Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats.
OBJECTIVE
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.
International Cooperation Laboratory on Signal Transduction, Liver Centre of SMMU, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China.
Hui-Lu
HL
Zhang
Le-Xing
LX
Yu
Wen
W
Yang
Liang
L
Tang
Yan
Y
Lin
Han
H
Wu
Bo
B
Zhai
Ye-Xiong
YX
Tan
Lei
L
Shan
Qiong
Q
Liu
Hai-Yang
HY
Chen
Rong-Yang
RY
Dai
Bi-Jun
BJ
Qiu
Ya-Qin
YQ
He
Chao
C
Wang
Long-Yi
LY
Zheng
Yu-Qiong
YQ
Li
Fu-Quan
FQ
Wu
Zhong
Z
Li
He-Xin
HX
Yan
Hong-Yang
HY
Wang
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001644:Bifidobacterium / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000209:etiology / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000494:pharmacology; D004052:Diethylnitrosamine / Q000494:pharmacology / Q000633:toxicity; D018450:Disease Progression; D004731:Endotoxins / Q000097:blood / Q000378:metabolism*; D016983:Enterococcus / Q000187:drug effects; D005759:Gastroenteritis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000382:microbiology* / Q000503:physiopathology; D024243:HMGB1 Protein / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007778:Lactobacillus / Q000187:drug effects; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000382:microbiology / Q000473:pathology*; D008297:Male; D010406:Penicillins / Q000494:pharmacology; D019936:Probiotics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D000477:Alkylating Agents; D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D024243:HMGB1 Protein; D010406:Penicillins; D004052:Diethylnitrosamine; D016264:Dextran Sulfate