Search

ABSTRACT Gut microbiota and their secreted metabolites have an influence on the initiation and progression of colon cancer. Probiotics are extensively perceived as a potential microbiota-modulation strategy to promote the health of the host, while the effectiveness of preventing colon cancer based on microbiota therapy has not been confirmed, and antitumor mechanisms influenced by microbiota and their metabolites with the intervention of probiotics remain to be further investigated. In vitro, Lactobacillus (JY300-8 and JMR-01) significantly inhibited the proliferation of CT26, HT29, and HCT116 cells. Moreover, we studied the prevention and therapy efficiency of Lactobacillus and its underlying antitumor mechanism through the alteration of gut microbiota and their metabolites regulated by Lactobacillus in colon cancer models in mice. We demonstrated that the pre-administration of Lactobacillus (JY300-8 and JMR-01) for 20 days before establishing tumor models resulted in an 86.21% reduction in tumor formation rate compared to tumor control group. Subsequently, continuous oral administration of living Lactobacillus significantly suppresses tumor growth, and tumor volumes decrease by 65.2%. Microbiome and metabolome analyses reveal that Lactobacillus suppresses colonic tumorigenesis and progression through the modulation of gut microbiota homeostasis and metabolites, including the down-regulation of secondary bile acids, sphingosine 1-phosphate (S1P), and pyrimidine metabolism, as well as the production of anticarcinogenic compounds in tumor-bearing mice. Additionally, metabolome analyses of Lactobacillus (JY300-8 and JMR-01) indicate that living Lactobacillus could reduce the relative abundance of alanine and L-serine to suppress tumor progression by regulating the tumor microenvironment, including down-regulation of pyrimidine metabolism and S1P signaling in cancer. These findings provide a potential prevention strategy and therapeutic target for colon cancer through the intervention of dietary Lactobacillus. IMPORTANCE The modulation of gut microbiota and metabolites has a significant influence on the progression of colon cancer. Our research indicated that the intervention of probiotics is a potentially feasible strategy for preventing colon cancer. We have also revealed the underlying antitumor mechanism through the alteration of gut microbiota and their metabolites, which could lead to broader biomedical impacts on the prevention and therapy of colon cancer with microbiota-based therapy regulated by probiotics.

Abstract Background The major challenge of facing the efficient utilization of biomass is the high cost of cellulolytic enzyme, while the Trichoderma longibrachiatum plays an essential role in the production of industrial enzymes and biomass recycling. Results The cellulase hyper‑producing mutants of LC-M4 and LC-M16 derived from the wild type T. longibrachiatum LC strain through heavy ion mutagenesis exhibited the high-efficiency secretion ability of cellulase and hemicellulose. The FPase activities of LC-M4 (4.51 IU/mL) and LC-M16 (4.16 IU/mL) mutants increased by 46.91% and 35.5% when compared to the LC strain, respectively. Moreover, these two cellulase hyper-producing mutants showed faster growth rate on the cellulosic substrates (Avicel and CMC-Na) plate than that of LC strain. Therefore, an integrative transcriptome and proteome profiling analysis of T. longibrachiatum LC and its cellulase hyper‑producing mutant LC-M4 and LC-M16 were employed to reveal the key genes involved in cellulolytic enzymes regulation. It was showed that the transcriptome and proteome profiles changed dramatically between the wild strain and mutant strains. Notably, the overlapped genes obtained from integrative analysis identified that the protein processing in ER involved in protein secretory pathway, starch and sucrose metabolism pathway and N-glycan biosynthesis pathway were significantly changed both in cellulase hyper-producing mutants and thereby improving the enzyme secretion efficiency, which maybe the main reason of cellulase hyper-production in LC-M4 and LC-M16 mutants. In addition, the three DEGs/DEPs (PDI, Sec61, VIP36) related with protein secretion in ER and two DEGs/DEPs (OST, MOGS) related with N-glycan biosynthesis were identified as key candidate genes participating in enzyme protein biosynthesis and secretion. Conclusions In this study, a hypothetical secretory model of cellulase protein in filamentous fungi was established on the basis of DEGs/DEPs and key genes identified from the omics analysis, which were of great guidance on the rational genetic engineering and/or breeding of filamentous fungi for improving cellulase production.