Will probiotics usher in a new era of liver cancer prevention?

，。，，。，，，。，，，，。，？？，。？，。，，。，、、、、、。80-90%。，、，，。，，。20%，，。About 50% of liver cancer cases in the world are related to hepatitis B virus (HBV) infection, and people with chronic hepatitis B virus infection are more likely to develop liver cancer. Hepatitis B virus-induced liver cancer is driven by genomic instability caused by insertional mutations and the production of oncoproteins HBx and pre-S2. HBx can promote cell proliferation, tumor angiogenesis, oxidative stress-mediated liver damage and liver cancer metastasis; and the accumulation of pre-S2 mutant protein in the endoplasmic reticulum of liver cells can cause endoplasmic reticulum stress and promote the occurrence of liver cancer. The development of characteristic ground-glass-like hepatocytes. The endoplasmic reticulum stress produced by the pre-S2 mutant protein can also induce oxidative damage to hepatocyte DNA. Chronic hepatitis C virus (HCV) infection is the main risk factor for liver cancer in most western countries. 75-80% of patients with hepatitis C virus infection will develop chronic infection, increasing the risk of liver cancer by 15-20 times. The core protein of hepatitis C virus promotes hepatocyte adipogenesis, induces oxidative stress, and significantly affects the cell signaling pathway that regulates hepatocyte proliferation and the expression of tumor suppressor genes. The non-structural proteins of hepatitis C virus promote liver fibrosis and liver cancer metastasis. In addition, the hepatitis C virus increases chronic liver inflammation by inhibiting the production of type I interferon and the differentiation of CD8+ T cells. The influx of pro-inflammatory cytokines into the liver will also further promote liver inflammation. 　　Non-alcoholic fatty liver 　　Non-alcoholic fatty liver is positively correlated with the incidence of liver cancer. With its worldwide prevalence, non-alcoholic fatty liver is becoming a major risk factor. In patients with non-alcoholic fatty liver, the influx of fatty acids in the liver can induce liver steatosis and lipotoxicity, leading to mitochondrial dysfunction, endoplasmic reticulum stress and liver oxidative stress. Steatosis of the liver induces liver inflammation by increasing the production of pro-inflammatory cytokines. The activation of natural killer T cells during non-alcoholic fatty liver can also promote liver steatosis, and together with CD8+ T cells, induce liver damage. Liver injury can induce inflammation, activate immune cells, induce the production of pro-inflammatory cytokines and concentrate on the injured site, thereby promoting liver inflammation. DNA oxidative damage, DNA methylation defects and decreased expression of tumor suppressor genes further promote the transformation of fatty liver to liver cancer. 　　alcoholism　　Alcoholism and subsequent alcoholic liver disease is also a major risk factor, accounting for 30% of liver cancer cases. The onset of alcoholic liver disease begins with simple steatosis, and then progresses to alcoholic hepatitis, fibrosis and cirrhosis. The liver metabolism of alcohol directly promotes the occurrence of liver cancer by promoting the formation of DNA adducts, oxidative stress, and the consumption of retinol and retinoic acid. In the process of alcohol metabolism, increased cytochrome P450 (CYP) 2E1 activity will increase liver oxidative stress and activate some pre-carcinogens, including nitrosamines, polycyclic hydrocarbons and hydrazines. In addition, increased CYP2E1 activity will deplete retinol and retinoic acid from liver tissue, destroying cell growth and differentiation. Acetaldehyde produced by alcohol metabolism has carcinogenic effects through the formation of DNA adducts and gene mutations. 　　Genetic factors 　　Genetic factors also play a certain role in the occurrence of liver cancer. Germline mutations and single nucleotide polymorphisms (SNPs) are both inherent risk factors for liver cancer. Some genetic predisposing factors may make a person susceptible to liver cancer. 　　Mutations in the germline genes of the hereditary hemochromatosis protein HFE and copper transporter ATP7B can lead to chronic liver damage and develop liver cancer due to the accumulation of excessive iron (hemochromatosis) and copper (Wilson's disease) in the liver, respectively. Germline mutations and external risk factors can significantly increase the risk of liver cancer. In non-alcoholic fatty liver cases, germline mutations in the telomerase reverse transcriptase (TERT) gene may determine the progression of non-alcoholic fatty liver to cirrhosis and liver cancer. 　　SNP is a single base pair replacement in the coding or non-coding region of DNA, which can change DNA repair, cell regulation and immunity, and significantly increase the risk of cancer. Certain gene SNPs can promote the pathogenesis of liver cancer, such as TNF-α, AFP, TLR2, miR-146a, miR-196a-2, and IL-1β. Vascular endothelial growth factor (VEGF) gene polymorphism can promote the recurrence of liver cancer after liver transplantation. 　　