Can microbes also help humans fight cancer? - New therapeutic potential of intestinal flora

Can microbes also help humans fight cancer? - New therapeutic potential of intestinal flora

From the moment we are born, microbes begin to "colonize" the intestines. Initially, the baby's intestines are sterile, but with contact with maternal microbes during delivery, as well as subsequent feeding and environmental exposure, the intestinal flora is gradually established. Over time, these microbial communities continue to enrich and stabilize, forming a complex and diverse ecosystem.

Figure 1 Development of intestinal flora during infancy

(Image adapted from: https://biorender.com/)
The intestinal flora is not only involved in food digestion and nutrient absorption, but also regulates the immune system and trains immune cells to recognize "self" and "non-self", thereby resisting the invasion of pathogens. In recent years, scientists have discovered that there is a remarkable potential relationship between the intestinal microbiome and cancer. Although traditional cancer treatments (such as surgery, chemotherapy, and radiotherapy) can control tumors to a certain extent, they also have many side effects and limitations. In recent years, emerging therapies such as immunotherapy have brought new hope for cancer treatment. However, their efficacy also varies significantly among different patients. Studies have shown that the intestinal microbiome may be one of the important factors affecting the response to cancer treatment. Regulating the intestinal microbiome is expected to improve the treatment effect of cancer patients and increase survival rates.

What are gut microbes?

The intestinal microbiota is a general term for various microorganisms that colonize the human intestine, including bacteria, fungi, viruses, and other unknown microorganisms. Among them, bacteria are the main component of intestinal microorganisms, accounting for more than 99% of the total intestinal microorganisms. They mainly include obligate anaerobes (such as Bacteroides, Bifidobacterium, Clostridium, etc.) and facultative anaerobes or aerobic bacteria (such as Escherichia coli, Streptococcus, etc.). These microorganisms form a complex ecosystem in the intestine, and the microbial composition of different parts (such as the small intestine and colon) is also different.

The composition of the intestinal microbiota is affected by many factors, including genetics, age, dietary habits, lifestyle and environment. In healthy people, the intestinal microbiota is usually in a dynamic equilibrium. With age, the diversity of the intestinal microbiota may decrease and the proportion of harmful bacteria may increase. A complex interaction is formed between intestinal microorganisms and the host, which not only maintains the normal function of the intestine, but also has a profound impact on the health of the whole body.

Figure 2 Distribution of intestinal flora (Source: https://www.vcg.com/creative/1454398491.html)

How do intestinal microbes affect tumorigenesis?

The key role of the intestinal microbiota in health and disease has received increasing attention, especially in the field of cancer, where the intestinal microbiota is closely related to the occurrence and development of cancer. A healthy intestinal microbiota plays a positive role in the anti-cancer process. Some beneficial bacteria (such as bifidobacteria and lactic acid bacteria) can improve the body's ability to identify and eliminate cancer cells by regulating immune responses, inhibiting inflammation, and enhancing the activity of immune cells. For example, metabolites such as short-chain fatty acids can enhance the function of immune cells and promote anti-tumor immune responses [1]. It is worth noting that some harmful bacteria (such as certain pathogenic strains of Escherichia coli) can produce genomic toxins, such as cytolethal distending toxin and colicin, which can directly damage the DNA of intestinal cells and induce gene mutations, thereby increasing the risk of intestinal cancer. In addition, an imbalance in the intestinal microbiota may also weaken the surveillance function of the immune system, allowing cancer cells to escape the immune system's pursuit, thereby promoting tumor growth and metastasis [2].

Regulating the intestinal microbiota through interventions such as diet, probiotics, and prebiotics is expected to become a new strategy for cancer prevention and treatment. For example, foods rich in dietary fiber can promote the growth of beneficial bacteria, improve the intestinal microecology, and thus reduce the risk of cancer. Therefore, in-depth research on the relationship between intestinal microbiota and cancer not only provides new ideas and targets for cancer treatment, but also opens up new ways for cancer prevention and health management.

Figure 3 The role of intestinal microorganisms in tumors (Source: https://www.vcg.com/creative/1431623445.html)

The potential of gut microbes in cancer treatment

In this era when people are afraid of the word "cancer", treatment options for cancer are constantly emerging: the well-known chemotherapy, radiotherapy, and the highly anticipated immunotherapy... Studies have shown that regulation of intestinal microorganisms can not only enhance the body's immunity and inhibit tumor growth and invasion, but also improve treatment tolerance and reduce adverse reactions.

Let’s first take a look at how they “show their prowess” in chemotherapy.

Chemotherapy, one of the traditional methods to fight cancer, refers to the use of drugs to kill or control rapidly dividing cells. However, this often harms some normal cells, and the side effects are great, causing patients to experience adverse reactions such as nausea, diarrhea, hair loss, and exhaustion. The intestinal microbiota can regulate the effect of chemotherapy by providing a tumor microenvironment that is conducive to the toxic effects of drugs on cancer cells and maintaining anti-cancer adaptive immunity after drug-induced immunogenic cell death. Some, such as Escherichia coli, can affect the toxicity of chemotherapeutic drugs; probiotics may also alleviate mucositis and diarrhea by maintaining barrier function or inhibiting inflammatory factors; the most typical example is gemcitabine, and the efficacy of gemcitabine in the treatment of pancreatic ductal adenocarcinoma may be affected by intestinal microorganisms. γ-Proteobacteria can metabolize gemcitabine and convert it into inactive 2′, 2′-difluorodeoxyuracil. Therefore, it may be possible to improve the anti-cancer effect of gemcitabine in the future by combining anti-γ-Proteobacteria antibiotics with chemotherapy. In addition, butyrate, a metabolite of intestinal microorganisms, can also enhance the efficacy of gemcitabine against cancer cells by inducing apoptosis.

