Microbe-Based Management for Colorectal Cancer

Microbe-Based Management for Colorectal Cancer

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking second in cancer-related deaths in the United States. In 2018, CRC accounted for 10.9% of new cancer cases in males and 9.5% in females. The incidence and mortality of CRC have been increasing, particularly in economically transitioning countries. In China, CRC is a leading cancer, with new cases and deaths rising significantly from 2015 to 2020. The development of CRC is influenced by both hereditary and environmental factors, including overweight, obesity, Western dietary habits, smoking, and heavy alcohol consumption. These factors not only increase the risk of CRC but also alter the gut microbiome, which plays a crucial role in CRC pathogenesis.

The human intestinal tract harbors a vast and diverse microbiota that contributes to both physiological and pathological functions. The gut microbiota interacts with the host immune system, and dysbiosis—an imbalance in the microbial community—can lead to chronic inflammation, DNA damage, and abnormal metabolites, all of which are implicated in CRC development. Pathogenic bacteria such as enterotoxigenic Bacteroides fragilis (ETBF), Fusobacterium nucleatum, and Streptococcus gallolyticus have been identified as contributors to CRC. Conversely, beneficial bacteria like Akkermansia muciniphila and butyrate-producing bacteria have shown protective effects against CRC. The modulation of gut microbiota through probiotics, prebiotics, postbiotics, fecal microbiota transplantation (FMT), and dietary interventions has emerged as a novel approach for CRC prevention and treatment.

Mechanisms of Bacteria-Induced Colorectal Carcinogenesis

The pathogenic mechanisms by which bacteria contribute to CRC involve several pathways, including chronic inflammation, genotoxin production, and metabolic alterations. Chronic inflammation is a well-known driver of cancer, and certain bacteria can induce an inflammatory environment that promotes tumorigenesis. For example, ETBF produces B. fragilis toxin (BFT), which disrupts the intestinal barrier, activates the STAT3 pathway, and induces the production of pro-inflammatory cytokines such as IL-17 and IL-6. This inflammatory cascade promotes CRC proliferation. Similarly, Fusobacterium nucleatum, which is enriched in CRC tissues, recruits tumor-infiltrating myeloid cells and activates Toll-like receptor 4 (TLR4) signaling, leading to the upregulation of NF-kB and miR-21, both of which are involved in chronic inflammation and tumorigenesis.

Genotoxins produced by certain bacteria can directly damage host DNA, leading to mutations and cancer. Escherichia coli strains carrying the pks island produce colibactin, a genotoxin that induces DNA double-strand breaks and promotes tumor growth. Peptostreptococcus anaerobius, another CRC-associated bacterium, produces reactive oxidative species (ROS) that stimulate cholesterol biosynthesis and contribute to tumorigenesis. Additionally, dysbiosis can lead to the accumulation of abnormal metabolites, such as secondary bile acids, which have been linked to CRC development.

Protective Bacteria and Their Anticancer Mechanisms

While pathogenic bacteria promote CRC, certain beneficial bacteria have been shown to exert protective effects. Akkermansia muciniphila, a mucin-degrading bacterium, has anti-inflammatory properties and can suppress tumor growth. It modulates the immune system by activating M1-like macrophages and enhancing the efficacy of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. Another beneficial bacterium, Clostridium butyricum, produces butyrate, a short-chain fatty acid (SCFA) that inhibits tumor growth by regulating the Wnt/b-catenin signaling pathway and promoting the growth of other SCFA-producing bacteria.

Probiotics, defined as live microorganisms that confer health benefits when administered in adequate amounts, have shown promise in CRC prevention and treatment. Lactobacillus rhamnosus GG, for example, promotes anti-inflammatory responses and exerts antitumor effects by increasing the abundance of CD8+ T cells. Similarly, Streptococcus thermophilus, a probiotic used in dairy products, produces β-galactosidase, which reduces colon tumorigenesis in mouse models.

Microbe-Based Management Strategies for CRC

Probiotics

Probiotics are widely used to treat various diseases, including CRC. They interact with host cells and other gut microbiota to restore intestinal microbial balance, enhance the intestinal barrier, and modulate the immune system. Probiotics can inhibit the proliferation of cancer cells, regulate immune responses, and reduce the activity of pathogenic bacterial enzymes. For example, Clostridium butyricum and Bacillus subtilis have been shown to inhibit CRC cell growth, induce cell cycle arrest, and promote apoptosis in mouse models.

Prebiotics and Postbiotics

Prebiotics are substrates that selectively stimulate the growth of beneficial gut microbiota. Dietary fibers, such as those found in fruits, vegetables, and whole grains, are common prebiotics that promote the growth of SCFA-producing bacteria. Gynostemma pentaphyllum saponins (GpS), a dietary herbal medicine, has prebiotic properties that reduce polyps in mouse models and promote the growth of Bifidobacterium animalis, which suppresses CRC development.

Postbiotics are soluble factors secreted by live bacteria or released after bacterial lysis. They include inactivated microbial cells, cell fractions, and metabolites such as SCFAs. Butyrate, the most studied SCFA, has strong anticancer properties and regulates signaling pathways involved in CRC development. Postbiotics can induce apoptosis of CRC cells, prevent pathogen translocation, and modulate immune activity to fight inflammation.

Fecal Microbiota Transplantation (FMT)

FMT involves the transfer of fecal microbiota from a healthy donor to a recipient to restore gut microbial balance. FMT has shown potential in treating CRC by reprogramming the gut microbiota composition. For example, FMT from CRC patients has been shown to promote tumorigenesis in mouse models, while FMT from CRC survivors who consume rice bran daily reduces tumorigenesis. FMT can also modulate the efficacy of chemotherapy and immunotherapy by altering the gut microbiota.

Dietary Interventions

Diet plays a crucial role in shaping the gut microbiota and influencing CRC risk. High-fiber diets, which promote the growth of SCFA-producing bacteria, are associated with a reduced risk of CRC. In contrast, high-fat and low-fiber diets, such as the Western diet, are linked to an increased risk of CRC and disease recurrence after surgery. Dietary interventions, including the consumption of traditional Chinese medicine (TCM) like curcumin and berberine, have shown promise in modulating the gut microbiota and preventing CRC.

Conclusion

The gut microbiota plays a critical role in the development and progression of CRC. Pathogenic bacteria such as ETBF, Fusobacterium nucleatum, and Escherichia coli contribute to CRC through chronic inflammation, genotoxin production, and metabolic alterations. Conversely, beneficial bacteria like Akkermansia muciniphila and Clostridium butyricum exert protective effects by modulating the immune system and producing anticancer metabolites. Microbe-based management strategies, including probiotics, prebiotics, postbiotics, FMT, and dietary interventions, offer promising approaches for CRC prevention and treatment. Further research is needed to translate these findings into clinical applications and to explore the potential of combining microbiota modulation with conventional therapies for CRC management.

doi.org/10.1097/CM9.0000000000001887

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