The relationship between the intestinal flora and the occurrence of liver cancer The 　　liver is directly connected to the intestine through the portal circulation, and the occurrence of liver cancer is related to harmful changes in the intestinal flora. This important two-way communication pathway between the intestine and liver is called the "gut-liver axis". The gut liver axis can participate in the occurrence of liver cancer by exposing the liver to bacterial lipopolysaccharide (LPS), DNA, peptidoglycan, and flagellin. 　　Many risk factors for liver cancer, including hepatitis B and C virus infections, alcoholic liver disease, and non-alcoholic fatty liver, can stimulate the imbalance of intestinal flora and increase intestinal permeability. The nature of intestinal flora imbalance in patients with liver cancer depends to a large extent on the cause of the disease and the physiological factors of the host. It is usually manifested as an increase in pro-inflammatory bacteria and a decrease in anti-inflammatory short-chain fatty acid-producing bacteria. Short-chain fatty acids can regulate anti-inflammatory response and regulate cell differentiation and proliferation. 　　The host immune system is very sensitive to intestinal bacteria and their derivatives. Imbalance of the intestinal flora will destroy the integrity of the intestinal epithelial barrier and increase the permeability of the intestinal tract. Then intestinal bacteria and their derivatives may leak into the body circulation and affect organ function. When they reach the liver, they promote liver inflammation by stimulating immune cells to produce pro-inflammatory cytokines. 　　There is a strong correlation between liver cancer and the levels of flagellin and LPS antibodies in the blood. LPS derived from intestinal bacteria can activate Kupffer cells (special macrophages in the liver) in the liver through Toll-like receptors and subsequently secreted inflammatory cytokines. 　　Lipoteichoic acid is a component of obesity-induced Gram-positive intestinal bacteria, which can promote obesity-related liver cancer in mice through Toll-like receptor signaling. Lipoteichoic acid can also up-regulate the expression of COX-2 and senescence-related secreted phenotypic factors in hepatic stellate cells together with deoxycholic acid, another obesity-induced intestinal bacterial metabolite. The secretion of senescence-related secreted phenotypic factors can promote the occurrence of liver cancer through the expression of inflammatory factors and growth-regulating oncogenes, and the overexpression of COX-2 can inhibit anti-tumor immunity by stimulating the prostaglandin E2 receptors on immune cells. Overexpression of COX-2 and increased production of prostaglandin E2 are common in stellate cells of some liver cancer patients. 　　In addition, the potential of the intestinal flora to convert primary bile acids (such as cholic acid and chenodeoxycholic acid) into secondary bile acids (such as deoxycholic acid) may also promote the development of fatty liver to liver cancer. 　　Probiotics may reduce the risk of liver cancer. 　　Many in vitro and in vivo studies have investigated the inhibitory effect of probiotics on the pathogenesis of liver cancer. Probiotics may inhibit the occurrence of liver cancer in a variety of ways. 　　Probiotics can restore the complexity and colonization resistance of intestinal bacteria to overcome the dysbiosis associated with liver cancer. 　　The anatomical connection between the intestine and the liver and the relationship between the intestinal flora and the occurrence of liver cancer suggest that probiotics may play a role in preventing the occurrence of liver cancer. 　　1. Probiotics can help promote the growth of healthy intestinal bacteria, thereby producing anti-inflammatory metabolites with tumor suppressor activity. For example, probiotics can stimulate the growth of beneficial short-chain fatty acid-producing bacteria in the intestine. It is well known that short-chain fatty acids can regulate anti-inflammatory responses and regulate cell differentiation and proliferation. 　　2. Probiotics can also protect the intestinal epithelial barrier function by up-regulating the expression of tight junction proteins, restrict the translocation of intestinal bacteria and their derivatives into the liver and prevent bacterial endotoxemia. Endotoxemia caused by changes in intestinal flora has been identified as the main risk factor for liver cancer, which promotes the occurrence of liver cancer through chronic liver inflammation. 　　3. The cell surface protein of probiotics can attenuate the inflammatory response of intestinal epithelial cells, inhibit epithelial cell apoptosis, and maintain the integrity of intestinal epithelial cells. 　　