Potential Use of Biotherapeutic Bacteria to Target Colorectal Cancer-Associated Taxa

Abstract

The role of the gut microbiome in human health and disease is the focus of much attention. It has been widely agreed upon that our gut bacteria play a role in host immunity, nutrient absorption, digestion, metabolism, and other key drivers of health. Furthermore, certain microbial signatures and specific taxa have also been associated with the development of diseases, such as obesity; inflammatory bowel disease; and, indeed, colorectal cancer (CRC), which is the focus of this review. By extension, such taxa represent potential therapeutic targets. In particular, the emerging human pathogen Fusobacterium nucleatum represents an important agent in CRC development and its control within the gastrointestinal tract is desirable. This paper reviews the principal bacterial pathogens that have been associated with CRC to date and discusses the in vitro and human studies that have shown the potential use of biotherapeutic strains as a means of targeting CRC-associated bacteria.

Keywords: Fusobacterium nucleatum; biotherapeutics; colorectal cancer; microbiota; probiotics.

Figure 1

Overview of proposed mechanisms implicating principle CRC-associated bacterial pathogens in CRC development: Specific bacterial species may promote CRC through several mechanisms, such as the secretion of virulence factors by F. nucleatum (FadA) and B. fragilis (BFT), which activate NF-kB and β-catenin signaling pathways, leading to the development of pro-inflammatory cytokines which promotes pro-inflammatory microenvironments. Virulence factors may interfere with E-cadherin, a transmembrane protein essential for maintaining the epithelium cell layer, thus mediating the invasion of pathogenic bacteria. Cyclomodulin and genotoxin-producing E. coli (colibactin) may interfere with natural cellular events and may induce apoptosis. Biofilms predominantly colonized by genotoxin-producing E. coli and BFT-producing B. fragilis may be a synergistic driver of CRC. These events culminate in the development of chronic inflammation and genomic instability, which leads to epithelial cellular proliferation and, ultimately, CRC. This figure was created with BioRender.

Figure 2

Proposed mechanism of action by which probiotic supplementation may decrease the risk of developing colon cancer by inhibiting F. nucleatum through (1) bacteriocin production, (2) competition for nutrients, (3) co-aggregation, and (4) competitive exclusion through biofilm formation. This figure was Created with BioRender.