The colorectal cancer (CRC) ranks among the top 3 most frequent and deadly cancers in both men and women. Although the gut microbiota plays a pivotal role in maintaining intestinal homeostasis and overall health, recent research suggests its significant involvement in the pathogenesis of CRC. This article explores how the gut microbiota contributes to CRC initiation and progression and discusses current preventive and therapeutic strategies targeting these microbes.
Oncomicrobes as alleged attackers
Our gut fosters a complex community of trillions of microorganisms. Most are friendly and contribute to our good health, through symbiotic relationships. In exchange for shelter and meals, they provide us with useful metabolites and maintain an intense dialogue with many of our cells, notably those of the immune system. However, this win-win interplay can sometimes go off the rails.
Indeed, certain microorganisms have been implicated in CRC initiation. Some bacteria can induce genetic mutations and promote carcinogenesis. For instance, Escherichia coli strains producing colibactin, a genotoxin, can cause DNA damages in host cells, leading to mutations that drive cancer development. Campylobacter jejuni also produces a toxin able to break DNA double strands and trigger tumorigenesis (1). In the same way, Enterococcus faecalis produces a reactive oxygen species which promotes DNA damage and chromosomal instability in epithelial cells of the colon. Increased production of metabolites like hydrogen sulfide by certain bacteria (such as Desulfovibrio spp.) can also damage DNA, disrupt the epithelial barrier and promote inflammation (2). Similarly, Bacteroides fragilis (enterotoxigenic subtype) or Fusobacterium nucleatum promote tumour formation by disrupting E-cadherin-mediated cell adhesion and activating β-catenin signaling pathways. These interactions highlight the direct role of specific “oncomicrobes” in triggering the carcinogenic process. Some of the above mentioned strains are found more abundant in the colonic mucosa of CRC patients than in that of healthy controls (1). Meanwhile beneficial genera such as Lactobacillus, Bifidobacterium and Streptococcus are found depleted (3–5).
The role of less abundant, but biologically active micro-organisms of the gut ecosystem such as archaea, fungi and bacteriophages viruses has also been described. Multi-kingdom interactions remain to be deciphered. For example, the Human Papillomavirus, better known for its role in cervix cancer, is also pointed out in colorectal tumorigenesis, parts of its genome being able to integrate the host DNA of mucosal cells. Other pathogens, such as Epstein–Barr virus, John Cunningham virus, Human Cytomegalovirus, and hepatitis B and C viruses, are also suspected to initiate or promote CRC through various pathways (1).
Some microbes help the tumour progress, other are in the defensive ranks
Beyond initiation, the gut microbiota influences CRC progression through various mechanisms. In particular, chronic inflammation creates a microenvironment conducive to tumour growth. F. nucleatum, commonly enriched in CRC tissues, can exacerbate inflammation by recruiting tumour-infiltrating immune cells, thereby facilitating cancer progression (3) but also tumour virulence and ability to produce metastases. Therefore, F. nucleatum would be both a risk factor of CRC and a biomarker of CRC progression, as well as a bad prognostic factor for long-term survival (1). The lipopolysaccharide (LPS) present on the membrane of gram-negative bacteria promotes the production of pro-inflammatory cytokines by epithelial cells and limits the action of antitumorigenic immune cells of the host. Other bacteria, such as E. faecalis, Streptococcus gallolyticus, Helicobacter pylori or Clostridium septicum are also suspected of playing the tumour game against the human host (1).
Conversely, preventative action of many microbes against CRC appear to rely on three main mechanisms: induction of apoptosis and inhibition of proliferation of tumoral cells; upregulation of the host immune system, notably via the stimulation of CD8+ T cells and the limitation of proinflammatory cytokines production; synergistic interactions counteracting the gut dysbiosis and pro-carcinogenic microbes. Short-chain fatty acids (SCFAs), such as butyrate, could reduce the risk of CRC by maintaining mucosal integrity and limiting colonic inflammation. However, a low-fibre diet can reduce SCFA-producing bacteria, diminishing these protective effects (2).
Be careful, however, about drawing definitive conclusions, as the role of each microbe remains difficult to decipher. In particular, the mode of sampling gut microbiota is a huge issue to have a clear picture of what’s happening. Faecal samples are easy to collect, but represent the lumen-associated microbiota. Biopsies obtained during colonoscopy, or swabs, brushes or washing aspirates, represent the mucosal-associated microbiota, more likely to depict the microbes present at the tumour site, but their collection is invasive and samples are more likely to be contaminated by host cells, which complexify the sequencing by shot-gun metagenomics. The role of a specific bacteria could depend on its location. For example, Akkermansia muciniphila is less abundant in gut microbiota of severe CRC than in controls, suggesting a protective action. However, it is quite abundant in tumour tissue, and is suspected to help it outwit the immune system and promote tumour survival (5). Hydrogen sulfide can be locally toxic at high concentrations, but may also be protective for the mucosal barrier at lower levels (6).
Divert microbial strategies for preventive and therapeutic purposes
Understanding the microbiota’s role in CRC open the way towards various preventive or therapeutic strategies.
– Diet profoundly influences gut microbiota composition. High-fibre diets enhance the growth of beneficial SCFA-producing bacteria, which exert protective effects against CRC. Conversely, diets high in red and processed meats can promote the growth of harmful bacteria linked to increased cancer risk.
– Beneficial bacteria (probiotics), compounds that promote their growth (prebiotics) or components derived from them (postbiotics) could be defensive allies to reinforce the gut barrier, reduce inflammation, and suppress tumour-promoting bacteria. Strategies based on the consumption of bacteria known to be depleted in the gut of CRC patients is currently explored, to reorientate the microbiota composition towards that of healthy subjects. Some bacteria or fungi are also under investigation as adjuvant to
chemotherapies for their capacity to boost antiproliferative properties, to overcome chemoresistance or to help restore the damaged gut flora. Some strains may also boost response to immunotherapies. However, although in vitro or animal data are encouraging, the effectiveness of these treatments in humans remains to be proven (7).
– Faecal Microbiota Transplantation involves transferring stool from a donor to a recipient, in the hope of improving their chances of responding to anti-cancer treatments. Indeed, as observed for live biotherapeutic products made of one or several microbes, preliminary studies suggest that FMT can modulate the tumour microenvironment and enhance responses to immunotherapy based on immune check-point inhibitors, via a better activation of CD8+ T cells and dendritic cells. However more research is needed to establish its efficacy and safety (8).
– Selective antibiotics can reduce or eliminate specific pathogenic bacteria implicated in CRC. However, this approach must be carefully managed to avoid disrupting beneficial microbes and to prevent antibiotic resistance (1).
– The causative role of bacteria and viruses in CRC initiation and progression, their overrepresentation in the tumour microenvironment, suggests that vaccines targeting well-selected microbial antigens could help immune cells fight cancer. However, this promising perspective is still in its infancy (1).
Conclusion
There is growing evidence that the gut microbiota plays a multifaceted role in the development and progression of CRC. Therefore, targeting microbial composition and function presents promising avenues for prevention and treatment. Future research could shift towards personalized interventions that considering individual microbiota profiles to optimize therapeutic outcomes. However, there is still much to decipher in the complex relationship between host and microbes.
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