Decrease of 'health-benefiting' microbes and increase of pathogenic bacteria (a condition termed dysbiosis) in intensive care unit patients is considered to induce or aggravate sepsis (gut-origin sepsis). Orally administered probiotics have been effective in the prevention of nosocomial infections. However, the mechanisms of probiotic-induced anti-infection and anti-sepsis remain to be explored. In the present study, 4-week-old C57BL6 mice were orally administrated with Lactobacillus rhamnosus GG (LGG) or normal saline (control) 4 weeks prior to cecal ligation and puncture (CLP). A subset of the mice were sacrificed at 24 h post-CLP, and the others were used for survival studies. Ileum tissues, blood and fecal samples were collected. The survival rate of septic mice pretreated with LGG was significantly improved compared with untreated mice. The levels of inflammatory cytokines were reduced in LGG-pretreated septic mice. A decrease of colonic proliferation and epithelial tight junctions and an increase of colonic apoptosis were observed in control septic CLP+saline mice. LGG pretreatment reversed the colonic proliferation, apoptosis and expression of tight junction proteins to the levels of the sham group. LGG pretreatment improved the richness and diversity of intestinal microbiota in septic mice. The principal coordinates analysis clustering plots revealed a significant separate clustering in microbiota structure between three groups. Bacteria associated with energy consumption, including Bacteroidetes, with opportunistic infection, including Proteobacteria, Staphylococcaceae and Enterococcaceae, lipopolysaccharide producers, including Enterobacteriaceae, and facultative anaerobes, such as Bacteroidaceae and Erysipelotrichaceae, increased in septic mice. By contrast, bacteria associated with energy harvest, including Firmicutes, intestinal barrier function regulators, including Akkermansia, hepatic function regulators, including Coprococcus and Oscillospira, and obligate anaerobes, including Prevotellaceae, decreased in septic mice. With LGG pretreatment, the sepsis-induced microbiota dysbiosis was reversed. The present results elucidated the potential mechanism of LGG treatment in sepsis, by improving intestinal permeability and modulating microbiota dysbiosis.
Background Recently, it has been found that the gut microbiota may affect the development of lung cancer through the “gut‐lung axis.” To investigate this relationship, we performed this study to determine whether the gut microbiota in non‐small‐cell lung cancer (NSCLC) patients is different from that in healthy adults. Methods Quantitative PCR (qPCR) was used to detect the expression levels of eight gut butyrate‐producing bacteria in healthy adults and NSCLC patients. We enrolled 30 patients with NSCLC and 30 subjects from 100 healthy adults after matching for age and sex. Results Compared to healthy adults, most of the gut butyrate‐producing bacteria in NSCLC patients were significantly decreased; these included Faecalibacterium prausnitzii , Clostridium leptum , Clostridial cluster I , Ruminococcus spp., Clostridial Cluster XIVa , and Roseburia spp. Among the gut butyrate‐producing bacteria, we analyzed Clostridial cluster IV and Eubacterium rectale were not decreased in NSCLC patients. Conclusions We conclude that NSCLC patients had gut butyrate‐producing bacteria dysbiosis. Further studies should be performed to investigate the underlying mechanisms of how these specific bacteria affect lung cancer progression and prognosis.
The vacuolar H-ATPase (V-ATPase) is commonly highly activated in cancer cells and is a potential target of anti-cancer therapy. Bafilomycin A1 is a specific inhibitor of the c subunit of V-ATPase. In the present study, the effects of bafilomycin A1 on the BEL-7402 hepatocellular carcinoma and HO-8910 ovarian cancer cell lines were respectively studied. In addition, the bafilomycin A1-induced alterations in the mRNAs and microRNAs (miRNAs) in the cells were detected using microarray methods. The results demonstrated that the growth of the two cell lines was retarded and the metastatic potential was inhibited by bafilomycin A1. Transmission electron microscopy and assays of capsase-3 and -9 suggested that bafilomycin A1 induced apoptosis. Gene Ontology analysis of the microarrays of mRNA-miRNA integrity showed altered pathways following bafilomycin A1 treatment, including pathways regulating glucose or lipid metabolism, DNA repair or duplication and lysosomes. Quantitative polymerase chain reaction analysis confirmed that miR-923, miR-1246, miR-149*, miR-638 and miR-210 were upregulated and miR-99a, miR-181a-2* and miR-339-5p were downregulated following bafilomycin A1 treatment. The overlapped altered miRs may be effective targets for the two types of solid tumor, and may have potential for application to the treatment of other types of solid tumor.
Longevity assurance homolog 2 of yeast LAG1 (Lass2) gene is capable of suppressing the proliferation and metastasis of several types of tumours including liver cancer. In the present study, hepatocyte-specific Lass2-knockout (Lass2 KO) and wild-type (WT) mice were exposed to the carcinogen, diethylnitrosamine (DEN), to induced liver tumours. At week 23 following DEN injection, tumours were produced in 100% of the Lass2 KO mice and 21.4% of the WT mice. At week 40, 100% of the Lass2 KO mice and 78.6% of the WT mice developed tumours, with no distinct significant difference in tumour occurrences between the two genotypes; yet, tumours in the Lass2 KO mouse livers were more numerous and larger in size. Hepatocellular carcinoma (HCC) was confirmed by α-fetoprotein (AFP). PCNA and EdU assays indicated more active proliferation whereas TUNEL assay revealed decreased apoptosis in Lass2 KO livers, when compared with the WT control. The expression of plasminogen activator inhibitor type-1 (PAI-1), a tumour-promoting gene, in the liver tissues of the 2 genotypes was detected using qPCR and western blotting, showing that PAI-1 levels were significantly elevated in Lass2 KO livers at week 40 following DEN introduction. Moreover, the expression of PAI-1-related TGF-β1, Smad-4 and -7 was detected, displaying an elevation in TGF-β1 and Smad-4 (not including Smad-7) in the Lass2 KO livers. Our data demonstrates that i) Lass2 is a protective gene against DEN-induced liver tumourigenesis; and ii) upregulation of the TGF-β1-Smad4-PAI-1 axis may contribute to the vulnerability of Lass2-knockout mice to DEN.
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