4. Probiotics can increase the mucus secretion of goblet cells and the release of antibacterial peptides, and protect the intestinal epithelium from the invasion of pathogenic bacteria. 　　For example, a compound probiotic called Prohep can promote the growth of propionic acid-producing Prussella bacteria and tremorobacter bacteria that are involved in the homeostasis of IL-10-producing regulatory T cells. Compared with the control group, the tumor growth of mice fed with probiotic Prohep and subcutaneously injected with Hepa1-6 mouse liver cancer cells decreased by 40%. At the same time, the probiotic also significantly reduces the expression of the inflammatory cytokine IL-17 in the tumor by inhibiting the number of Th17 cells and the infiltration of Th17 cells from the intestinal and peripheral circulation into the tumor. In addition, supplementing with probiotics can also up-regulate the expression of some anti-inflammatory cytokines. In mice supplemented with probiotic Prohep, the expression of angiogenic factors was also down-regulated, thereby inhibiting tumor angiogenesis. 　　When intestinal permeability increases, intestinal bacteria and their derivatives translocate into the liver, which can promote the occurrence of liver cancer through the inflammatory response mediated by Toll-like receptors. Supplementing probiotics can inhibit the occurrence of liver cancer by down-regulating the expression of liver inflammation induced by Toll-like receptors. In rats with drug-induced liver cirrhosis, supplementation of probiotic Lactobacillus plantarum can reduce the low expression of TLR4 and reduce liver damage. In rats supplemented with probiotics, the expression of CXCL9 and PREX-2 genes was also low, and CXCL9 could promote the aggressiveness of liver cancer through PREX-2. Therefore, the down-regulation of TLR4 and CXCL9/PREX-2 by probiotics can inhibit the occurrence of drug-induced liver cirrhosis, thereby reducing the risk of liver cancer. 　　Probiotics can promote the epigenetic regulation of host gene expression, which is also conducive to reducing the risk of liver cancer. 　　The interaction between the host and the intestinal flora is involved in the regulation of host gene expression, including DNA methylation and histone modification. 　　The probiotics Lactobacillus acidophilus and Bifidobacterium bifidum can reduce the expression of some carcinogenic small RNA molecules and oncogenes in the liver of mice treated with colon carcinogen azomethane. In addition, the expression of some tumor suppressor genes increased. 　　Since acquired gene mutations play a key role in the occurrence of liver cancer, supplementing with probiotics may also reduce the risk of liver cancer by protecting the liver cell genome. For example, the probiotic Lactobacillus plantarum can reduce diabetes-induced liver DNA damage in rats, which may solve the oxidative stress in the liver of diabetic rats by restoring superoxide dismutase activity. In addition, supplementation of probiotics in diabetic rats can also improve liver cell damage by restoring Akt activity and preventing the degradation of caspase 3 precursor protein. Supplementation of Lactobacillus plantarum can also reduce liver inflammation and fibrosis by down-regulating the expression of C/EBP/β and A2MG genes. C/EBP/β is a cytokine-induced transcription factor expressed in hepatocyte differentiation and inflammation, which promotes liver fibrosis; and A2MG can promote fibrosis by inhibiting the catabolism of liver matrix proteins. 　　，SIRT1，。SIRT1、，。　　。　　HBsAg，HepG2HBsAg。MxA，MxA。。　　。。，，-α。　　。　　。，、。，。，TNF-α。，、。　　。，、。LPSTLR4，。　　　　，。、B1，。。　　，。　　，ATPHepG2。　　，，。，、、。　　　　，，、、、。，、。，，，。，。　　。、、、。，，，。。，。、，，，。，。。　　，。，。，，。　　，，、、。，，，。　　：　　Thilakarathna, W. P. D. W. , et al. (2021). "Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma. " Int J Mol Sci 22: 2606.      ：，。，、、、，，。          1. ，。2. 、，，，，bio14912。3. 86371366@qq. com，，。

　　，。，，。，，，。　　，，，，。，？？　　，。　　？　　，。，，。，、、、、、。80-90%。　　，、，，。，，。20%，，。　　　　50%（HBV），。HBxpre-S2。HBx、、；pre-S2，。pre-S2DNA。　　（HCV）。75-80%，15-20。，，。。，ICD8+ T。。　　　　，，。，，、。。T，CD8+ T，。，，，。DNA、DNA。　　　　，30%。，、。DNA、。，P450（CYP）2E1，，、。，CYP2E1，。DNA。　　　　，（SNP）。。　　HFEATP7B，（）（）。。，（TERT）。　　SNPDNA，DNA、，。SNP， TNF-α、AFP、TLR2、miR-146a、miR-196a-2IL-1β。（VEGF）。　　　　，。“”。（LPS）、DNA、。　　，、，。，，。，。　　。，，，。。　　LPS。LPSTollKupffer（）。　　，Toll。，COX-2。，COX-2E2 。COX-2E2。　　，（）（）。　　　　，。　　，。　　。　　1、，。，，，，。　　2、，。，。　　3、，，。　　4、，。　　，Prohep，IL-10T。，ProhepHepa1-640%。，Th17Th17IL-17。，。Prohep，。　　，，Toll。Toll。，TLR4，。，CXCL9PREX-2，CXCL9PREX-2。，TLR4CXCL9/PREX-2，。　　，。　　，DNA。　　RNA。，。　　，。，DNA，。，Aktcaspase 3。C/EBP/βA2MG。C/EBP/β，；A2MG。　　，SIRT1，。SIRT1、，。　　。　　HBsAg，HepG2HBsAg。MxA，MxA。。　　。。，，-α。　　。　　。，、。，。，TNF-α。，、。　　。，、。LPSTLR4，。　　　　，。、B1，。。　　，。　　，ATPHepG2。　　，，。，、、。　　　　，，、、、。，、。，，，。，。　　。、、、。，，，。。，。、，，，。，。。　　，。，。，，。　　，，、、。，，，。　　：　　Thilakarathna, W.
