![]() The aim of this study is to perform detailed metabolomics analysis of HCC patients and healthy liver donors to reveal previously unreported metabolic alterations in HCC patients.Ī total of 660 samples, including 102 portal vein blood samples, 102 central vein blood samples, 52 HCC tissues, 52 adjacent non-cancerous, 50 normal liver tissues and 102 faecal samples were collected in the discovery cohort from November 2018 to June 2019. Therefore, comparing metabolic changes in portal vein, central vein, liver tissue and stool samples between patients with HCC and healthy subjects may be helpful for in-depth understanding on the gut-liver axis, evaluating potential aetiology and novel therapeutic targets for HCC patients. 9 However, because of the poor accessibility of portal vein blood, most metabolomics studies are limited by the use of peripheral blood that may not reflect changes in the portal venous blood and the liver. The milieu of the portal vein system may play an important role in HCC development.Īccumulating evidence suggests that metabolites are important for HCC formation. Because of the structural link to the intestine, the liver is the first organ to receive gut-derived metabolites and serves a critical function between foreign substances and the systemic milieu. Liver has a unique vascular system (portal vein) to receive metabolites from the gut and deliver it directly to the liver. 8 These studies supported the important role of metabolites in the development and progression of liver diseases. 7 In addition, propionate, a metabolite from gut microbiota, inhibits cancer cell proliferation in the liver. A gut bacterial metabolite deoxycholic acid (DCA) causes DNA damage and activate tumour-promoting factors in the liver while blocking DCA production prevents HCC development in an obese mice model. 6 Intestinal dysbiosis affects the development of HCC in part through microbial metabolites. 5 A recent study using metabolomics in peripheral blood plasma samples discovered that N, N, N-trimethyl-5-aminovaleric acid could induce fatty liver disease through increased lipolysis and decreased fatty acid oxidation. Metabolomics is a promising approach for the identification of metabolites which may provide insights into aetiology, treatment and early diagnosis of diseases. 3 4 Therefore, there is an urgent need to further understand the possible aetiological factors and new therapeutic methods to improve the prognosis of HCC patients. 2 Moreover, due to the lack of early diagnostic marker, most patients with HCC are often diagnosed in an advanced stage with poor prognosis. 1 Although surgical treatment may be effective in HCC patients, the 5-year survival rate is only 50%–70%. ( F) Scatter plots comparing histological scores (Ishak lobular inflammation, Ishak portal inflammation, Ishak periportal hepatitis, Ishak fibrosis, and perisinusoidal fibrosis scores) with total, lobular, and portal CD45 + cell density per mm 2 for 28 IA (red diamond) and 6 IT (blue X) subjects, with Spearman’s correlations and P values.Hepatocellular carcinoma (HCC) is the third-leading cause of cancer deaths worldwide. A single outlier with portal CD45 + immune cell density at 43,365 was not shown graphically, although it was included in calculating the Spearman’s correlation and P values (shown in red fonts for P < 0.05). ( E) Scatter plots comparing %portal/total area, ALT, HBV DNA, and age relative to total, lobular, and portal CD45 + cell density per mm 2 for 28 IA (red diamond) and 6 IT (blue X) subjects. ( D) Tissue image reproduced with portal and/or lobular location of bile ducts, hepatocytes, and immune cells by applying x/ y spatial coordinates to analyzed IMC data. ( C) Overlay of lobular CD45 –HepPar1 + (green), lobular CD45 +HepPar1 – (purple), and all portal (orange) events show HBsAg expression limited to CD45 –HepPar1 + cells, CK19 expression limited to portal cells, and CD68 expression in both lobular CD45 +HepPar1 – immune cells and portal cells. ( B) Representative contour plot and histogram overlays provide comparisons for portal (red) versus lobular (blue) detection of HepPar1, CD45, and/or CD3 expression, with expected lobular but not portal detection for HepPar1 + hepatocytes and both lobular and portal detection for CD45 + or CD3 + immune cells. Far right contour plot overlay shows that CD68 +CD45 + gate (red) is enriched for concurrent CD16/CD14 expression, compared with CD68 –CD45 + gate (blue). ( A) Acquired IMC images are visualized in representative pseudocolor plots and histogram with overlays to show that HepPar1 + events can be gated separately from CD45 + events, and that CD45 + events are enriched for immune markers (e.g., CD3, CD8, CD68).
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