Hepatic stellate cell activation and senescence induced by intrahepatic microbiota disturbances drive progression of liver cirrhosis toward hepatocellular carcinoma

Abstract

BackgroundThe significance of the relationship between the microbiota and diseases is increasingly being recognized. However, the characterization of tumor microbiome and their precise molecular mechanisms through which microbiota promotes hepatocellular carcinoma (HCC) development are still unclear.MethodsThe intrahepatic microbiota was investigated from tumor, normal adjacent tissues in 46 patients with HCC and normal hepatic tissues in 33 patients with hemangioma by 16S rRNA gene sequencing. Taxonomic composition differences in patients were evaluated using Linear discriminant analysis Effect Size (LefSe) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict microbial functional pathways. Associations between the most relevant taxa and clinical characteristics of HCC patients were analyzed by Spearman rank correlations. The effects of microbe on hepatic stellate cells (HSCs) activation and HCC progression were examined.ResultsWe observed intrahepatic microbiota disturbances by reduced microbial diversity in HCC. The tumor microbiota of the HCC patients with cirrhosis showed higher abundance of Stenotrophomonas maltophilia (S. maltophilia). S. maltophilia provoked senescence-associated secretory phenotype (SASP) in HSCs by activating TLR-4-mediated NF-κB signaling pathway, which in turn induced NLRP3 inflammasome complex formation and secreted various inflammatory factors in the liver, thus facilitating HCC progression in mice. Moreover, signs of SASP were also observed in the HSCs in the area of HCC with higher S. maltophilia enrichment arising in patients with cirrhosis.ConclusionsOur analysis of the hepatic microbiota revealed for the first time that patients with HCC exhibited a dysbiotic microbial community with higher S. maltophilia abundance, which induced the expression SASP factors of HSCs and cirrhosis in the liver, concurring in the process of hepatocarcinogenesis.

Microbiome typing in uveal melanoma is associated with plaque radiotherapy

“…Stenotrophonomoas has the highest relative abundance in UM microbiome, which is consistent with recent report [15]. Previous studies have shown that as a new opportunistic pathogen, patients with longterm neutropenia and exposure to broad-spectrum antibiotics have a higher risk of Stenotrophonomoas infected, leading to pneumonia, bacteremia, catheter-related infection and other diseases [19].…”

“…With the improvement of microbial detection technology, scientists have paid more and more attention to the research of ora. In recent years, variates studies have found that the existence of bacteria in tumor and it is related to the occurrence and development of disease [9,15]. In this study, we found the existence of bacteria in UM for the rst time, explained the characteristics of UM microbiota and its relationship with PRT and clinical features.…”

Stenotrophomonas maltophilia promotes lung adenocarcinoma progression by upregulating histone deacetylase 5

“…Most recently, a higher abundance of S . maltophilia was found in hepatocellular carcinoma microbiota of the patients with cirrhosis, which induced the senescence of hepatic stellate cells and promoted the process of hepatocarcinogenesis ( Liu et al, 2022 ). Notably, we demonstrated for the first time that the upregulation of HDAC5 caused by S .…”

“…Before visualization, DAPI was added to the slides. The S. maltophilia probe used for FISH was: GTC GTC CAG TAT CCA CTG C, 5′ modification: Cy3(Liu et al, 2022). Then the images were captured using Confocal Laser Scanning microscopy (Carl Zeiss Microscopy, United States).…”

Dysbiosis of human tumor microbiome and aberrant residence of Actinomyces in tumor-associated fibroblasts in young-onset colorectal cancer

“…Cai et al reported that a conserved intracellular bacterial profile was detected in breast cancer, which played an important role in promoting cancer metastasis (22). Studies of hepatocellular carcinoma (HCC) have found that patients with HCC exhibited imbalances in the tumor microbiome, with a higher abundance of S. maltophilia, which induced the expression of senescence-associated secretory phenotype in hepatic stellate cells and liver cirrhosis, contributing to the progression of HCC (23). Specific gut bacteria can invade CRC tumor tissue (24); therefore, the gut microbiome does not fully reflect the microbial composition in tumors, owing to differences in the invasive and colonizing abilities of different bacteria.…”