P.
D.
W.
, et al.
(2021).
"Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.
" Int J Mol Sci 22: 2606.

---

　　，。，，。，，，。　　，，，，。，？？　　，。　　？　　，。，，。，、、、、、。80-90%。　　，、，，。，，。20%，，。　　　　50%（HBV），。HBxpre-S2。HBx、、；pre-S2，。pre-S2DNA。　　（HCV）。75-80%，15-20。，，。。，ICD8+ T。。　　　　，，。，，、。。T，CD8+ T，。，，，。DNA、DNA。　　　　，30%。，、。DNA、。，P450（CYP）2E1，，、。，CYP2E1，。DNA。　　　　，（SNP）。。　　HFEATP7B，（）（）。。，（TERT）。　　SNPDNA，DNA、，。SNP， TNF-α、AFP、TLR2、miR-146a、miR-196a-2IL-1β。（VEGF）。　　　　，。“”。（LPS）、DNA、。　　，、，。，，。，。　　。，，，。。　　LPS。LPSTollKupffer（）。　　，Toll。，COX-2。，COX-2E2 。COX-2E2。　　，（）（）。　　　　，。　　，。　　。　　1、，。，，，，。　　2、，。，。　　3、，，。　　4、，。　　，Prohep，IL-10T。，ProhepHepa1-640%。，Th17Th17IL-17。，。Prohep，。　　，，Toll。Toll。，TLR4，。，CXCL9PREX-2，CXCL9PREX-2。，TLR4CXCL9/PREX-2，。　　，。　　，DNA。　　RNA。，。　　，。，DNA，。，Aktcaspase 3。C/EBP/βA2MG。C/EBP/β，；A2MG。　　，SIRT1，。SIRT1、，。　　。　　HBsAg，HepG2HBsAg。MxA，MxA。。　　。。，，-α。　　。　　。，、。，。，TNF-α。，、。　　。，、。LPSTLR4，。　　　　，。、B1，。。　　，。　　，ATPHepG2。　　，，。，、、。　　　　，，、、、。，、。，，，。，。　　。、、、。，，，。。，。、，，，。，。。　　，。，。，，。　　，，、、。，，，。　　：　　Thilakarathna, W.
P.
D.
W.
, et al.
(2021).
"Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.
" Int J Mol Sci 22: 2606.

---

Liver cancer is the fifth most common cancer in the world and the third leading cause of cancer deaths.
my country is one of the countries with the heaviest burden of liver cancer.
The high incidence and large population have caused more than half of the world's liver cancer patients to live in my country.
Not long ago, the well-known musician Zhao Yingjun and the famous Hong Kong film star Wu Mengda passed away from liver cancer.
This has once again sounded the health alarm to us all.
How to prevent liver cancer has once again become the focus of attention.
A healthy diet and life>So, do probiotics have the potential to prevent liver cancer? Will it start a new era of liver cancer prevention in the future? To understand this, we first need to understand the cause of liver cancer.
How does liver cancer happen? Liver cancer is a very complex disease.
There are multiple risk factors that determine the progression and pathogenesis of liver cancer.
Among them, many risk factors are external and can be changed by changing life>For example, hepatitis B and C virus infection, smoking, alcoholism, non-alcoholic fatty liver, obesity and diabetes, liver damage caused by aflatoxin, etc.
are the main external risk factors for liver cancer.
About 80-90% of patients have cirrhosis before liver cancer is diagnosed.
The long-term existence of these risk factors, especially hepatitis virus infection, alcohol and non-alcoholic fatty liver, can promote liver inflammation, and then develop liver fibrosis and cirrhosis.
Chronic damage and inflammation of liver cirrhosis can lead to a high regeneration rate of liver cells, which may lead to the accumulation of malignant gene mutations, which can lead to cancer.
Only about 20% of liver cancer cases occur without cirrhosis.
However, the etiology and risk factors of non-cirrhotic liver cancer are very similar to those of cirrhotic liver cancer.
