The relevance of the gut microbiota in cancer development, treatment, and clinical outcomes is an emerging area of translational research that could open up new avenues for cancer treatment.
The gut microbiota exerts immunomodulatory and antitumor roles in cancer, and gut microbial dysregulation can induce the release of toxic metabolites and exhibit pro-tumor effects in the host. The gut microbiota also regulates the efficacy of standard chemotherapy drugs and natural anti-cancer drugs.
This article lists five common cancers (colorectal, lung, breast, prostate, and gastric cancers) and the complex role of the gut microbiota in cancer.
Overview of the relationship between gut microbiota and cancer pathogenesis
Before moving on to the specific chapters on the 5 types of cancer, let's first understand the relationship between the microbiota and cancer. Some researchers divide the relationship between the microbiota and cancer into three levels: primary, secondary, and tertiary interactions.
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Primary, secondary, and tertiary interactions of the microbiota with the tumor microenvironment
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Primary Interaction (Primary)
The main interaction takes into account the direct link between the tumor microenvironment and the microbiota. Several in vivo and in vitro studies have supported this relationship in two main ways:
a) The gut microbiota can cause carcinogenesis through biological dysregulation
b) Gut microbes can interfere with the efficacy of chemotherapy drugs by modulating tumor activity
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Secondary Interactions (Secondary)
Secondary interactions consider the link between the microbiota of tissues or organ systems and tumors within the same gross division. This level of interaction helps identify potential biomarkers for screening for different cancer types. In particular, secondary microbiota from the local tissue or organ environment can contain traces from the tumor microenvironment and primary microbial communities, which can be used as biomarkers for cancer; But these diagnostic processes are often complex.
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Three-level interaction
Tertiary interactions between gut microbiota and tumors explain the effects of microbiota on tumors located at different sites in the body. The study of this level of interaction is important for determining the relationship between physiologically distant microbial species and tumors of interest, which also has clinical relevance for determining the efficacy of potential treatment options in cancer patients.
These tertiary interactions can affect cancer in the following ways:
- Regulates the efficacy and toxicity of chemotherapy
- Modify the immune system
- Production of metabolites that regulate hormone or host metabolism (said metabolites can influence cancer phenotype and/or outcomes)
The gut microbiota can regulate oral drug metabolism by initiating metabolic processes, including hydrolysis and reduction, which directly affects drug toxicity and can enhance or inhibit drug activity. The tertiary interaction between the microbiota and the tumor can also help diagnose different types of cancer.
Pro-tumor, anti-tumor, and immunomodulatory effects of the gut microbiota
Understanding these interactions facilitates the understanding of cancers described in later sections. Here are 5 common cancers and how they relate to the microbiome.
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Five common cancers and their relationship to the microbiota
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Colorectal cancer
Among the various cancers associated with the gut microbiota, colorectal cancer has been the most extensively studied to date, and there is a strong correlation between the gut microbiota and disease progression.
dysbiosis and carcinogenesis
The presence of dysbiosis in colorectal cancer patients implies its potential role in the development of colorectal cancer. Colorectal cancer is directly related to dietary factors and lifestyle, which alter the unique intestinal flora of humans.
Colorectal cancer occurs through a variety of mechanisms such as inflammation, activation of carcinogens, tumorigenic pathways, and alteration/destruction of host DNA.
Bacteria that have carcinogenic effects on colorectal cancer
已经确定了肠道微生物群中的几种菌，这些细菌除了它们的致病性之外，还被假设对结肠直肠癌具有致癌作用(主要是通过初级相互作用)，包括幽门螺杆菌、肝螺杆菌Helicobacter hepaticus、牛链球菌Streptococcus bovis、大肠杆菌、脆弱拟杆菌B. fragilis、败血梭菌Clostridium septicum、粪肠球菌Enterococcus faecalis、具核梭杆菌F. nucleatum、厌氧消化球菌Peptostreptococcus anaerobius和牙龈卟啉单胞菌Porphyromonas gingivalis，所有这些细菌都显示出潜在的致癌作用。
How do these bacteria induce colorectal cancer?
