Risk factors and outcomes of Clostridioides difficile infection in patients with colorectal cancer: critical perspective in management

Abstract

Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide, causing a serious threat to global health and social burden. Clostridioides difficile infection (CDI) is one of the most important nosocomial infections and has a higher incidence in cancerous population compared with non-cancerous cases. Different risk factors, including gut microbiota dysbiosis, extensive surgery, chemotherapy, prolonged hospitalization, and antimicrobial therapy, compromise host defenses against CDI and contribute to cancer patients' susceptibility to this infection. The emergence of CDI in patients with CRC creates conditions for therapy escalation and prolonged hospitalization, highlighting the need for correct and effective CDI management in these patients. Here, common risk factors associated with CDI in patients with CRC are discussed. In addition, different available techniques for the prevention, detection, and treatment of CDI with the lowest impact on gut microbiota diversity are summarized. This review aims to improve the understanding of the interplay between CDI and CRC and provide new insights into restoring and maintaining gut microbiota balance during CDI management in patients with CRC.

Keywords: Clostridioides difficile infection; Colorectal cancer; Diagnosis; Gut microbiota; Treatment.

Fig. 1

Schematic representation of the composition of the gut microbiota in healthy and disease states. A A healthy gut microbiota is composed by a high taxonomic diversity of bacterial species, helping the maintenance of gut homeostasis. B In CRC patients, a dysbiotic gut is caused by various factors, such as antibiotic therapy and chemotherapy, resulting in the enrichment of pathobionts, such as F. nucleatum, enterotoxigenic B. fragilis, C. difficile, and E. coli. These bacteria induce DNA damage and activate different antigen-presenting cells (APCs), including macrophages, DCs, neutrophils, and T cells, which produce pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-23, and TNF-α), and signaling pathways related to inflammation and cancer progression, such as the NF-κB and Wnt/β-catenin signaling pathway. Activation of these signaling pathways and DNA damage contribute to tumorigenesis. C Gut microbiota dysbiosis increases the susceptibility to C. difficile. The adherence of C. difficile to intestinal epithelium activates APCs increases levels of cytokines, such asIL-6, IL-8, and TNFα, and contributes to neutrophil influx, which determine pseudomembrane formation, that characterizes C. difficile colitis. In addition, internalization of toxin TcdA and toxin TcdB activate signaling pathways related to inflammation and the release of inflammatory cytokines. TcdB may also play a role in tumorigenesis through activating Wnt/β-catenin signaling. APCs antigen-presenting cells; BFT Bacteroides fragilis toxin; B. fragilis, Bacteroides fragilis; C. difficile, Clostridioides difficile; CDI, Clostridioides difficile infection; CRC, colorectal cancer; DCs dendritic cells, IL interleukin; E. coli, Escherichia coli; F. nucleatum, Fusobacterium nucleatum, NF-κB nuclear factor κB, TcdA toxin A, TcdB, toxin B, TNF-α tumor necrosis factor alpha, Wnt wingless-related integration site

Fig. 2

Schematic representation of gut microbiota modulation using probiotic therapy or FMT. The gut microbiota of patients with CRC or CDI have low bacterial diversity, which leads to a decrease in beneficial bacterial metabolites such as SCFAs and an increase in drug-resistant bacterial strains. This state can elevate the inflammation, tumorigenesis, and overgrowth of opportunistic bacteria like C. difficile. Restoring gut microbiota using probiotic administration or FMT helps increase in diversity of bacterial species, resulting in improving the balance of microbiota and mucosal barriers and restoring gut homeostasis. In addition, modulation of gut microbiota can increase the antitumor activity and efficacy of immunotherapy. CDI Clostridioides difficile infection, CRC colorectal cancer, SCFAs short-chain fatty acid, FMT fecal microbiota transplant