Hepatocellular carcinoma (HCC) occurs in patients with chronic liver damage, inflammation and cirrhosis. The facilitators involved in increasing the HCC risk in the damaged liver are yet to be discovered. Diet and lifestyle have a profound effect on the liver inflammation and HCC. The term “gut liver axis” describes the bidirectional relationship between the liver and the gut, which are both anatomically and functionally related. Chronic liver damage is characterised by increased intestinal permeability that allows the translocation of various components and metabolites from the gut microbiota to the liver, resulting in liver inflammation and fibrosis.
- Gut-Liver Axis and Liver Disease
- gut microbiome
- hepatocellular carcinoma
- chronic liver disease
1. Introduction
Hepatocellular carcinoma (HCC) is the most common primary cancer in adults representing third of all cancer-related deaths [1]. Patients with chronic liver disease (CLD), inflammation and cirrhosis have an 80% risk to develop HCC. The factors that facilitate HCC onset and development remain to be discovered. We do know from epidemiological and observational data that a healthy diet can offer protection for a number of different cancer kinds, whereas an unbalanced diet augments the risk for cancer. The majority of studies on the association of diet and HCC pathogenesis agree that there is a protective role of vegetables, fruit, cereals and fish in HCC risk [2][3].
Diet exerts a powerful influence on gut microbial composition that may impact liver disease. Humans are thought to have evolved a symbiotic relationship with gut microbiota; however, the molecular mechanisms underpinning this mutually benefiting relationship remain poorly understood. DNA-based analysis has enabled the identification of the microbes that reside in gut microbiome, but understanding their precise function is still a challenge. For example, gut microbiota produces low molecular weight substances, including metabolic derivatives that can regulate biochemical and molecular pathways.
The notion that cirrhosis positively correlates with intestinal dysbiosis was proposed by Sherlock and his team in the 1950s. They reported that there was an overload of coliform bacteria in the ileum of cirrhotic patients [4]. Today we know for a fact that chronic liver inflammation induces intestinal permeability followed by the translocation of gut bacteria, their components and/or metabolites, which are causing the characteristic complications of advanced liver disease stages [5][6].
In chronic liver inflammation, new-forming tumour cells and the resident liver cells and/or the tumour-forming cells are both regulated by inflammatory signals to survive. Due to the lack of comprehensive and prospective studies on chronic liver injury in humans, we have underestimated the contribution of inflammatory pathways induced from gut microbial components to HCC.
2. The Gut-Liver Axis
Gut microbiome is crucial for the host’s survival as it metabolizes ingested food that could not be processed by the host otherwise. Bioinformatics, metabolomics and next-generation sequencing have led to the assessment of the intestinal composition by identifying the DNA sequences of the 16S ribosomal RNA gene and other microbial genes. In addition, the functional relevance of the intestinal microbial community shows that gut microbial components and their metabolites influence greatly human pathology [7].
Anatomically and functionally, the liver and the intestine are connected. The liver, however, is not directly in contact with gut bacteria, but it is the first organ where gut bacteria are translocating via the systemic circulation. Therefore, gut microbes and metabolites influence also organs distant from the intestine via portal circulation [7].
The “gut liver axis” is defined as the bidirectional relationship between the liver and the intestinal microbiome and involves signaling pathways induced by genetic, dietary and environmental elements. The intestinal barrier function can be compromised by disproportionate consumption of tissue damaging foods, like high-fat diet (HFD) components. As a result, the levels of intestinal microbes, termed pathogen-associated molecular patterns (PAMPs), surge and are allowed to be transferred to the liver. PAMPs translocation induces inflammatory responses via the Toll-like receptors (TLRs) and can lead to CLD by promoting inflammation and fibrosis [8]. For each TLR, there is an assumed corresponding gut bacterial product that acts as a ligand (Table 2). Furthermore, a compromised intestinal barrier allows the release of bacterial products in the portal circulation and the liver cells are the first to be exposed to. Continuous damage to the liver can lead to further transportation of bacterial components, which is characteristic of CLD and contributes to cirrhosis and HCC.
Table 2. Toll–like receptors (TLR) and their corresponding ligands in the liver.
| Toll Like Receptors | Cellular Targets in the Liver |
|---|---|
| TLR2, TLR4 and TLR9 | Hepatic stellate cells (HSC) |
| TLR2, TLR3, TLR4 and TLR9 | Kupffer cells |
| TLR1-9 | Hepatic cells |
Dapito et al., have shown that HCC was dramatically reduced at the last stages in a mouse model by gut sterilization after antibiotic administration [6]. Moreover, in almost 80% of murine, HCCs were prevented by a complete decontamination of the intestine suggesting that the intestinal microbiota is a potential target for HCC prevention [6].
3. How Does A HCC Protective Diet Influence the Gut Microbiome?
The majority of the studies agree that consumption of vegetables, fruits, cereals, nuts, legumes, modest consumption of fish and dairy, and decreased intake of red and/or processed meat and sugar has a chemoprotective role in HCC development. The closest to such a diet is the Mediterranean, which is rich in fiber and unsaturated fats and is known to be a balanced and healthy regime [9]. The Mediterranean diet contributes to cancer prevention by modulating gut microbiota and by reducing metabolic endoxermia [10]. The latter is defined as a twofold surge of the circulating levels of bacterial endotoxins generated in the gut, such as Lipoteichoic acid (LTA) and Lipopolysaccharide (LPS) [11].
Firm adherence to a Mediterranean diet is significantly associated to a vegan diet and microbiome composition and function [12]. Vegetarian and vegan diets were found to enrich fiber-degrading Prevotella and Lachnospira bacteria in the gut, compared to an omnivorous diet [12]. In addition, short-chain fatty acids (SCFA) levels significantly correlate with Mediterranean diet patterns [12]. Clinical and observational studies, in which total food interventions were used, showed that increased walnut or almond consumption, rich in unsaturated fats and fiber, elevates some Gram-positive bacteria such as the Clostridia genera including Oscillospira, Lachnospira, Faecalibacterium, Roseburia and Clostridium, while it reduces other bacteria species such as Dorea, Ruminococcus, and Bifidobacterium [11].
On the contrary, a diet that contains low fiber levels and surged saturated fat levels can contribute to metabolic endotoxemia via alterations in the composition of the gut microbiome, the products of bacterial fermentation, gut barrier permeability and function, and circulating levels of enterohepatic bile acids [11]. Undoubtedly, there is a need to conduct large-scale prospective clinical trials to understand the processes by which a Mediterranean diet can protect against HCC.
This entry is adapted from the peer-reviewed paper 10.3390/livers1010004
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