这些细菌可通过激活STAT3、NF-κB、Wnt和SREBP-2途径、诱导COX-2表达、与TRL2和TRL4相互作用、刺激促炎细胞因子(IL-1β、IL-6、IL-8、IL-17、TNF-α和IFN-γ)产生、调节NLRP3炎症体活性，通过氧化应激活性氧(ROS)和活性氮(RNS)DNA损伤来诱导结直肠癌的发生。
"Driver-passenger" theory
Intestinal bacteria (drivers, like drivers) induce colorectal cancer by destroying epithelial DNA that causes tumorigenesis, which in turn promotes the proliferation of bacteria (passengers) and gives them a growth advantage in the tumor microenvironment.
The tumor microenvironment consists of genetically altered cancer cells, non-tumor cells, and a variety of microorganisms.
In the tumor microenvironment of colorectal cancer, Fusobacterium enrichment, Bacteroidetes and Firmicutes decrease, and butyric acid-producing bacteria are significantly reduced, resulting in an increase in pathogenic bacteria.
Butyric-producing bacteria form functional groups in the intestine and exhibit anaerobic and oxygen-sensitive activity after colonization on the mucosal layer of intestinal epithelial cells, which increases the bioavailability of butyrate. This microbiota promotes intestinal homeostasis by preserving intestinal epithelial function and releasing immunomodulatory and anti-inflammatory agents.
The contribution of pathogenic factors to the etiology and progression of colorectal cancer is related to the cumulative effect of gut microbial metabolites, rather than the role of a single strain.
Changes in early metabolites in colorectal cancer
The microbial metabolome in the gut and the carcinogenic functions of specific bacterial and fungal pathogens can all catalyze carcinogenesis.
Elevated intestinal metabolites such as bioactive lipids (including polyunsaturated fatty acids, secondary bile acids, and sphingolipids) in patients with colorectal adenoma (a precursor to colorectal cancer) highlight potential early driver metabolites in the pathogenesis of colorectal cancer. A stronger gut microbiome-metabolomic association was observed in women compared to men.
The role of gut microbiota in anticancer treatment of colon cancer
Michy transplantation
The efficacy of fecal microbiota transplantation in the treatment of colorectal cancer is mediated by the regulation of immunotherapy efficacy, the improvement of bile acid metabolism, and the restoration of intestinal microbial diversity. The safety and efficacy of this approach still need to be carefully evaluated.
Probiotics, prebiotics
Prebiotics such as inulin, β(1–4) galacto-oligosaccharides, fructooligosaccharides, lactulose, resistant starch, and wheat bran play beneficial roles in colorectal cancer.
In vitro experiments were conducted to study the antibacterial activity of bacteriocins, an important metabolite produced by lactic acid bacteria, against different strains of Helicobacter pylori, and it was found that lactobacillus A164 and lactobacillus BH5 had significant antibacterial activity against Helicobacter pylori.
The study also showed that lactic acid produced by probiotic strains - Lactobacillus acidophilus P38, Bifidobacterium longum P29 and Lactococcus lactis M92 could inhibit the growth of H. pylori, indicating the potential therapeutic application of probiotics in H. pylori-related ulcers and cancers.
Women suppress colorectal cancer through estrogen
Worldwide, colorectal cancer is more common in men than in women. Estrogen affects the composition of the gut microbiota.
Two studies demonstrated that 17β-estradiol (an estrogen) altered the gut microbiota and inhibited colorectal cancer induction by upcalling Nrf2 in oxidized azomethane/sodium sulfate-treated male ICR mice.
Since most of the studies in the literature are conducted in vitro and in vivo, there is a need for more clinical studies that take into account genetics, environmental factors, age, gender, ethnicity, culture, diet, and geographic location before developing a prebiotic-based colorectal cancer strategy. Overall, these clinical findings have a positive contribution to the diagnosis, prevention, and potential treatment strategies of colorectal cancer centered on the gut microbiota.
