Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats

Background & Aims Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progressi...

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Published in:Journal of hepatology 2012-10, Vol.57 (4), p.803-812
Main Authors: Zhang, Hui-Lu, Yu, Le-Xing, Yang, Wen, Tang, Liang, Lin, Yan, Wu, Han, Zhai, Bo, Tan, Ye-Xiong, Shan, Lei, Liu, Qiong, Chen, Hai-Yang, Dai, Rong-Yang, Qiu, Bi-Jun, He, Ya-Qin, Wang, Chao, Zheng, Long-Yi, Li, Yu-Qiong, Wu, Fu-Quan, Li, Zhong, Yan, He-Xin, Wang, Hong-Yang
Format: Article
Language:English
Subjects:
Alkylating Agents - pharmacology
Animals
Anti-Bacterial Agents - pharmacology
Bifidobacterium - drug effects
Biological and medical sciences
Carcinoma, Hepatocellular - blood
Carcinoma, Hepatocellular - etiology
Carcinoma, Hepatocellular - pathology
Cytokines - biosynthesis
Dextran Sulfate - pharmacology
Diethylnitrosamine - pharmacology
Diethylnitrosamine - toxicity
Disease Progression
Diseases of the digestive system
Endotoxin
Endotoxins - blood
Endotoxins - metabolism
Enterococcus - drug effects
Gastroenteritis - chemically induced
Gastroenteritis - drug therapy
Gastroenteritis - metabolism
Gastroenterology and Hepatology
Gastroenterology. Liver. Pancreas. Abdomen
Gastrointestinal Tract - microbiology
Gastrointestinal Tract - physiopathology
Gut homeostasis
Hepatocellular carcinoma
HMGB1 Protein - metabolism
Homeostasis - drug effects
Humans
Lactobacillus - drug effects
Liver Cirrhosis - blood
Liver Cirrhosis - complications
Liver Neoplasms, Experimental - chemically induced
Liver Neoplasms, Experimental - microbiology
Liver Neoplasms, Experimental - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Penicillins - pharmacology
Probiotics
Probiotics - pharmacology
Probiotics - therapeutic use
Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)
Rats
Rats, Sprague-Dawley
Tumors
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Summary:Background & Aims Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC). Methods Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. Results Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver. Conclusions The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2012.06.011