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    Home > Active Ingredient News > Digestive System Information > Prof. Zhao Changlin: Do circadian clock disorders and intestinal flora imbalance increase the risk of colorectal cancer?

    Prof. Zhao Changlin: Do circadian clock disorders and intestinal flora imbalance increase the risk of colorectal cancer?

    • Last Update: 2022-04-28
    • Source: Internet
    • Author: User
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    Author: Zhao Changlin This article is published with the authorization of the author, and please do not reprint without authorization
    .

    Colorectal cancer (CRC) in China is rapidly rising at a rate of 7.
    4% per year, and has risen to the second place in the incidence of malignant tumors.
    Among them, the incidence of young people has increased, and it has become the country with the largest number of new cases of CRC in the world, morbidity and death.
    The rate showed a severe situation of "double high"
    .

    About 120 million people are at high risk of CRC
    .

    More and more evidence shows that up to 90% of the risk of CRC is caused by factors such as diet and environment, and more than 50% of CRC can be prevented or reduced by factors such as healthy diet and healthy life>
    .

    It is currently known that unhealthy diet (such as low fiber, red meat and processed meat and low calcium, excessive alcohol consumption, etc.
    ) and heavy smoking can increase the risk of CRC; Poor bowel habits and prolonged sedentary life are associated with cancer risk
    .

    So, do circadian clock disturbances and intestinal flora imbalance increase the risk of colorectal cancer? Expert Profile Professor Zhao Changlin, National Level 3 Professor, Chief Physician, Xinhua Hospital Affiliated to Dalian University, Chief Physician, Dalian Colon and Rectal Cancer Diagnosis and Treatment Base, Vice President, Dalian Community Health Service Research Association, Chairman, Dalian Community Cancer Prevention Committee, China Anti-Cancer Association, Liaoning Province Gastric Cancer Member of the Standing Committee of the Professional Committee Member of the Liaoning Base of the Chinese Medical Education Association Abdominal Tumor Special Committee Member of the Third Editorial Board of the Chinese General Surgery Literature (Electronic Edition) Editorial Board of the Second Editorial Board of the Chinese Electronic Journal of Colorectal Diseases Invited Reviewer , Long-term staying up late and the risk of CRC The research evidence that long-term staying up late and irregular work and rest are closely related to the risk of cancer is sufficient, and the conclusion has been recognized
    .

    So why does staying up late for a long time increase the risk of CRC? As early as 2007, the International Agency for Research on Cancer (IARC) has defined staying up late as a class 2A carcinogen, which means "increasing the risk of cancer"
    .

    Dozens of animal experiments have proved that disrupting or disrupting the circadian rhythm of animals can accelerate the occurrence of cancer in animals, and the conclusion that “disturbing or disrupting the circadian rhythm in animals can cause cancer” is almost undisputed
    .

    A large number of human social epidemiological studies have proved that: for humans, staying up late and irregular work and rest are carcinogenic factors; frequent changes in life and sleep rhythm, resulting in circadian rhythm disorders are harmful to health
    .

    Humans and most living organisms have biological clocks governed by light
    .

    The central circadian clock, located in the brain's suprachiasmatic nucleus, receives information about light levels from the retina and uses hormones and other signaling molecules to transmit the information to various cells in the body
    .

    Cells need the light signal, which is like a reset button on the biological clock, and if you lose this signal, you lose the normal circadian rhythm of every cell in your body
    .

    The biological clock regulates the operation of key links in the function of the human body and other organisms by controlling the activities of cell metabolism and division
    .

    On the correlation between biological clocks and cancer
    .

    A large number of studies have found that if you stay up late for a long time and often work irregularly, it can lead to disturbance of the biological clock and bring about a variety of chronic diseases, including cancer, obesity, diabetes, high blood pressure,
    etc.

    There have been 8 large-scale studies on "biological clock and cancer probability", and 6 of them have found that irregular work and rest can increase the risk of cancer
    .

    The results of the study proved that there are important genes that control the biological clock in the human body, and also proved that the important genes that control the biological clock play a key role in regulating cell growth and carcinogenesis
    .

    Compared with normal cells, the biological clock of cancer cells is usually disordered
    .

    The MIT biology team found through studies in mice that the Bmal1 and Per2 genes are responsible for initiating the activity of the biological clock and controlling the circadian rhythm of cells
    .

    Under normal circumstances, the amount of protein produced by the genes encoded by these genes fluctuates up and down as the light changes throughout the day
    .

    When the normal light-dark cycle was disrupted, the up-and-down changes in these proteins disappeared
    .

    If staying up late for a long time disturbs the normal state of the biological clock genes of all cells in the body, then under normal circumstances, light signals cannot be received, and eventually the biological clock is disturbed or destroyed
    .