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Lung cancer
Lung cancer is one of the common malignancies, and there is an urgent need to develop effective treatment strategies for lung cancer. Studies have shown that there is a complex connection between the gut and lung microbiota on a bidirectional axis through the lymphatic and circulatory systems. The gut-lung axis is a recent scientific understanding and may be a potential future direction for lung cancer treatment.
Immunomodulation of gut microbiota in anticancer therapy of lung cancer
A specific microbiota whose function is to modulate the immune response against tumorigenesis and increase the efficacy of immunotherapies against cancer (tertiary interaction).
The gut microbiota produces metabolites and signaling molecules, including SCFAs, inosine, lipopolysaccharide (LPS), and IFN-γ, which regulate the activity of T cells, B cells, NK cells, dendritic cells, and macrophages against the tumor microenvironment.
Targeting the gut microbiota, CD8+ T cells, natural killer cells, and macrophages produce perforin, granzyme, interleukin-12, interleukin-1β, and tumor necrosis factor to inhibit tumors.
Alterations in one part of the gut-lung axis may affect another, which may be directly related to changes in the composition of the gut and lung microbiota or the function of the immune system. The importance of the gut microbiota in the anti-cancer response of lung cancer has been considered by the cancer immune cycle.
How does anti-cancer immunity occur?
The cancer immune cycle acknowledges that the anti-cancer response is constituted by the release of pro-inflammatory cytokines derived from metabolites of the gut microbiota, which further leads to the activation of effector T cells against cancer-specific antigens. Activation of effector T cells leads to invasion of tumor cell beds, binding to specific tumor antigens, effectively destroying malignant lung cancer cells.
The role of the gut microbiota in this
The priming and maturation of B and T cells by the gut microbiome enhances mucosal protection through the action of antibodies, as it begins in the intestinal mucosal layer and spreads along other mucosal surfaces through the lymphatic and circulatory systems. This initiates an immune response far from the site of origin.
The intestinal microbiota has a significant effect on the efficacy of ICIs in cancer treatment
The gut microbiota has been shown to have a significant impact on the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. For example, administration of antibiotics inhibited PD-1/PD-L1 in patients and mice targeted by ICIs for non-small cell lung cancer.
Note: PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1
Metagenomic analysis of patient stool samples found that the relative abundance of Akkermansia muciniphila, one of the most abundant bacteria in the ileal microbiota, correlated with a favorable clinical response to ICIs in patients with non-small cell lung cancer, however, the mechanism of immunomodulatory effects remains unclear.
Intestinal dysbiosis reduces efficacy
Other studies have also shown that antibiotic-associated gut microbial dysbiosis reduces the clinical efficacy of ICIs in patients with non-small cell lung cancer, and that an intact gut microbiota is required to mobilize the immune system, regardless of tumor site.
One retrospective study reported the adverse effects of antibiotics on clinical outcomes of anti-PD-1 ICIs in 109 patients with advanced non-small cell lung cancer in China. The adverse effect of antibiotic-associated gut microbial dysregulation on the efficacy of standard chemotherapy (e.g., cisplatin) was also demonstrated by up-regulating VEGFA expression and down-regulating BAX and CDKN1B expression in a mouse model of lung cancer to promote tumor growth and reduce survival.
Mice treated with Lactobacillus acidophilus in combination with cisplatin exhibit enhanced antitumor responses, up-regulated expression of IFN-γ, granzyme B, and perforin 1.
Antibiotics plus aerosol therapy
An interesting study showed that antibiotic and probiotic aerosol therapy altered the lung microbiota, preventing melanoma B16 lung metastases and enhancing the response to chemotherapy in female C57BL/6 mice.
They implemented vancomycin/neomycin aerosol therapy to reduce regulatory T cells and increase T cell and NK cell activation, which led to a decrease in bacterial load and a significant reduction in melanoma B16 lung metastases.
