Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome.

AIMS: Ageing is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF. METHODS AND RESULTS: Herein, by using a faecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NOD-like receptor protein (NLRP)-3 inflammasome, promoting the development of AF, which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then, we conducted cross-sectional clinical studies to explore the effect of ageing on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the ageing phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF. CONCLUSIONS: Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.

Multiple effects of ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis.

Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer in the world. Phytochemicals have become a research hotspot in recent years as cancer prevention and treatment agents due to their low toxicity and limited side-effects. Ellagic acid (EA), a natural phenolic constituent, displays various biological activities, including anticancer effects. However, the detailed anticancer mechanisms of EA remain unclear. In the present study, we found that EA inhibited the growth of HCT-116 colon cancer cells. Moreover, we identified differentially expressed genes (DEGs) by microarray profiling of HCT-116 cells treated with EA. A total of 857 DEGs (363 upregulated and 494 downregulated) were identified with a >1.5-fold change in expression after treatment with EA for 72 h. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that a large number of cellular functions were modified by EA including proliferation, apoptosis, cell cycle and angiogenesis. Interaction network analysis using DEGs provided details of their interactions and predicted the key target pathways of EA. To verify the result of cDNA microarray, 10 selected DEGs related to proliferation, apoptosis or cell cycle were further confirmed by real-time RT-PCR. Based on microarray data, we identified several crucial functions of EA. These results provide important new data for EA in anti-CRC research.

A functional module-based exploration between inflammation and cancer in esophagus.

Inflammation contributing to the underlying progression of diverse human cancers has been generally appreciated, however, explorations into the molecular links between inflammation and cancer in esophagus are still at its early stage. In our study, we presented a functional module-based approach, in combination with multiple data resource (gene expression, protein-protein interactions (PPI), transcriptional and post-transcriptional regulations) to decipher the underlying links. Via mapping differentially expressed disease genes, functional disease modules were identified. As indicated, those common genes and interactions tended to play important roles in linking inflammation and cancer. Based on crosstalk analysis, we demonstrated that, although most disease genes were not shared by both kinds of modules, they might act through participating in the same or similar functions to complete the molecular links. Additionally, we applied pivot analysis to extract significant regulators for per significant crosstalk module pair. As shown, pivot regulators might manipulate vital parts of the module subnetworks, and then work together to bridge inflammation and cancer in esophagus. Collectively, based on our functional module analysis, we demonstrated that shared genes or interactions, significant crosstalk modules, and those significant pivot regulators were served as different functional parts underlying the molecular links between inflammation and cancer in esophagus.