    Previous studies have shown that the c-myc gene is associated with tumorigenesis and development
    .

    c-myc gene is one of the important members of the myc gene family.
    It is not only a regulatable gene regulated by a variety of substances, but also a gene that can promote cell division, promote cell infinite proliferation, and inhibit cell apoptosis
    .

    The c-myc gene is mainly activated by amplification and chromosomal translocation rearrangement, which enhances the expression of c-myc, promotes the malignant transformation of cells, and finally leads to the occurrence of tumors
    .

    At present, it is believed that colon cancer, gastric cancer, breast cancer, cervical cancer and other tumors have the amplification or overexpression of c-myc gene
    .

    Bmal1 and Per2 genes are involved in the regulation of c-myc protein.
    When Bmal1 and Per2 genes are destroyed, the production and accumulation of c-myc protein that promotes the infinite proliferation of cancer cells increases, which will stimulate cancer cells to carry out more metabolism and proliferation, and then Puts cancer cells into an uncontrolled growth pattern
    .

    Therefore, whether it is to destroy the two genes or to disrupt the normal light-dark cycle, as long as the control of the c-myc protein by the two genes Bmal1 and Per2 is lost, the inhibitory effect on the tumor will be lost, and the tumor will become more invasive
    .

    Not only that, but also studies have found that the disturbance of the biological clock not only increases the probability of cancer, but also makes cancer more malignant, more drug-resistant, and patients have a shorter lifespan
    .

    The research paper published in Cell Metabolism by Professor Tyler Jacks, director of MIT's Koch Institute for Comprehensive Cancer Research, provides evidence for an important link between circadian clock defects and cancer
    .

    He pointed out in the article: "If you disrupt the biological clock, cancer can occur via both pathways
    .

    " In October 2017, American genetic scientists Jeffrey Hall, Michael Rosbash, and Michael Young reported on " Molecular mechanisms that control circadian rhythms" won the 2017 Nobel Prize in Physiology or Medicine
    .

    The three scientists were awarded a Nobel Prize of SEK 9 million for their research results
    .

    In their study, three scientists discovered rhythm genes, also known as cycle genes, and the mechanism of self-regulating circadian rhythms
    .

    That is, when Per gene is active, it can synthesize Per messenger RNA and enter the cytoplasm to synthesize Per protein, and then Per protein enters the nucleus and accumulates gradually, inhibiting the activity of Per gene and reducing the production of Per protein
    .

    This creates an inhibitory feedback mechanism that shapes the circadian rhythm; a second cycle gene, which encodes the TIM protein required for normal circadian rhythm, was discovered while studying how the Per protein enters the nucleus
    .

    When TIM protein combines with Per protein to form two protein complexes, it can enter the nucleus, and then regulate the activity of cycle genes; another rhythm gene was found, which encodes DBT protein, which can delay the accumulation of Per protein and further regulate the biological clock.
    The cycle of increase and decrease of Per protein is fixed at about 24 hours
    .

    The findings explain how plants, animals and humans adapt their biological rhythms to day and night, in short, the biological clock
    .

    The biological clock is closely related to human health, and it regulates important functions of the human body, such as: behavior, sleep, hormone levels, body temperature,
    etc.

    When people are awake, when they sleep, when the hormone levels in the human body rise and when they fall, and the changes in body temperature during the day and night are all managed by the biological clock
    .

    The three scientists came to several conclusions through a series of sophisticated experiments: (1) staying up late for a long time will break the delicate biological clock in the human body, and diseases will come quietly; (2) staying up late for a long time will cause the brain to start swallowing itself, and staying up late for a long time will shorten life; (3) ) Long-term stay up late leads to the disorder of the biological clock.
    When the key genes regulating circadian rhythm fail, it will promote the occurrence of cancer; (4) Consciously caring for one's biological clock can prevent cancer
    .

    The most appropriate explanation for the research results of this "molecular mechanism that controls the operation of the biological clock" is: don't stay up late for a long time! 6 short words, every word is precious
    .

    Since the biological clock is closely related to human health, staying up late for a long time causes the key genes that regulate the circadian rhythm to fail, which can lead to the disturbance of the biological clock and promote cancer, so the colorectum is no exception
    .

    In addition to the increased expression of c-myc due to the disturbance of the biological clock, which can promote the malignant transformation of colorectal cells and the occurrence of CRC, the disturbance of the biological clock can also cause colorectal dysfunction
    .

    Under normal conditions, the primary function of the colorectum is to absorb water and electrolytes, and to form, store, and excrete feces
    .

    If colorectal dysfunction occurs, the function of absorbing water and electrolytes is weakened, diarrhea, or decreased bowel motility, excessive accumulation of food in the intestines for too long, feces cannot be excreted in time, and stay in the colorectum for too long.
    For a long time, the water in the stool will be absorbed, and the stool will become dry and hard, which will cause habitual constipation or difficulty in defecation
    .