The study also found that aerosol therapy with Lactobacillus rhamnosus GG and Bifidobacterium bifidum MIMBb23sg significantly increased the anti-tumor effects of standard chemotherapy drugs. In addition, Lactobacillus rhamnosus GG strongly promotes immunity to B16 metastatic tumors by increasing the expression of CD69 in NK cells and T cells.
Taken together, these findings highlight the important impact of the gut microbiota, especially in the treatment and prognosis of lung cancer. However, more research is needed to elucidate the molecular mechanisms underlying the immunomodulatory effects of the gut microbiota and their relevance in the development of effective lung cancer treatment strategies.
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breast cancer
Breast cancer is one of the most common cancers and the leading cause of cancer-related deaths in women worldwide. At present, the understanding of the gut microbiota is deepening, and the relationship between gut microbiota and breast cancer has been further studied. In addition to genetics, the gut microbiota may play an important role in the pathogenesis of breast cancer.
dysbiosis and carcinogenesis
A study of postmenopausal women investigated the interrelationship between breast cancer and alterations in the gut metabolomics. Differences in the composition and biological activity of the gut microbiome were found between healthy control subjects and postmenopausal breast cancer patients, with the gut metagenome of postmenopausal breast cancer patients having genes encoding β-oxidation, iron complex transport system, and lipopolysaccharide biosynthesis.
In vitro studies provide functional evidence supporting the link between the gut microbiota and the progression of metastases in breast cancer, where microbial metabolites can be transmitted through the bloodstream, affecting the function of breast cancer cells and immune cells.
In addition, it has been established that pre-existing disturbances in the gut microbiota increase breast cancer cell metastasis, however, further research is needed to determine the relevance of these findings in a clinical setting.
The link between gut microbiota and hormone regulation
Several interesting aspects of the multifactorial effects of the gut microbiota on breast cancer have also been reported, mediated by modulation of steroid hormone metabolism and mucosal and systemic immune responses. For example, the gut microbiota may play an important role in the development of breast cancer by mediating the metabolism of steroid hormones and the synthesis of bioactive metabolites that mimic estrogen.
The figure below depicts physiological effects caused by impaired hormone-releasing activity in the host, including changes in metabolic processes and regulation of inflammation and cancer in the gut.
The interconnections between gut microbiota and hormone regulation are a promising area of research to identify precision therapies for breast cancer.
Existing studies provide an assessment of gut microbiota contribution and breast cancer risk
Although the correlation and causal relationship between the gut microbiota and breast cancer is not well understood, the risk of breast cancer is related to the composition and function of the gut and breast microbiota and exposure to harmful environmental pollutants such as endocrine disruptors that can cause biological dysregulation. Although case-control clinical studies are currently underway (NCT03885648), it provides a potential first assessment of the contribution of the gut microbiota (bacteria, archaea, viruses, and fungi) and changes in breast cancer-related risk from environmental stresses, which may contribute to the understanding of risk factors, improve prognosis, and define new interventions for breast cancer.
The role of gut microbiota in anti-cancer therapy for breast cancer
Two recent reviews explored the role of the gut microbiota in breast cancer. They reviewed several preclinical and clinical studies involving probiotics such as Lactobacillus reuteri, Lactobacillus helveticus R389, Lactobacillus paracasei, Lactobacillus acidophilus, and Bifidobacterium, as well as the mechanisms underlying their potential therapeutic effects on breast cancer:
Direct mechanism: inhibition of early carcinogenesis, induction of apoptosis of breast cancer cells and inhibition of tumor growth
Indirect mechanism: Immunomodulation by increasing IL-10 and decreasing IL-6 levels
Two ongoing clinical trials (NCT03358511 and NCT03760653, registered in ClinicalTrials, are also investigating the therapeutic effects of probiotics in breast cancer.
