## 5 Liver Cancer
### Liver Cirrhosis-Related Microbiota
#### 5.2.2 Liver Cirrhosis  
Liver cirrhosis can be described as increased systemic liver inflammation. The main risk factor for liver cirrhosis development is chronic inflammation triggered by sepsis, endotoxemia, and other infections. Triggered immune system activates immune cells to produce disease-specific mediators. Mediators stimulate liver cells, that is, hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, cholangiocarcinomaytes, and hepatic T cells, to release inflammatory molecules, such as TNF, TGF-\(\beta\)1 (tumor growth factor Beta1), and IL-6. Those molecules activate HSCs to form myofibplastics, the main effectors of fibrosis in all tissues. Myofibroblasts synthesize collagen, which, over time, results in the development of liver fibrosis and cirrhotic transformation [94; 95]. In addition to liver inflammation and injury, cirrhosis outcome is also associated with a defective intestinal barrier, altered bile acids' (BAs) profile, and changes in gut microbiota [95]. Impairments in the intestinal barrier increase intestinal permeability, which enables bacterial products, such as endotoxins, peptidoglycans, and microbial DNA, to access and stimulate the intestinal immune system. Triggered inflammatory response increases the synthesis of potent cytokines such as IL-1, IL-6, IL-8, and TNF. Moreover, increased intestinal permeability enables bacteria and bacterial products to travel to the liver via the portal vein. Once in the liver, those bacterial products interact with the innate sensors (Toll-like receptors (TLRs) and NLRs) of hepatocytes and Kupffer cells, resulting in further production of inflammatory mediators and cirrhosis [94]. The microbiota of patients with liver cirrhosis differs from that of healthy patients [96]. This phenomenon is believed to be associated with Bas' synthesis in the human gut, as cirrhosis patients exhibit five times lower secretion of BAs in the intestine compared with healthy subjects [97]. It has been found that decreased BA secretion in the intestine might influence the composition of the gut microbiota as they are tightly connected. BAs regulate the composition of gut microbiota, and the microbiota of the small and large intestine contribute to bile acid synthesis by hydrolysing conjugated bile to free bile acids [98]. Reduced secretion of BAs during liver cirrhosis can lead to the overgrowth of harmful bacteria in the large intestine with simultaneous decrease of otherwise protective bacteria. Alterations in gut microbiota lead to the translocation of immunogenic bacterial products, such as LPS or bacterial DNA, from the gut to liver. It has been found that patients with liver cirrhosis exhibit higher LPS levels. LPS is a strong endotoxin that can induce the inflammatory cascade by binding to receptors on many cells of the immune system. Excessive and persistent liver inflammation leads to repeated hepatocyte damage, hepatic fibrosis, cirrhosis, and finally HCC [91,99]. Additionally, BAs exhibit anti-inflammatory properties on intestinal epithelial cells; it has thus been proposed that reduction of BA secretion in the gut may additionally enhance chronic inflammation [91]. [PERSON] et al., [PERSON] et al., and [PERSON] et al. reported that the gut microbiota in patients with liver cirrhosis showed a higher prevalence of pathogenic bacteria such as _Enterobacteriaceae_, _Streptococcus_, and _Veilonella_, and a lower prevalence of beneficial bacteria such as Bifidobacteria, Bacteroidetes, Firmicutes, and Lachospiraceae from the order _Clostridiales_ compared with healthy controls [100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112]. _Veilonella parvola_ has been reported to colonize different niches within the tumour [103], and has been associated with dental infections and inflammatory-related diseases such as osteomyelitisitis, meningitis [104], and prosthetic joint infection [105]. Those reports are based on a one-patient case study, and require confirmation on a larger study group.