    Therefore, colorectal dysfunction often manifests as diarrhea, constipation, or alternating diarrhea and constipation
    .

    Inflammation is a recognized internal environmental factor associated with the occurrence of CRC
    .

    Colorectal dysfunction makes the homeostasis of the colorectal microenvironment abnormal, which can lead to intestinal epithelial cell damage.
    Colorectal polyps and adenomas develop from advanced adenomas to precancerous lesions to CRC after 5 to 10 years
    .

    Studies have shown that intestinal bacterial metastasis and the production of various cancer-related pro-inflammatory factors caused by intestinal barrier defects can increase the risk of CRC
    .

    It can be said that staying up late for a long time can cause the disorder of the biological clock, and the disorder of the biological clock can lead to the disorder of colorectal function, which in turn causes a series of physiological and pathological changes, which increases the risk of CRC
    .

    Although staying up late is detrimental to health, staying up late occasionally, or short-term circadian rhythm changes, such as night shifts for work, business trips abroad, travel, study abroad, etc.
    , can self-regulate the biological clock to make the human body adapt to the time difference between day and night.
    It is not harmful to human health
    .

    Only in the case of staying up late for a long time, frequent irregular work and rest, and bad bowel habits, will the risk of CRC increase
    .

    If you stay up late for a long time, heavy smoking or excessive drinking will increase the risk of CRC
    .

     2.
    The relationship between intestinal flora imbalance and the risk of CRC is a hot topic of research by scholars at home and abroad.
    Although there are many possible mechanisms, they have not been studied globally due to insufficient direct evidence.
    recognized by the academic community
    .

    So what factors can cause intestinal flora imbalance in humans? Is gut dysbiosis associated with CRC risk? Intestinal flora is a huge and complex microbial community that resides in the human intestine, including bacteria, fungi and archaea, and is customarily called gut flora
    .

    The gut has co-evolved with a diverse gut microbiota ecosystem, in part by forming a strong immune system in the host to promote the mutual coexistence of the host and gut microbiota
    .

    The gut provides an internal environment for the intestinal flora to survive, and the key to maintaining the homeostasis is the intestinal epithelial cells, which form a single-layer physical barrier at the host-gut flora interface, called the gut barrier
    .

    The normal physiological functions of intestinal flora: (1) affect the normal structure and morphological changes of the intestine; (2) maintain the integrity and normal function of the intestinal barrier; (3) regulate the immune response of the host intestinal mucosa; (4) participate in the regulation of cell cycle and gene status; A metabolic enzyme that affects host metabolism,
    etc.

    The intestinal flora is affected by the internal and external environment of the human body
    .

    In the process of mutual adaptation between the intestinal flora and the host, a dynamic balance is achieved between the intestinal flora, the host and the intestinal microenvironment
    .

    When external environmental factors change, the intestinal flora also changes.
    The main external factors are diet, life>
    .

    Unhealthy diet and unhealthy life>
    .

    Intestinal flora imbalance is mainly manifested as changes in the overall structure and species of intestinal microorganisms, reduction of beneficial bacteria and increase of pathogenic bacteria
    .

    Intestinal flora imbalance can often lead to impaired systemic/local immune function of the human body, so that cancer cells with abnormal genetic mutations cannot be recognized and eliminated by the host intestinal immune system in a timely manner by way of immune escape
    .

    At present, more and more relevant research evidence shows that intestinal flora imbalance is related to the risk of CRC.
    When the internal and external environment changes, intestinal flora imbalance, reduction of probiotics, and proliferation of pathogenic bacteria can occur through Various possible mechanisms are involved in the occurrence and development of CRC
    .

    The research team of Fiona Powrie from the University of Oxford, UK, published a review, systematic review and review entitled "Host-microbiota interaction and risk of CRC/Host-microbiota maladaptation in colorectal cancer" in the journal Nature The host-gut microbiota interactions in CRC that have been reported so far, focusing on the analysis of gut microbiota, intestinal barrier disruption, genotoxicity and inflammatory responses and possible mechanisms of CRC occurrence
    .

    However, until now, the direct causes and underlying mechanisms of gut dysbiosis leading to CRC remain unclear
    .

    Therefore, while studying the correlation between circadian clock and cancer, diet and CRC risk, it is necessary to elucidate the interaction between circadian clock, diet and gut microbiota, and further research on the relationship between circadian clock disturbance and intestinal flora imbalance is needed.
    Interactions, circadian clock disturbances, and gut dysbiosis in relation to the risk of CRC
    .

    The circadian clock The potential role of the circadian clock in maintaining the normal physiological function of the gut microbiota is biologically plausible, but human data on the interaction between the circadian clock and the gut microbiota are currently lacking
    .

    However, in daily activities, healthy people who can consciously care for their own biological clock, do not stay up late for a long time, and have a regular schedule and rest can maintain the normal physiological function of the intestinal flora
    .