Overall, more research is needed to understand the efficacy of probiotics in breast cancer treatment. In addition, future research should focus on a comprehensive understanding of the direct and indirect mechanisms of action of the gut microbiota against breast cancer, and how probiotics affect the efficacy of standard and adjuvant chemotherapy in breast cancer.
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prostate cancer
Prostate cancer is a common cancer in the male population, and while it is common, its risk factors have not been well identified or studied.
dysbiosis and carcinogenesis
There is growing evidence to support the biological relationship between dysbiosis and prostate cancer. The link between malignancy and inflammation has become an important consideration in many existing studies, highlighting the possible significance of inflammatory stimulation (tertiary interaction) in the development and progression of prostate cancer.
Changes in intestinal microbiota in prostate cancer
Information on this early study was very limited. In 2018, a case-control study of 20 participants of Caucasian descent found that the composition of the gut microbiome was very different between benign control subjects and men with prostate cancer, which may be adapted to the pathogenesis of prostate cancer and further research on its risk factors. In particular, the relative abundance of Bacteroides massiliensis was higher in prostate cancer cases compared to the control group, while the relative abundance of Faecalibacterium prausnitzii and Eubacterium rectalie was higher in the control group. The pilot study also reported biologically significant differences in the abundance of relevant genes, pathways, and enzymes.
Changes in tumor tissue microbiota
Other studies have reported significant differences in the abundance of pro-inflammatory bacteroides and streptococcus, and significant alterations in folate and arginine pathways. Analysis of the prostate tumor microenvironment revealed significantly more staphylococcus in tumor/peritumoral tissues compared to non-neoplastic tissues, while Propionibacterium was most abundant in all tumor/peritumoral and non-neoplastic tissues tested.
The role of gut microbiota in anti-cancer treatment of prostate cancer
Similar to colorectal and breast cancers, estrogen modulates the interrelationship between the gut microbiota and prostate cancer.
A cross-sectional study of 30 patients further validated the interaction between gut microbiota, hormone regulation, and cancer treatment efficacy. The authors found significant differences in gut microbiota composition among men treated with oral androgen receptor axis-targeted therapy.
The study identified a large number of Akkermansia muciniphila and Ruminococcaceae bacteria, which were once thought to be associated with anti-PD-1 immunotherapy responses.
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Stomach cancer
As the third leading cause of cancer-related deaths worldwide, gastric cancer has been extensively studied in terms of risk factors and prevention.
dysbiosis and carcinogenesis
The most important and known risk factor for gastric cancer is infection caused by Helicobacter pylori, a gram-negative microaerophilic bacterium that leads to the formation of precancerous lesions, including dysplasia, which may further lead to gastrointestinal cancer. The International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) consider H. pylori to be a class of adenocarcinomas and mucosa-associated lymphoid tissue lymphomas.
The link between gut microbiota and gastric cancer can be further divided into Helicobacter pylori and non-Helicobacter pylori microbiota as pathogens for dysbiosis and cancer pathogenesis.
Compared to H. pylori-positive individuals, H. pylori-negative individuals have a more complex and highly diverse microbiota, mainly composed of 5 dominant phyla: Proteobacteria, Firmicutes, Actinomycetes, Bacteroidetes, and Fusobacterium. Specifically, gastric cancer is thought to be inflammation-related (indirect mechanism) because Helicobacter pylori can initiate an inflammatory response and induce dysplasia, altering the regulation of many signaling pathways within the gastrointestinal tract.
Highly virulent proteins derived from Helicobacter species, such as adventitial phospholipase proteins, contribute to bacterial colonization in the mucosal layer of the gastrointestinal tract, triggering gastritis flare-ups and thus increasing the risk of intragastric tumors.
In addition, the production of high levels of reactive oxygen species by Helicobacter pylori in the stomach and the consequent DNA damage are also associated with carcinogenic effects (major interactions). Helicobacter pylori also reduces stomach acid secretion, and the environment in which stomach acid is reduced slowly becomes viable for many bacteria, leading to acid deficiency and alterations in the stomach microbiota.