Hepatitis virus infectionAbout 50% of liver cancer cases in the world are related to hepatitis B virus (HBV) infection, and people with chronic hepatitis B virus infection are more likely to develop liver cancer.
Hepatitis B virus-induced liver cancer is driven by genomic instability caused by insertional mutations and the production of oncoproteins HBx and pre-S2.
HBx can promote cell proliferation, tumor angiogenesis, oxidative stress-mediated liver damage and liver cancer metastasis; and the accumulation of pre-S2 mutant protein in the endoplasmic reticulum of liver cells can cause endoplasmic reticulum stress and promote the occurrence of liver cancer.
The development of characteristic ground-glass-like hepatocytes.
The endoplasmic reticulum stress produced by the pre-S2 mutant protein can also induce oxidative damage to hepatocyte DNA.
Chronic hepatitis C virus (HCV) infection is the main risk factor for liver cancer in most western countries.
75-80% of patients with hepatitis C virus infection will develop chronic infection, increasing the risk of liver cancer by 15-20 times.
The core protein of hepatitis C virus promotes hepatocyte adipogenesis, induces oxidative stress, and significantly affects the cell signaling pathway that regulates hepatocyte proliferation and the expression of tumor suppressor genes.
The non-structural proteins of hepatitis C virus promote liver fibrosis and liver cancer metastasis.
In addition, the hepatitis C virus increases chronic liver inflammation by inhibiting the production of type I interferon and the differentiation of CD8+ T cells.
The influx of pro-inflammatory cytokines into the liver will also further promote liver inflammation.
Non-alcoholic fatty liver Non-alcoholic fatty liver is positively correlated with the incidence of liver cancer.
With its worldwide prevalence, non-alcoholic fatty liver is becoming a major risk factor.
In patients with non-alcoholic fatty liver, the influx of fatty acids in the liver can induce liver steatosis and lipotoxicity, leading to mitochondrial dysfunction, endoplasmic reticulum stress and liver oxidative stress.
Steatosis of the liver induces liver inflammation by increasing the production of pro-inflammatory cytokines.
The activation of natural killer T cells during non-alcoholic fatty liver can also promote liver steatosis, and together with CD8+ T cells, induce liver damage.
Liver injury can induce inflammation, activate immune cells, induce the production of pro-inflammatory cytokines and concentrate on the injured site, thereby promoting liver inflammation.
DNA oxidative damage, DNA methylation defects and decreased expression of tumor suppressor genes further promote the transformation of fatty liver to liver cancer.
alcoholismAlcoholism and subsequent alcoholic liver disease is also a major risk factor, accounting for 30% of liver cancer cases.
The onset of alcoholic liver disease begins with simple steatosis, and then progresses to alcoholic hepatitis, fibrosis and cirrhosis.
The liver metabolism of alcohol directly promotes the occurrence of liver cancer by promoting the formation of DNA adducts, oxidative stress, and the consumption of retinol and retinoic acid.
In the process of alcohol metabolism, increased cytochrome P450 (CYP) 2E1 activity will increase liver oxidative stress and activate some pre-carcinogens, including nitrosamines, polycyclic hydrocarbons and hydrazines.
In addition, increased CYP2E1 activity will deplete retinol and retinoic acid from liver tissue, destroying cell growth and differentiation.
Acetaldehyde produced by alcohol metabolism has carcinogenic effects through the formation of DNA adducts and gene mutations.
Genetic factors Genetic factors also play a certain role in the occurrence of liver cancer.
Germline mutations and single nucleotide polymorphisms (SNPs) are both inherent risk factors for liver cancer.
Some genetic predisposing factors may make a person susceptible to liver cancer.
Mutations in the germline genes of the hereditary hemochromatosis protein HFE and copper transporter ATP7B can lead to chronic liver damage and develop liver cancer due to the accumulation of excessive iron (hemochromatosis) and copper (Wilson's disease) in the liver, respectively.
Germline mutations and external risk factors can significantly increase the risk of liver cancer.
In non-alcoholic fatty liver cases, germline mutations in the telomerase reverse transcriptase (TERT) gene may determine the progression of non-alcoholic fatty liver to cirrhosis and liver cancer.
SNP is a single base pair replacement in the coding or non-coding region of DNA, which can change DNA repair, cell regulation and immunity, and significantly increase the risk of cancer.
Certain gene SNPs can promote the pathogenesis of liver cancer, such as TNF-α, AFP, TLR2, miR-146a, miR-196a-2, and IL-1β.
Vascular endothelial growth factor (VEGF) gene polymorphism can promote the recurrence of liver cancer after liver transplantation.
