Lamees El Nihum

Introduction. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and third in cancer-related death¹. Five-year survival rates of patients undergoing curative therapies including liver transplant and hepatic resection range between 40-75%¹. Hepatic fibrosis, a response to chronic inflammation, is the strongest predisposing factor for HCC and increasingly caused by obesity-induced non-alcoholic fatty liver disease^1,2. Obesity-associated rise of Gram-positive bacteria in the GI tract promotes enterohepatic circulation of gut bacterial metabolites including the secondary bile acid deoxycholic acid (DCA)^3,4,5. DCA induces senescence in hepatic stellate cells, which remain metabolically active with a pro-inflammatory secretome termed the senescence associated secretory phenotype (SASP)^6,7. Persistent inflammation triggers transformation of damaged hepatocytes, leading to cancer⁷. Methods. DMBA-administered mice were fed a normal diet (ND) or high-fat diet (HFD) for 30 weeks³. Gut bacterial populations were determined by assessing fecal matter, serum DCA recorded and antibiotics treatment performed³. Post-mortem distribution of tumors and biomarker evidence of HSC activation were analyzed³. The experiment was elaborated further by treating HFD mice at 13 weeks onwards with antibiotics with or without DCA feeding³. In another study, western blot analysis analyzed phosphorylation of mTOR in HFD versus ND mice⁸. Results. HCC lesions with senescent HSCs, marked by the presence of senescence markers such as p21^Waf1/Cip1 and p16^INK4a and DNA damage markers 53BP1 and γ-H2AX, were observed in HFD mice³. A substantial increase in Gram-positive Clostridium cluster XI and XIVa was observed in HFD mice³. Serum DCA was substantially increased in HFD mice and fell with vancomycin treatment³. Tumor suppression in DCA-fed HFD mice was enhanced significantly by a combination of four antibiotics compared to vancomycin only³. HCC and SASP were observed in DCA-fed HFD mice with and without the presence of antibiotics, implying that DCA alone can provoke HCC in HFD mice without the presence of Gram-positive bacteria; however, DCA alone was insufficient to enhance HCC in ND mice³. This suggests that an additional obesity-associated factor, such as increased gut permeability, exists to promote obesity-associated HCC^3,9. mTOR phosphorylation was significantly elevated in HFD mice and suppressed with antibiotics, suggesting that hepatic mTOR activation is mediated by gut microbiota-generated deoxycholic acid⁸. Conclusions. Genetically obese ND mice show high levels of DCA, implying that obesity, not HFD, causes HCC^3,4. The precise mechanism by which deoxycholic acid initiates mTOR and the oncogenic process in the liver remains unclear⁸. Deoxycholic acid-induced HCC is likely augmented by obesity-induced pro-inflammatory changes in the liver⁸.

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