几项研究表明，胃癌中非幽门螺杆菌细菌，如乳酸菌Lactobacillus、毛螺菌科Lachnospiraceae、Escherichia-Shigella、硝化螺旋菌门Nitrospirae和伯克氏菌属Burkholderia的丰度增加。
The role of gut microbiota in anticancer treatment of gastric cancer
There is growing evidence supporting the therapeutic use of probiotics and prebiotics, which have significant anticancer effects against gastrointestinal malignancies in vitro and in vivo. The introduction of probiotics into the intestinal epithelium has been determined to reduce tumor progression and recurrence and enhance the efficacy of chemotherapy drugs.
Further study of the function of probiotics may allow for dosing based on individual commensal microbial composition. Although promising conclusions have been drawn between the gut microbiota and the development of gastrointestinal cancer, further research is essential to elucidate the underlying mechanisms of these biological processes.
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Interaction of gut microbiota with standard anticancer drugs
The association between gut microbiota and chemotherapy is usually bidirectional.
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Gut microbiota – > standard anticancer drug
Biological interactions between the gut microbiota and the host may interfere with the pharmacokinetics of anticancer drugs. For example, many studies have shown that the resident gut microbiota can modulate the activity of anticancer drugs and therapeutics, as well as the host response to these treatment regimens.
The gut microbiota can mediate host response to chemotherapy through three primary clinical outcomes:
1) Improve the efficacy of drugs
2) Disruption and impairment of anti-cancer effects
3) Modulation of toxicity
These studies demonstrate a close link between gut bacterial species and the pharmacological effects of chemotherapy and immunotherapy.
除了改善总体健康和降低代谢紊乱和慢性炎症的风险，肠道菌群如A.muciniphila, 脆弱拟杆菌B.fragilis, Bifidobacterium, Faecalibacterium，已被证明有助于动物模型和人类的抗癌免疫反应。
Interestingly, certain gut bacteria, such as Streptomyces WAC04685, inactivate anticancer drugs through in vitro deglycosylation mechanisms. The microbial community metabolizes chemotherapeutic agents to produce toxic secondary metabolites, which will directly interfere with the host's immune response to chemometabolism while altering the host's gut microbiota structure.
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Standard anticancer drugs – > gut microbiota
Platinum-based chemotherapy has been shown to interfere with the gut microbiota by showing cell-damaging effects and altering DNA structure.
Inflammatory response to chemotherapy drugs
Studies have shown that chemotherapy drugs damage the intestinal epithelium and mucosal barrier, each of which dramatically alters the gut microbiota and increases the probability of infection and disease. In particular, chemotherapy in cancer patients has been shown to cause intestinal epithelial inflammation and mucositis through ROS-induced DNA damage and cytokine signaling molecules (NFκB pathway, IL-1β, TNF-α, and IL-12).
When the mucosal barrier is compromised, pathogenic bacteria coexist with commensal bacteria, and the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) released by damaged epithelial cells and pathogen-causing bacteria, respectively, are in turn recognized by Toll-like receptors (TLRs), ultimately leading to inflammation.
The mechanistic framework of these regulatory activities includes translocation, immunomodulation, metabolism, enzymatic degradation, and reduction in diversity and variation, and is scientifically considered a "timer" framework.
The researchers determined that the biological interaction between the gut microbiome and the immune system was constituted by a post-chemotherapy-induced bacterial translocation that occurred within the lymphoid organs and within the lumina.
Changes in microbiota in chemotherapy patients
对接受化疗的癌症患者的人类粪便微生物群进行的16S rRNA测序显示，双歧杆菌属、乳杆菌属、韦荣球菌属 Veillonella和粪肠球菌属 Faecalibacterium prausnitzii 的数量减少，同时出现致病性和炎症性艰难梭菌Clostridium difficile和粪肠球菌Enterococcus faecium。
A study in breast cancer survivors found a direct association between the composition of the unique gut microbiota and fear of cancer recurrence (FCR), implying that chemotherapy drug-induced changes in the microbiota may be responsible for influencing FCR.
