Profound Impact Of Gut Homeostasis On Chemically Induced Hepatocarcinogenesis

Increasing evidence suggest that the development of many cancers is closelyassociated with the persistence of chronic inflammation. In particular, most cases of HCCare secondary to chronic inflammatory liver diseases such as those caused by viralinfection, alcohol consumption, or hepatic metabolic disorders, although the bridgingmechanisms have not been identified. The unique immunological environment in the liverhas been attributed to its close connection to the gut. The liver is constantly exposed tomicrobial products from the enteric microflora, a major component of which is endotoxin(lipopolysaccharide [LPS]) from Gram-negative bacteria. These microbial products areabsorbed from the gut and transported via the portal vein to the liver, in which it is rapidlycleared by the Kupffer cells. Several lines of evidence indicate that accumulation of LPSplays a contributory role in the pathogenesis of HCC by eliciting proinflammatoryresponses in liver. The accumulation of LPS is likely due to changes in the guthomeostasis, namely increased intestinal mucosal permeability and bacterial translocation,coupled with deficient clarification of the hepatic reticuloendothelial system. On the otherhand, intestinal inflammation causes release of pro-inflammatory cytokines from theintestinal cells, which may also contribute to the development of HCC in patients withchronic inflammatory liver diseases. However, the exact impact of gut homeostasis on inflammation-associated HCC remains to be established.The intestine hosts the majority of the bacterial mass in the body and has developedan adaptive commensal relationship with them. Among the dynamic mixture of microbesin intestinal microflora, aerobic Gram-negative(G-) bacteria (specifically Escherichia coli,Klebsiella pneumoniae, and other Enterobacteriaceae) have been found to be the mostadaptive at translocation and the major source of serum endotoxin. By contrast, intestinalanaerobic bacteria, which outnumber aerobic bacteria by100:1to1,000:1, very rarelytranslocate. Moreover, anaerobic bacteria limit the colonization and overgrowth of otherpotentially invasive microbes, thereby confining potentially pathogenic bacteria. Theseendogenous probiotic bacteria of the gut such as Bifidobacterium and Lactobacillus play avital role in maintaining the intestinal mucosal barrier and reducing bacterial translocationin models of liver disease.Probiotics have been proposed as a means of re-equilibrating gut flora in favor ofprotective anaerobic bacteria. There is evidence that some probiotic microorganisms couldrestore the microbiologic and immunologic equilibrium in the intestinal wall in cirrhoticpatients and help in the treatment of complications due to cirrhosis. In animal models ofacute liver injury and cirrhosis, administration of probiotics has been reported to correctbacterial overgrowth, stabilize mucosal barrier function, reduce bacterial translocation andendotoxemia, and thereby improve survival. But if the benefit of probiotics would help inprevention of endotoxin-related hepatocarcinogenesis is still obscure. Here we show that endotoxin accumulation and cytokines deregulation consistentlyexist in the systemic circulation of both patients and carcinogen-treated animals withcirrhosis and HCC. In accordance, disruption of gut homeostasis as a result of intestinalmucosal damage and bacterial overgrowth also persist during the multiple stages ofcarcinogen-induced hepatocarcinogenesis and were shown to aggravateinflammation-associated tumorigenesis. Probiotics treatment, however, not only restoredthe intestinal flora balance, intestinal inflammtion and mucosal barrier function but alsodramatically improved the cirrhotic condition and prevented HCC development. Theseresults suggest that the restoration of gut homeostasis by probiotics administration couldhave preventive and therapeutic effects in patients with cirrhosis or HCC.