia, microevolutionary analysis of the C. difficile core genome shows strains common to humans and animals (livestock or companion animals) do not form distinct populations but share a recent evolutionary history. Moreover, for C. difficile sequence type 11 and PCR ribotypes 078 and 014, major lineages of One Health importance, this approach has substantiated inter-species clonal transmission between animals and humans. These findings indicate either a zoonosis or anthroponosis. Moreover, they challenge the existing paradigm and the long-held misconception that CDI is primarily a healthcare-associated infection. In this article, evolutionary, and zoonotic aspects of CDI are discussed, including the anthropomorphic factors that contribute to the spread of C. difficile from the farm to the community.

A publicly accessible database for Clostridioides difficile genome sequences supports tracing of transmission chains and epidemics

“…S7). At least some of this enormous diversity may be due to the occupation of multiple, distinct ecological niches, as exemplified by differential propensities for colonizing non-human host species () [43, 44]. Individual CCs may also differ in their aptitudes for epidemic spread, as indicated by drastically different proportions of genomes assigned to HC2 chains: only 7% of CC141 were assigned to HC2 clusters versus 35% of CC34 and 77% of CC4 ().…”

Clostridium difficile in soil conditioners, mulches and garden mixes with evidence of a clonal relationship with historical food and clinical isolates

“…One possible source of C. difficile acquisition in the community is exposure to composted products during gardening and/or farming as composted products frequently contain animal manure (USDA Organic Composting Guidelines, 2017) and dewatered human biosolids from wastewater treatment plants (Xu et al ., 2016). With the widespread use of antimicrobials in large‐scale animal farms, production animals have become amplification hosts for C. difficile (Knight and Riley, 2019). Several studies have also demonstrated a high prevalence of C. difficile in raw and treated wastewater (Romano et al ., 2012; Xu et al ., 2014), human biosolids (Xu et al ., 2014) and in rivers that received the treated wastewater (Xu et al ., 2014).…”

Comparative genomics of Clostridioides difficile toxinotypes identifies module-based toxin gene evolution

“…Toxinotypes are therefore important from clinical, diagnostic, research and development perspectives. However, so far, only a few toxinotype representatives have been included in comparative genomic studies, performed either for epidemiological purposes [14][15][16][17] or for understanding virulence [18][19][20]. In addition, the evolution of the PaLoc was previously investigated with respect to the known population structure of the species, but in these reports not all known PaLoc variants, as defined by toxinotype, were included [21][22][23][24].…”