Lifestyle and antibiotics alter the microbiota
In addition to chemotherapy drugs, disruption of lifestyle factors, including host environment and diet, has been shown to interfere with the composition of the gut microbiota. Lifestyle factors can disrupt the symbiotic relationship between the gut microbiota and the host by altering the structure of the microbial community, leading to adverse chemotherapy efficacy and outcomes.
In addition, antibiotic administration has also been shown to disrupt the gut microbiota, leading to a weakened response to anticancer chemotherapy and immunotherapy. Thus, these findings provide a niche area for future research to understand the effects of standard chemotherapy on the gut microbiota, define precise anti-cancer regimens, and determine clinical outcomes for different cancer types.
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Immunotherapy and natural anticancers interact with the microbiota
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Cancer immunotherapy and gut microbiota
Current cancer immunotherapies focus on self-regulating the cancer immune cycle using specific antibodies, which ensures the propagation of the response without biological disruption.
Alterations in the microbiome interrupt and weaken chemical signals, leading to pathogenic states, including inflammation-related diseases and cancers.
Germ-free mice have deficiencies in their immune systems, including both innate and adaptive immune systems. This immunity is modulated by PAMPs through receptors designed for pattern recognition, where signaling pathways can be enhanced by gut microbial metabolites.
The regulatory activity of the gut microbiota in the anticancer immune response is also associated with influencing the efficacy of PD-L1 and CTLA-4 inhibitors through the microbiota. When combined with oral administration of Bifidobacteria, administration of PD-L1-specific antibody therapies can significantly modulate tumor development, but tumor growth is virtually eliminated in mouse models.
Blocker efficacy depends on the presence of bacteroides
Similarly, the efficacy of CTLA-4 blockade depends on the presence of bacteroides in the gut microbiota. Bacteroides fragilis B. fragilis fragilis and Bacteroides multiforme B. The specific T-cell immune response of thetaiotaomicron correlates with the efficacy of CTLA-4 blockers, and in the absence of these microbial communities, tumor progression is resistant to blockers.
A study in mice identified a link between ICI efficacy and gut microbiota, where CTLA-4 and PD-1 inhibitors were only able to reduce tumor growth in the presence of the commensal bacteria Bacteroides and Bifidobacteria. Further findings determined that tumor growth in mouse models was resistant to CTLA-4 inhibitor blockade unless treated with immunotherapy, which enhanced the efficacy of these inhibitors by activating the T cell response.
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Natural anti-cancer compounds and intestinal flora
We have previously known that there is a close relationship between cancer chemotherapy/immunotherapy and the gut microbiota, and that cancer prevention through natural medicines is a promising approach in oncology. Natural medicines include dietary polyphenols, fiber, phytoestrogens and vitamin D.
Interaction between dietary polyphenols and intestinal microbiota
Dietary polyphenols have shown significant anticancer activity in several preclinical and clinical studies. The link between the gut microbiota and dietary polyphenols is bidirectional. For example, the gut microbiota is able to biotransform dietary polyphenols, which can modulate the composition and function of the gut microbiota by inhibiting the proliferation of "bad" bacteria and stimulating "good" bacteria.
Polyphenols alter the composition and function of the gut microbiota, and the gut microbiota produces polyphenol metabolites, which may collectively contribute to a protective effect against colorectal cancer.
Epigallocatechin adjuvant therapy for breast cancer
Another study in breast cancer showed that tea polyphenols-epigallocatechin-3 gallate (EGCG) significantly reduced the activities of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and metalloproteinase-9 (MMP9) and metalloproteinase-2 (MMP2) in the serum plus radiotherapy group compared with the radiotherapy alone group, suggesting the adjuvant therapeutic effect of EGCG on breast cancer.