    Dietary gut microbiota is largely affected by dietary intake.
    Different dietary structures shape significantly different gut microbiota community structures.
    For example, a high-fiber diet can increase the content of Lactobacillus and Bifidobacterium in the gut.
    A high-fat diet, on the other hand, favors the growth of bile-tolerant microorganisms
    .

    Although diet, such as red and processed meat, can directly cause cancer, diet can also affect gut microbiota by altering the abundance and metabolites of specific species
    .

    A fiber-free diet and long-term chronic disease, such as type 2 diabetes, and many other clinical stressors alter the composition of the gut microbiota, resulting in a dramatic decrease in the diversity of the gut microbiota and an increase in pathogenic bacterial species
    .

    Therefore, a high-fiber diet can play a role in maintaining the normal physiological function of intestinal flora and reducing the risk of CRC
    .

    Exercise Exercise modulates gut flora
    .

    Some studies have found that the diversity of gut microbiota and the abundance of beneficial bacteria were significantly increased in subjects who exercised reasonably compared with subjects who were sedentary, which was beneficial for reducing the risk of CRC
    .

    The American Cancer Society recommends that moderate-intensity exercise, that is, at least 30 minutes at least 5 days a week, can reduce the risk of CRC by 50%
    .

    Antibiotics Antibiotics can interfere with the normal physiological function of human intestinal flora and cause intestinal flora imbalance
    .

    In September 2019, the team of Bali Pulendran of Stanford University published online in the journal Cell, entitled "Antibiotic-induced intestinal flora disturbance affects the body's immune response to vaccines/Antibiotics-Driven GutMicrobiome Perturbation Alters Immunity to Vaccines in Humans" research paper
    .

    Twenty-two healthy volunteers aged 18-45 were divided into an antibiotic group and a placebo group.
    After receiving the influenza vaccine, it was found that the intestinal flora caused by antibiotics was disturbed, leading to an inflammatory reaction in the body, which in turn affected the body's response to the vaccine.
    immune response
    .

    The authors verified this conclusion using high performance liquid chromatography, and compared with the placebo group, the ratio of primary cholic acid/secondary cholic acid in the antibiotic group was significantly higher than that in the placebo group, which is also related to the effect of intestinal flora imbalance.
    match
    .

    Secondary bile acids are known to be recognized carcinogens, and their prolonged action on colonic epithelial cells can enhance mitosis and increase the risk of CRC
    .

    Therefore, to avoid the abuse of antibiotics, rational use of antibiotics
    .

    Intestinal dysbiosis, whether caused by internal or external environmental factors, usually involves disruption of homeostatic immunity and gut microbiota-derived signaling, stimulates intestinal epithelial cells to produce an overrepair response, and modulates DNA damage by regulating DNA damage.
    , inflammation level, apoptosis level and carcinogen activity and other pathways, leading to a series of mutations in intestinal stem cells, such as APC, KRAS or PIK3CA gene mutations, and finally CRC
    .

    Existing studies have indisputably proved that high levels of pathogenic bacteria such as Clostridium nucleatum, Escherichia coli, Bacteroides fragilis, Enterococcus faecalis, Streptococcus urealyticum and Peptostreptococcus were detected in CRC tissues, while The number of probiotics with protective effect on the gut, including Roche, Clostridium, Fika and Bifidobacterium, was significantly reduced
    .

    Compared with healthy control individuals, CRC patients do have pathological changes in gut dysbiosis
    .

    Studies have shown that the composition of gut microbiota in high-risk groups of CRC is different from that in low-risk groups
    .

    High-risk groups of CRC also have intestinal flora imbalance, and some "carcinogenic bacteria" can play a carcinogenic role by producing virulence factors
    .

    The virulence factors produced by the "carcinogenic bacteria" group mainly include two categories: ① Genotoxic genotoxins, which can directly cause DNA damage and chromosomal instability, or reduce the repair ability of DNA, so that mutations accumulate and eventually lead to cell growth disorders and progression.
    CRC; ② other aggressive virulence factors, while destroying the intestinal barrier, can also induce intestinal epithelial cell proliferation and malignant transformation by regulating the expression of mutant genes, and participate in the occurrence and development of CRC
    .

    Figure 2 Schematic diagram of gut dysbiosis and the risk of CRC At the same time, the influx of pathogenic bacteria causes the depletion of immunocompetent CD8+ T cells in the immune response to clear pathogenic bacteria, which leads to impaired intestinal immune function and increases the risk of CRC
    .

    In conclusion, the biological clock and diet are closely related to the risk of CRC
    .

    There may be an interaction relationship between unhealthy life>
    .

    In conclusion, the direct causes and underlying mechanisms of CRC caused by circadian clock disturbance and intestinal flora imbalance need to be further studied and explored
    .

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