The gut microbiota: a new potent tool against colorectal cancer.

The gut microbiota is composed of 30 trillion (30.000.000.000.000) living bacteria and other microorganisms in the intestine. The gut microorganisms actively interact with the host. On one side, some bacteria of the gut microbiota have shown anti-cancer activity. On the other side, alteration of the equilibrium between gut microbiota and the host (a condition called “dysbiosis”) contributes to cancer initiation. An imbalanced gut microbial composition has been found in colorectal cancer patients. Indeed, fecal samples from colorectal cancer patients show low bacterial diversity compared to healthy individuals, in particular with specific types of bacteria being more or less present; this may affect the immune system response, impairing immune surveillance and thus promoting tumor development. Interestingly, transplant of gut microbiota from colorectal cancer patients into mice is sufficient to cause inflammation and dysbiosis.

Several factors are known to be involved in the onset of colorectal cancer –among these, diet, sedentary lifestyle, smoking and alcohol intake– and gut microbiota might likely be the connecting link between such risk factors and colorectal cancer development. In particular, the World Cancer Research Foundation considers diet one of the most important exogenous factors in colorectal cancer development; hence, dietary modifications are being increasingly used to flank conventional cancer therapy as, on one side, altering nutrient availability, they change the metabolic activity of cancer cells, ultimately affecting drug sensitivity and cell proliferation; on the other side, they affect the composition of the gut microbiota, which in turn has an impact on cancer metabolism, drug sensitivity and cell proliferation.

The composition of the gut microbiota is also affected by other factors. For instance, gut microbiota is influenced by anti-cancer therapy and in turn affects therapy outcome. Indeed, on one hand, chemotherapy creates dysbiosis, enhancing the effect of deleterious bacteria and thus resulting into reduced efficacy and increased toxicity of cancer therapy; on the other hand, specific bacteria of the gut microbiota play a role in chemoresistance.

Furthermore, the gut microbiota affects the immune system, promoting a stronger immune surveillance against tumor cell growth, thus affecting efficacy of immunotherapy. For instance, distinct types of bacteria were enriched in patients who responded to immunotherapy treatment, while other bacteria types were enriched in patients who did not respond to treatment.

That said, is it possible, in a clinical setting, to modulate gut microbiota in order to manage or even prevent colorectal cancer development? In his regard, several approaches have been tested, including dietary interventions, which show an increased risk of colorectal cancer under the so-called western diet (high fat) and a reduced risk under a grain-based diet or upon vitamin D supplementation. Similarly, altering gut microbiota by reduced calorie intake showed to be beneficial in preventing cancer and increasing therapy effect. Antibiotic treatment, selectively reducing specific damaging bacteria, has been shown to ultimately reduce cancer progression, even though being an aggressive means of gut microbiota manipulation may create further dysbiosis and somehow reduce immunotherapy efficacy. The use of probiotics (living microorganisms positively affecting the microbiota and in general the immune system), prebiotics (compounds that stimulate growth and activity of probiotics) and postbiotics (chemical compounds of microbial origin, including short chain fatty acids –shown to suppress inflammation–, enzymes, peptides, cell surface proteins, vitamins) have also been considered as potential strategy in cancer prevention and management.

Finally, fecal microbiota transplantation (namely the transfer of fecal bacteria and other microbes) from a healthy donor into a patient –explored as a therapeutic strategy in different pathological contexts– has shown promising results in animal models, restoring the normal gut microbiota, reducing tumor growth and inflammation, and is being considered also as a possible approach for the treatment of dysbiosis in colorectal cancer patients. However, as the impact of the fecal microbiota transplantation on the recipient immune system is unpredictable, the risk of infection due to dissemination in the body of unknown pathogens should be carefully considered.

Although the effects of gut microbiota modulation have been largely described, the underlying mechanisms are still being explored and a more complete understanding may be of great help in potentiating the effect of cancer therapies.

Reference: Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes. Perillo, Amoroso, Strati , Giuffrè, Díaz-Basabe, Lattanzi, Facciotti. Int J Mol Sci 2020.