The relationship between the intestinal flora and the occurrence of liver cancer The liver is directly connected to the intestine through the portal circulation, and the occurrence of liver cancer is related to harmful changes in the intestinal flora.
This important two-way communication pathway between the intestine and liver is called the "gut-liver axis".
The gut liver axis can participate in the occurrence of liver cancer by exposing the liver to bacterial lipopolysaccharide (LPS), DNA, peptidoglycan, and flagellin.
Many risk factors for liver cancer, including hepatitis B and C virus infections, alcoholic liver disease, and non-alcoholic fatty liver, can stimulate the imbalance of intestinal flora and increase intestinal permeability.
The nature of intestinal flora imbalance in patients with liver cancer depends to a large extent on the cause of the disease and the physiological factors of the host.
It is usually manifested as an increase in pro-inflammatory bacteria and a decrease in anti-inflammatory short-chain fatty acid-producing bacteria.
Short-chain fatty acids can regulate anti-inflammatory response and regulate cell differentiation and proliferation.
The host immune system is very sensitive to intestinal bacteria and their derivatives.
Imbalance of the intestinal flora will destroy the integrity of the intestinal epithelial barrier and increase the permeability of the intestinal tract.
Then intestinal bacteria and their derivatives may leak into the body circulation and affect organ function.
When they reach the liver, they promote liver inflammation by stimulating immune cells to produce pro-inflammatory cytokines.
There is a strong correlation between liver cancer and the levels of flagellin and LPS antibodies in the blood.
LPS derived from intestinal bacteria can activate Kupffer cells (special macrophages in the liver) in the liver through Toll-like receptors and subsequently secreted inflammatory cytokines.
Lipoteichoic acid is a component of obesity-induced Gram-positive intestinal bacteria, which can promote obesity-related liver cancer in mice through Toll-like receptor signaling.
Lipoteichoic acid can also up-regulate the expression of COX-2 and senescence-related secreted phenotypic factors in hepatic stellate cells together with deoxycholic acid, another obesity-induced intestinal bacterial metabolite.
The secretion of senescence-related secreted phenotypic factors can promote the occurrence of liver cancer through the expression of inflammatory factors and growth-regulating oncogenes, and the overexpression of COX-2 can inhibit anti-tumor immunity by stimulating the prostaglandin E2 receptors on immune cells.
Overexpression of COX-2 and increased production of prostaglandin E2 are common in stellate cells of some liver cancer patients.
In addition, the potential of the intestinal flora to convert primary bile acids (such as cholic acid and chenodeoxycholic acid) into secondary bile acids (such as deoxycholic acid) may also promote the development of fatty liver to liver cancer.
Probiotics may reduce the risk of liver cancer.
Many in vitro and in vivo studies have investigated the inhibitory effect of probiotics on the pathogenesis of liver cancer.
Probiotics may inhibit the occurrence of liver cancer in a variety of ways.
Probiotics can restore the complexity and colonization resistance of intestinal bacteria to overcome the dysbiosis associated with liver cancer.
The anatomical connection between the intestine and the liver and the relationship between the intestinal flora and the occurrence of liver cancer suggest that probiotics may play a role in preventing the occurrence of liver cancer.
1.
Probiotics can help promote the growth of healthy intestinal bacteria, thereby producing anti-inflammatory metabolites with tumor suppressor activity.
For example, probiotics can stimulate the growth of beneficial short-chain fatty acid-producing bacteria in the intestine.
It is well known that short-chain fatty acids can regulate anti-inflammatory responses and regulate cell differentiation and proliferation.
2.
Probiotics can also protect the intestinal epithelial barrier function by up-regulating the expression of tight junction proteins, restrict the translocation of intestinal bacteria and their derivatives into the liver and prevent bacterial endotoxemia.
Endotoxemia caused by changes in intestinal flora has been identified as the main risk factor for liver cancer, which promotes the occurrence of liver cancer through chronic liver inflammation.
3.
The cell surface protein of probiotics can attenuate the inflammatory response of intestinal epithelial cells, inhibit epithelial cell apoptosis, and maintain the integrity of intestinal epithelial cells.
4.
Probiotics can increase the mucus secretion of goblet cells and the release of antibacterial peptides, and protect the intestinal epithelium from the invasion of pathogenic bacteria.
For example, a compound probiotic called Prohep can promote the growth of propionic acid-producing Prussella bacteria and tremorobacter bacteria that are involved in the homeostasis of IL-10-producing regulatory T cells.
Compared with the control group, the tumor growth of mice fed with probiotic Prohep and subcutaneously injected with Hepa1-6 mouse liver cancer cells decreased by 40%.
At the same time, the probiotic also significantly reduces the expression of the inflammatory cytokine IL-17 in the tumor by inhibiting the number of Th17 cells and the infiltration of Th17 cells from the intestinal and peripheral circulation into the tumor.