Supplementation with dietary polyphenols increases beneficial bacteria and inhibits colorectal cancer
Several clinical and animal studies have confirmed that when supplemented with dietary polyphenols (curcumin, resveratrol, hesperidin, green tea polyphenols, anthocyanins, isoglycyrrhizin, and black raspberry anthocyanin extracts), the abundance of beneficial bacteria (butyric acid-producing bacteria and probiotics) such as lactobacilli and bifidobacteria increases, which may inhibit colorectal cancer. These findings suggest that the gut microbiota can be targeted and used to potentially improve the pharmacokinetic response of several natural anti-cancer therapies. However, further mechanistic studies are essential to elucidate the underlying molecular interactions.
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Interaction of viruses with gut microbiota
In 1911, the link between viruses and cancer was first discovered in chickens. Several carcinogenic viruses have since been discovered, including:
- Kaposi's sarcoma herpes virus (causes Kaposi's sarcoma and primary exudative lymphoma);
- human T-cell lymphotropic virus 1 (causes T-cell leukemia and lymphoma in adults);
- Epsteden-Barr virus (causing Burkitt lymphoma, immunosuppressive-associated non-Hodgkin lymphoma, extranodal NK/T-cell lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma);
- hepatitis C virus (causes hepatocellular carcinoma and non-Hodgkin lymphoma);
- hepatitis B virus (causing hepatocellular carcinoma);
- Merkel cell polyomavirus;
- Human cytomegalovirus.
Viral cancer-promoting mechanisms
Viruses can act carcinopro-through through different mechanisms:
a) Expression of host cell proteins, either directly by inducing viral oncoproteins or by regulating viral DNA integration sites
b) Viral DNA is not sustained indirectly by suppressing the immune system or by modifying the host cell genome
Oncoviruses are located inside tumor cells in monoclonal form, while indirectly acting viruses are present outside the tumor.
Viruses can also trigger oxidative stress, damage local tissues, and cause chronic inflammation.
Therefore, the direct and indirect mechanisms of viral carcinogenesis do not necessarily occur as separate pathways, and some tumors, including liver cancer and gastric cancer, rely on these two mechanisms. For example, it has been observed that hepatitis B and C viruses require two mechanisms to induce human hepatocellular carcinoma.
A recent study reported 142809 non-redundant enterovirus (phage) genomes distributed globally in the human gut microbiota, confirming the importance of viruses in the gut microbiota and the need for further research to recognize their interactions with the commensal microbiota.
Since most people infected with cancer viruses never develop cancer, the microbiota is thought to be a key factor in influencing the ability of viral infections to increase or decrease the development of cancer.
Despite the relevance of viruses in cancer and the gut microbiota, most microbiota studies ignore viruses and place more emphasis on the gut microbiota. This may be attributed to the challenge of discovering new viruses using current metagenomics and bioinformatics platforms, which can be mitigated by developing new methods for virus identification. Further emphasis should also be placed on the implementation of anti-cancer therapies that target viral interactions in the host (virus-virus, virus-host, virus-tumor, and virus-gut microbiota).
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Conclusion
The gut microbiota plays an important and complex role in preventing infection and maintaining health. This article focuses on helping to understand the direct and indirect roles of the gut microbiota in cancer initiation, cancer treatment, and prognosis.
Of course, the correlation and causal relationships of gut microbiota in cancer are not well understood, and further systems biology, in vivo, and clinical studies are needed to elucidate the complex molecular pathways involved. Research that precisely defines what constitutes a "good" and "bad" gut microbiome is also crucial.
Future clinical trials (randomized, double-blind, placebo-controlled design) should also take into account changes in age, gender, ethnicity, culture, and diet, as well as geographic location, when investigating the role of the gut microbiota in cancer.
In conclusion, the relevance of the gut microbiota in cancer development, treatment, and clinical outcomes is an emerging area of translational research that could open up new avenues for cancer treatment.
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