lipoteichoic-acid and Carcinoma--Hepatocellular

Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible nutrients and produce useful metabolites. Although gut microbiota primarily reside in and influence the intestine, they also regulate liver function via absorption and subsequent transfer of microbial components and metabolites through the portal vein to the liver. Due to this transfer, the liver may be continuously exposed to gut-derived metabolites and components. For example, short-chain fatty acids (SCFA) produced by gut microbiota, through the fermentation of dietary fiber, can suppress inflammation via regulatory T cell induction through SCFA-induced epigenetic mechanisms. Additionally, secondary bile acids (BA), such as deoxycholic acid, produced by gut bacteria through the 7α-dehydroxylation of primary BAs, are thought to induce DNA damage and contribute to the remodeling of tumor microenvironments. Other substances that are also thought to influence liver function include lipopolysaccharides (components of the outer membrane of gram-negative bacteria) and lipoteichoic acid (cell wall component of Gram-positive bacteria), which are ligands of innate immune receptors, Toll-like receptor-4, and Toll-like receptor-2, respectively, through which inflammatory signaling is elicited. In this review, we focus on the role of gut microbiota in the liver microenvironment, describing the anatomy of the gut-liver axis, the role of gut microbial metabolites, and the relationships that exist between gut microbiota and liver diseases, including liver cancer.

Topics: Bile Acids and Salts; Carcinoma, Hepatocellular; Cellular Senescence; Choline; DNA Damage; Ethanol; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gram-Positive Bacteria; Hepatitis, Alcoholic; Humans; Lipopolysaccharides; Liver; Liver Diseases; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Symbiosis; Teichoic Acids; Tumor Microenvironment

Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E

Topics: Animals; Carcinoma, Hepatocellular; Dinoprostone; Female; Gastrointestinal Microbiome; Humans; Lipopolysaccharides; Liver Neoplasms; Male; Mice, Inbred C57BL; Obesity; Teichoic Acids; Tumor Escape; Tumor Microenvironment

To investigate the cooperative effect of Bifidobacteria lipoteichoic acid (BLTA) combined with 5-fluorouracil on tumor cells growth and apoptosis in mice bearing H22.. Hepatoma-22 (H22) cells were cultured in RPMI1640. Establish tumor-bearing mice model of liver cancer by injecting intraperitoneally 1×10(6)/mL cells into the above-mentioned Balb/c mice. 5-FU alone, BLTA alone or BLTA in combination with 5-FU were used to treat tumor-bearing mice. The tumor size were observed and measured regularly. The growth-inhibiting rate (IR) of tumor was detected. Real-Time PCR and Western blot were used to detect Bcl-2, Bax and Caspase-3 expressions of mRNA and protein in tumor tissue of tumor-bearing mice. Detection of apoptotic cells in tumor tissue by HE staining analysis. Detection of the organ index was for evaluate the added-activity of immune organs in mouse. FCM was used to detect T subgroup ratio of spleen cells of tumor-bearing mice. Expression change of mRNA and proteins of Foxp3 and TIM-3 were detected by Real-Time PCR and Western blot in tumor-bearing mice tumor tissue.. BLTA and 5-FU significantly inhibited the proliferation of tumor and induced obvious apoptosis, the combined effects were greater than those of the individual agents (P<0.01). The underlying molecular mechanism of apoptotic process could be up-regulation of Bax and down-regulation of Bcl-2 and Caspase-3. The HE staining indicated that combined treat could both induce tissue cells necrosis and increase immune cells infiltration. Organ index showed that BLTA can enhance the proliferation of immune organs. The ratio of CD4(+)CD25(+) Treg significantly decreased and CD4(+) T cell increased in BLTA and 5-FU group (P<0.01). Compared to NS group, mRNA and proteins expression of Foxp3 and TIM-3 down regulated in BLTA and 5-FU group (P<0.01).. These results show that combined effects of Bifidobacteria lipoteichoic acid and 5-FU on H22 cells were superior to the individual. The combination did not only increase anti-tumor effect, but also could alleviate the side effects of chemotherapy, with inhibiting TIM-3/TIM-3L pathway, cutting down immunosuppressive activity of CD4(+)CD25(+) Treg and enhancing cell-mediated immunity.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bifidobacterium; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Cell Proliferation; Female; Fluorouracil; Forkhead Transcription Factors; Hepatitis A Virus Cellular Receptor 2; Immunity, Cellular; Lipopolysaccharides; Liver Neoplasms; Mice; Mice, Inbred BALB C; Necrosis; Neoplasm Proteins; Neoplasm Transplantation; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Receptors, Virus; RNA, Messenger; Spleen; T-Lymphocytes; Teichoic Acids

To investigate the therapeutic efficacy of lipoteichoic acid of Bifidobacterium (BLTA) in combination with 5-fluorouracil (5-FU) treatment on the mice bearing inoculated hepatoma-22 (H(22)) cells and the effects of BLTA on immunological regulation of organism, and explore its mechanisms.. Tumor-bearing mice were treated with 5-FU alone, BLTA alone or BLTA in combination with 5-FU. The tumor size were observed and measured regularly. The growth inhibiting rate (IR) of tumor was detected. MTT assay was used to evaluate the proliferation of T lymphocytes and splenic NK cell and CTL activity. Enzyme linked immunosorbent assay (ELISA) was used to detect the change of IFN-γ. FCM was used to detect T subgroup ratio of spleen cells of tumor-bearing mice. Expression change of mRNA and proteins of Foxp3 and TIM-3 were detected by Real-Time-PCR and Western blot in tumor-bearing mice tumor tissue.. Both 5-FU and BLTA had inhibition effect on tumor-growth. While in the 5-FU + BLTA group, the inhibition of tumor growth was more significant, with increased T lymphocyte proliferation and IFN-γproduction of spleen cells. Spleen cells of tumor-bearing mice had high CD4(+)CD25(+)regulatory T cell (CD4(+)CD25(+)T(reg)) ratio and high mRNA and proteins expression of Foxp3 and TIM-3, but in the BLTA and 5-FU group, CD4(+)CD25(+)T(reg) ratio degraded, with down regulation mRNA and proteins expression of Foxp3 and TIM-3. But CD4(+) T cells also decreased in spleen cells of tumor-bearing mice by alone 5-FU treated, splenic NK cell and CTL activity also degraded, while CD4(+) T cells and splenic NK cell and CTL activity significantly increased by BLTA treated. BLTA in combination with 5-FU could also enhance the ratio of CD4(+) T cells and splenic NK cell and CTL activity.. The present study suggested that BLTA in combination with 5-FU could enhance antitumor effect, with inhibiting TIM-3/TIM-3L pathway, cutting down immunosuppressive activity of CD4(+)CD25(+) T(reg) and enhancing cell-mediated immunity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bifidobacterium; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Fluorouracil; Forkhead Transcription Factors; Hepatitis A Virus Cellular Receptor 2; Interferon-gamma; Killer Cells, Natural; Lipopolysaccharides; Liver Neoplasms, Experimental; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Receptors, Virus; RNA, Messenger; Spleen; T-Lymphocytes, Regulatory; Teichoic Acids; Tumor Burden