In addition, supplementing with probiotics can also up-regulate the expression of some anti-inflammatory cytokines.
In mice supplemented with probiotic Prohep, the expression of angiogenic factors was also down-regulated, thereby inhibiting tumor angiogenesis.
When intestinal permeability increases, intestinal bacteria and their derivatives translocate into the liver, which can promote the occurrence of liver cancer through the inflammatory response mediated by Toll-like receptors.
Supplementing probiotics can inhibit the occurrence of liver cancer by down-regulating the expression of liver inflammation induced by Toll-like receptors.
In rats with drug-induced liver cirrhosis, supplementation of probiotic Lactobacillus plantarum can reduce the low expression of TLR4 and reduce liver damage.
In rats supplemented with probiotics, the expression of CXCL9 and PREX-2 genes was also low, and CXCL9 could promote the aggressiveness of liver cancer through PREX-2.
Therefore, the down-regulation of TLR4 and CXCL9/PREX-2 by probiotics can inhibit the occurrence of drug-induced liver cirrhosis, thereby reducing the risk of liver cancer.
Probiotics can promote the epigenetic regulation of host gene expression, which is also conducive to reducing the risk of liver cancer.
The interaction between the host and the intestinal flora is involved in the regulation of host gene expression, including DNA methylation and histone modification.
The probiotics Lactobacillus acidophilus and Bifidobacterium bifidum can reduce the expression of some carcinogenic small RNA molecules and oncogenes in the liver of mice treated with colon carcinogen azomethane.
In addition, the expression of some tumor suppressor genes increased.
Since acquired gene mutations play a key role in the occurrence of liver cancer, supplementing with probiotics may also reduce the risk of liver cancer by protecting the liver cell genome.
For example, the probiotic Lactobacillus plantarum can reduce diabetes-induced liver DNA damage in rats, which may solve the oxidative stress in the liver of diabetic rats by restoring superoxide dismutase activity.
In addition, supplementation of probiotics in diabetic rats can also improve liver cell damage by restoring Akt activity and preventing the degradation of caspase 3 precursor protein.
Supplementation of Lactobacillus plantarum can also reduce liver inflammation and fibrosis by down-regulating the expression of C/EBP/β and A2MG genes.
C/EBP/β is a cytokine-induced transcription factor expressed in hepatocyte differentiation and inflammation, which promotes liver fibrosis; and A2MG can promote fibrosis by inhibiting the catabolism of liver matrix proteins.
A composite probiotic composed of Saccharomyces cerevisiae and Lactobacillus acidophilus combined with selenium and glutathione can prevent tetrachloromethane-induced liver fibrosis by activating the SIRT1 gene in liver cells.
The activation of SIRT1 can improve tetrachloromethane-induced oxidative stress, endoplasmic reticulum stress and inflammatory response in the liver, which is manifested by decreased serum alanine aminotransferase and aspartate aminotransferase activities.
The antiviral activity of probiotics may reduce the occurrence of liver cancer by preventing hepatitis virus infection.
The cell extract of the probiotic Bifidobacterium adolescentis can inhibit the expression of hepatitis B virus surface antigen HBsAg gene at the transcription level, and limit the growth of hepatitis B virus and the secretion of HBsAg in human liver cancer HepG2 cells.
The antiviral activity of Bifidobacterium adolescentis is achieved by activating the MxA gene, which inhibits virus replication by binding and degrading the viral nucleocapsid and other viral components.
The metabolites of Lactobacillus bulgaricus can also reduce viral load and cell degeneration.
Supplementing probiotics can also improve liver function during hepatitis C virus infection.
Heat-killed Enterococcus faecalis can reduce the levels of alanine aminotransferase and aspartate aminotransferase in the serum of hepatitis C virus-positive subjects.
In addition, in patients with chronic hepatitis C virus infection, supplementation of probiotics Lactobacillus acidophilus and Bifidobacterium can improve the response of peginterferon-α combined with ribavirin to treat hepatitis C virus infection.
Probiotics can improve the liver damage of patients with non-alcoholic fatty liver and reduce the risk of developing liver cancer.
Non-alcoholic fatty liver is another major risk factor for liver cancer.
Supplementing Lactobacillus acidophilus and Bifidobacterium lactis can improve the liver damage of patients with non-alcoholic fatty liver, which is manifested in the levels of serum alanine aminotransferase, aspartate aminotransferase and total cholesterol.
In obese non-alcoholic fatty liver patients, taking probiotics can significantly reduce body weight and body fat content.
In addition, probiotics also reduce liver inflammation in obese non-alcoholic fatty liver patients by down-regulating the pro-inflammatory cytokine TNF-α.
