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 Table of Contents  
MINI REVIEW
Year : 2018  |  Volume : 4  |  Issue : 6  |  Page : 163-166

Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma


1 Department of Biliary- Surgery, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
2 Department of Traditional Chinese Medicine and Chemical Drug, Lanzhou Institutes for Food and Drug Control, Lanzhou, Gansu, China
3 Laboratory Animal Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
4 Boji Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

Date of Web Publication28-Dec-2018

Correspondence Address:
Dr. Ruiming Chang
Boji Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yan Jiang West Road, Guangzhou 510120, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_8_18

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  Abstract 


Hepatocellular carcinoma (HCC) mostly develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation, and regeneration. Increasing evidence points to the influence of bacterial gut microbiota influence on chronic liver disease and the development of HCC. We will review how bacterial gut microbiota contributes to HCC and relevant therapeutic strategies, focusing on alterations of the bacterial gut microbiota at different disease stages and mechanisms by which it contributes to disease progression and HCC development in different types of liver diseases.

Keywords: Bacteria gut microbiota, liver diseases, mechanisms


How to cite this article:
Zhang L, Qiu G, Xu X, Zhou Y, Chang R. Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma. Cancer Transl Med 2018;4:163-6

How to cite this URL:
Zhang L, Qiu G, Xu X, Zhou Y, Chang R. Novel insights into the role of bacterial gut microbiota in hepatocellular carcinoma. Cancer Transl Med [serial online] 2018 [cited 2019 Aug 19];4:163-6. Available from: http://www.cancertm.com/text.asp?2018/4/6/163/248974




  Introduction Top


Hepatocellular carcinoma (HCC) is the most common primary carcinoma of the liver. Most cases arise in chronically inflamed and subsequently cirrhotic livers. Drug abuse, alcohol abuse, autoimmunity, or infections are major risk factors.[1],[2] Large bodies of evidence have shown the influence of the gut microbiota on human health. Although it benefits the host in metabolism and immunity,[3],[4] it is also increasingly recognized in disease processes.[5] As bacteria are most dominant in the gut,[6] we will focus on the bacterial gut microbiota. It takes part in disease development not only via local effects but also at distant sites, such as the liver, along the gut-microbiota-liver axis.[7],[8],[9],[10] Owing to its anatomical connection, not only does the liver absorb nutrient substance, but it is also the first target of the bacterial gut microbiota. The intestinal mucosal barrier ensures that exposure is minimal; however, failing barrier contributes to the progression of liver diseases and thereby increases the risk of the development of HCC as the end stage of the chronic liver disease process.[11],[12] Here, we will concentrate on how bacterial gut microbiota contributes to liver disease progression at various stages and promote HCC in all processes and therapeutic strategies to interrupt this disease-promoting pathway.


  Mechanisms Underlying the Intestinal Mucosal Barrier Top


The intestinal mucosal barrier prevents microbes and metabolites crossing across the mucosa.[13],[14],[15] Its function relies on intact epithelial lining, mucosa-associated lymphoid tissue, mucus layer, and secretory IgA.[15] Intestinal mucosal barrier dysfunction can result in activation of the immune system and secretion of inflammatory mediators, which promote the development of disease processes.[12] Owing to its close anatomical connection to the liver, not only does the liver absorb nutrition but is also the first target of the bacterial gut microbiota.[16] Mechanisms underlying the failure of the intestinal mucosal barrier are most likely multifactorial, including bacterial dysbiosis, increased permeability, and inflammatory cytokines.[17] Liver diseases exert major effects on the bacterial gut microbiota, resulting in dysbacteriosis and increased intestinal permeability. It has been demonstrated that patients with cirrhosis show increased pathogenic bacteria, along with decreased beneficial properties.[18] However, the current understanding of bacterial gut microbiota remains incomplete. Thus, well-designed studies are still needed.

Liver fibrosis and cirrhosis

Although inflammation is a common feature of chronic hepatic diseases and correlates with the development and progression to HCC, the molecular mechanism among these processes of chronic liver injury is unclear.

Liver fibrosis is the hepatic response to long-term damage and commonly progresses to advanced chronic liver disease. The inflammatory responses are mediated by interaction between microbiota-associated molecular patterns and pattern recognition receptors, particularly the Toll-like receptors (TLRs).[19] Stimulation of TLRs in the liver, activates hepatic stellate cells (HSCs), which further increase liver fibrosis.[20] The majority of studies on the gut-microbiota-liver axis have focused on lipopolysaccharide (LPS) activity via binding to the receptor TLR4. Strong evidence points out important contribution of the LPS/TLR4 pathway to liver fibrosis. TLR4 is expressed in multiple hepatic cell types, including hepatocytes, HSCs, and Kupffer cells. LPS seems to promote liver diseases via multiple pathways. A study of Seki et al.[21] has shown intestinal microflora as the main source of portal LPS, representing an important prerequisite for the development of liver fibrosis during chronic liver injury, and antibiotics suppress hepatic fibrosis in part, which highlights a key role of TLR4. Disruption of the intestinal mucosal barrier results in increased LPS levels and fibrosis.[22] Conversely, the inhibition of TLR4 signal suppresses this process.[21] Mean LPS levels increase in patients with cirrhosis.[23] However, Tabibian et al. have shown an increased liver fibrosis in germ-free mice.[24] Further studies are needed to investigate how the bacterial gut microbiota affects liver fibrosis.