Don’t be too amazed. The intestinal flora not only plays a key regulatory role in traditional chemotherapy, but also plays an important role in tumor immunotherapy.

Immunotherapy is an innovative cancer treatment that allows the host's immune system to fight tumor cells.

Although immunotherapy has shown promising results, objective response rates vary widely among patients receiving immune checkpoint blockade therapy, and in some cases may be less than 30%. Moreover, immune checkpoint blockade therapy may overactivate the host immune system, leading to immune-related adverse events (including skin, gastrointestinal, and endocrine side effects, which range from mild to severe and even life-threatening).

But how can our "microbial friends" sit idly by? Their most direct assistance is to improve the efficacy of immunotherapy. Certain microbial communities (Bifidobacteria) can enhance the anti-tumor effect by activating immune cells. We can effectively let "microbial friends" join this battle to defend the human body through fecal microbial transplantation or the use of probiotics (produced with beneficial bacteria or bacteria with immune-enhancing effects) as immunosuppressive adjuvants. Of course, they can also be used as prognostic biomarkers for response to immunotherapy to improve the accuracy of treatment selection, and the higher the bacterial diversity in the intestine, the higher the response rate to immunotherapy during treatment. Not only that, the metabolites of the intestinal flora are also very useful. They can regulate the composition and activity of other bacteria, and some can pass through the intestinal barrier, affect the host physiology, and activate immunity, such as short-chain fatty acids, indolepropionic acid, tryptamine, etc.

Since immune checkpoint blockade therapy seems to have heterogeneous therapeutic effects on different individuals, the success of immunotherapy depends largely on the physiological and tumor characteristics of each patient, so personalized therapy becomes the key to success. Gut microorganisms play an irreplaceable and important role in tumor immune response and immunotherapy. Therefore, microbiome precision medicine, including FMT, prebiotics, probiotics, antibiotics and vaccines, is considered to be an ideal microbial therapeutic application in cancer treatment, which is safer and more effective. The intestinal flora will surely become a loyal guardian of human health and safety.

How to regulate gut microbes to prevent cancer

Since intestinal microorganisms are so closely related to our health, how can we prevent cancer by regulating intestinal microorganisms?

From the previous introduction, we know that intestinal flora is not innate. The fetus is in a sterile state in the womb, but after birth, every breath of fresh air and every bite of food are wrapped with a large number of fungi. They have discovered a new fertile and uncultivated "prairie", and they are eager to "set up camp" in the "conquest of the south and the north", forming a stable flora. From how the intestinal flora is produced, we can know how to regulate our intestinal flora.

The first is to keep the "pasture" fertile - a balanced diet, eat more vegetables, grains and other foods rich in fiber. Although we do not fully digest them, we can keep the intestinal flora well fed and healthy, and we can also supplement a variety of vitamins and trace elements.

The second is to ensure the good weather and harvest of the "pasture" - regular work and rest and diet. Some people may be curious, diet is understandable, but how can this work and rest be true? In fact, after so many years of getting along, the intestinal flora has also formed its own biological clock and diet. In other words, since the intestinal flora is bound to adapt to us, if we want to make the intestinal flora more stable, we should make our daily routine and diet more regular. Otherwise, the intestinal flora will be unpredictable for a long time, sometimes it will be windy, sometimes it will rain, and there will be no fixed time. The intestinal flora also has a "temper". Once it is out of balance, no one can say what diseases it will cause.

Following the clues, we can of course also add new members - "manually add" some beneficial intestinal flora. Eat more soy products, drink more yogurt, and continuously airdrop probiotics to the "prairie", so that the team of intestinal symbiotic bacteria will not grow!

The most important warning is to ensure the ecological balance of the intestinal "pasture" - don't think of "killing one thousand enemies and injuring eight hundred of your own" and blindly abuse antibiotics! The occurrence of tumors is closely related to the human immune status and environmental factors. Symbiotic bacteria and pathogenic bacteria have complex immune effects on systemic cancer immunity. What we expect is to resolve conflicts "peacefully", rather than completely intensify the conflicts and kill both the good and the bad. "Bone bones are exposed in the wild, and no roosters crow for thousands of miles." At the end of the war, it will only cause the intestinal flora to be unbalanced, bringing more serious harm to the human body.

The scientific thinking behind this and the call to develop healthy habits

"Look up at the vastness of the universe, and look down at the abundance of species." Nature has too many mysteries waiting for us to reveal. Through the magnifying glass of "intestinal microorganisms", we see the entanglement between humans and nature, which is complex, profound, intricate, and all-encompassing. In the long years of the vast human civilization, a group of tiny but huge lives have silently accompanied us. They have witnessed the transition of humans from being homeless to having thousands of lights, and heard the roar of steam turning into the creaking of electric current. They listened to the flywheel of technology rolling faster and faster in the dark, and finally at some point, they saw the light and met humans for the first time. We have to marvel at the wonders of this world. Humans cannot override nature. Only by respecting, being humble, creating, combining our own tools, and integrating multiple disciplines, can we observe this group from multiple perspectives such as microbiology, oncology, and immunology, and understand the true meaning of it. We are all witnesses, witnessing how the intestinal flora faces all of humanity; they are also witnesses, witnessing how humans step by step move from the vast galaxy to exploring themselves; we will communicate, decode the mysteries of life, and seek for human health.

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