Some compound probiotics can also significantly improve the liver histology of patients with non-alcoholic fatty liver, and reduce liver damage caused by hepatocyte ballooning degeneration, liver fibrosis and liver lobule inflammation.
The liver protection and anti-inflammatory effects of probiotics in patients with non-alcoholic fatty liver disease can also be achieved by improving the intestinal flora.
For example, probiotics can improve the destruction of mouse intestinal flora, colonization resistance and intestinal epithelial barrier function induced by a high-sugar and high-fat diet.
Restoring the balance of intestinal flora and intestinal epithelial barrier function will prevent the progression of non-alcoholic fatty liver by reducing the level of serum LPS and inhibiting the activation of TLR4-mediated liver inflammation.
Probiotics can be combined with aflatoxin.
In developing countries, food contamination with aflatoxin is a risk factor for liver cancer.
A probiotic yogurt containing Streptococcus thermophilus, Lactobacillus rhamnosus and Weisseria foods can significantly reduce the presence of aflatoxin metabolites in the urine after children eat corn contaminated with aflatoxin B1.
This may It is the result of reduced intestinal absorption due to combination with probiotics.
The probiotic Lactobacillus rhamnosus and Weisseria foods bind to aflatoxins through cell wall peptidoglycans.
Probiotics can bio-convert dietary ingredients into metabolites with anti-cancer properties.
This potential also helps prevent liver cancer.
The probiotic Lactobacillus rhamnosus can bioconvert cranberry flavonoids into simple phenolic acids.
These biotransformed flavonoids can inhibit the proliferation of human liver cancer HepG2 cells by consuming ATP.
Similarly, the combined use of probiotics and oligofructose can improve the physiological parameters of non-obese non-alcoholic fatty liver patients, and significantly reduce liver steatosis and fibrosis in patients.
In addition, they can effectively reduce the levels of serum aspartate aminotransferase, fasting blood glucose, triglycerides and certain inflammatory mediators.
Summary The occurrence of liver cancer is a very complex process, controlled by a variety of risk factors, including hepatitis B virus and hepatitis C virus infection, alcoholism, non-alcoholic fatty liver, genetic mutations and long-term exposure to aflatoxin.
These risk factors can easily lead to liver damage, which subsequently develops into liver fibrosis, cirrhosis and eventually liver cancer.
The incidence of liver cancer in my country ranks first in the world, and most liver cancer cases are detected late, the treatment cost is high, the effect is poor, and the mortality rate is high.
Therefore, the early prevention of liver cancer is particularly important.
The current understanding of the potential of probiotics to prevent the occurrence of liver cancer provides some new hints for future risk management and alternative treatment of liver cancer.
Probiotics can reduce the occurrence of liver cancer through various mechanisms such as regulating the host intestinal flora, preventing endotoxemia related to flora imbalance, maintaining the intestinal epithelial barrier function, and inhibiting the translocation of intestinal bacteria and their derivatives into the body circulation.
risk.
Probiotics can also increase the expression of antioxidant enzymes to promote the growth of beneficial microorganisms, produce anti-inflammatory metabolites, and reduce oxidative stress in the liver.
The antiviral activity of probiotics can reduce the risk of liver cancer by preventing chronic hepatitis B virus and hepatitis C virus infection.
In addition, probiotics can also prevent liver fat toxicity by improving obesity and non-alcoholic fatty liver.
Probiotics also have anti-angiogenesis, anti-proliferation and anti-tumor metastasis properties, and can up-regulate the expression of tumor suppressor factors and inhibit the expression of oncogenes, thereby reducing the risk of liver cancer.
Finally, probiotics can biologically convert non-nutritive dietary components such as flavonoids into simpler metabolites with anti-cancer effects.
These anti-cancer mechanisms all illustrate the potential of probiotics as liver cancer risk management and adjuvant treatment strategies.
However, clinical studies directly evaluating probiotics in the prevention or treatment of liver cancer are very limited.
In the future, further research is needed to explore the synergistic effects of different probiotics in reducing the risk of liver cancer, so as to form a compound probiotic that can provide excellent anti-cancer effects.
At the same time, the ability of probiotics to biotransform some dietary ingredients into metabolites with anti-cancer properties can also be further studied to form effective synbiotic preparations for the prevention and treatment of liver cancer.
Of course, the best way to prevent liver cancer is to have a healthy diet and life>At the same time, in today's society full of various insecurity factors, in this society where the intestinal flora is constantly impacted, we also look forward to probiotics to open a new era of liver cancer prevention.
References: Thilakarathna, WPDW, et al.
(2021).
"Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.
" Int J Mol Sci 22: 2606.

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