Alcoholic liver disease

Alcoholic liver disease (ALD) encompasses the manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and hepatitis with liver fibrosis or cirrhosis. ALD contributes to about half of all cirrhosis cases.[25],[26],[27] The ability of ethanol and its metabolite acetaldehyde to disrupt tight junctions contributes to the high levels of bacterial translocation in ALD.[28] Even single dose of alcohol has been shown to increase bacterial translocation and LPS level (14). A number of functional studies have shown a key contribution of the gut/microbiota/TLR4 axis to ALD,[29] which fits well with the well-established clinical observation that alcohol abuse is an important cofactor in promoting liver disease development and HCC.[30] Although ALD might have a lower relative risk of causing HCC,[31] the number of patients with alcoholic cirrhosis represents the high number of HCCs caused by ALD.

Fatty liver disease

Being recognized as a disease in recent years, fatty liver disease is becoming the leading cause of CLD.[32],[33],[34],[35] There is a strong association between fatty liver disease, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and bacterial gut microbiota. Studies have shown a close connection of the bacterial gut microbiota to metabolism, and the bacterial gut microbiota from obese individuals is more efficient at energy extraction.[36],[37] Henao-Mejia et al. found that increased intestinal permeability and metabolic endotoxemia contribute to the progression of NASH in mice.[38] Likewise, intestinal permeability is shown to be increased in patients with NAFLD.[39] Data from human studies also support the concept that the alternations of the bacterial gut microbiota contribute to the development of fatty liver diseases.

Liver cancer

Alterations in the bacterial gut microbiota not only occur in advanced CLD but also are characteristic in several types of early CLD. Hence, gut microbiota might contribute to disease progression at various stages and promote HCC in all processes. High LPS levels in rodents and patients with HCC demonstrate the presence of leaky gut.[40] Studies in animal model have provided evidence that the intestinal permeability contributes to HCC progression. TLR4 is present in multiple hepatic cell types, including Kupffer cells, HSCs, endothelial cells, and hepatocytes. TLR4 activation enhances invasive ability of HCC cells and induces the epithelial-mesenchymal transition.[41] Some experiments have provided evidence that the leaky gut, via LPS and its receptor TLR4, makes essential contributions to HCC. Disruption of the gut barrier not only results in increased systemic LPS levels and increased liver fibrosis but also promotes HCC formation.[22],[42] Conversely, the inhibition of TLR4 suppresses liver inflammation, fibrosis, and HCC formation.[11],[21]

Increasing evidence supports a key role of dysbiosis in the development of CLD and HCC. Evidence suggests that such effect is mediated by bacterial metabolites, possibly in a disease-specific manner. The finding that the bacterial gut microbiota of patients with compensated cirrhosis differs from that of patients with decompensated cirrhosis suggests that cirrhosis stage drives gut microbiota changes.[43] In addition to alterations in bacterial composition, evidence demonstrates bacterial overgrowth, which in turn is associated with increased circulating LPS levels.[44] In the past few years, studies have demonstrated differences in the duodenal and salivary microbiota between healthy individuals and patients with cirrhosis.[45],[46] This suggests that there are also qualitative and quantitative changes that might be linked to changes in the more distal microbiota, which might contribute to the pathophysiology of CLD as well as the development of HCC.


  Targeting Microbiota to Prevent Liver Diseases Top


On the basis of its contribution to liver diseases, the gut-microbiota-liver pathway is a promising target for prevention. With increased understanding of its underlying mechanisms, approaches to target the axis are increasing.

Probiotics and prokinetics

Probiotics have been used as a way of providing health benefits by restoring beneficial bacteria.[47],[48] Although studies have shown its effectiveness, controversy remains debating on the inability to permanently colonize the intestinal tract, unknown mechanisms, and lack of large-scale studies.[49] To date, probiotics have only been investigated in animal models. Further studies are required in human.

Gut dysmotility is another factor that contributes to bacterial overgrowth in liver cirrhosis.[50] The prokinetic drug cisapride not only decreases intestinal transit time but also inhibits intestinal bacterial overgrowth and bacterial translocation.[12] One of the purported mechanisms is increased adrenergic activity. Nonselective β-adrenergic blockers decrease intestinal transit time and reduce intestinal bacterial overgrowth, intestinal permeability, and bacterial translocation.[40],[51],[52]

Antibiotics

The composition of the intestinal microbiota can be altered with diet and probiotics, which produce mild temporary changes, or with antibiotics, which produce large changes in the bacterial composition of the intestines.[53] Antibiotics are one of the most efficient approaches to interrupt bacterial gut microbiota. Decreasing the number of bacterial gut microbiota will reduce translocation and inhibit inflammation. Administration of antibiotics at late stage was proven to be more efficient than administering at earlier stage of liver diseases,[11] which supports that the prevention of liver diseases by antibiotics could be applied in advanced patients. However, results from animal model cannot be converted to patients directly, as long-term treatment with antibiotics would be harmful, due to dysbacteriosis.[21] Thus, the use of single antibiotics with high safety might be the only feasible approach.

Fecal microbiota transplantation

The first description of fecal microbiota transplantation (FMT) as a therapeutic agent came from China.[54] The first use of FMT was described in 1958, for the treatment of pseudomembranous colitis.[55] To date, most clinical experience with the use of FMT has focused on relapsing Clostridium difficile infection.[56] However, patients receiving FMT are usually present with reduced microbial diversity.[56] Thus, these patients not only represent an ideal candidate for transplantation but also have a disease with reduced bacterial diversity. Moreover, it is of concern that infections might happen. In the future, FMT should be defined as clear mixtures of bacteria and with the same beneficial effects. Then, it will not only alleviate concerns about pathogens but also make it more acceptable.[57]


  Conclusion Top


It has been shown that bacterial gut microbiota makes a key influence to liver disease. Detailed knowledge about this disease-promoting axis could enable the development of therapeutic strategies. However, current understanding is largely from animal models, demanding more human studies in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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