An Akkermansia muciniphila subtype alleviates high-fat diet-induced metabolic disorders and inhibits the neurodegenerative process in mice.

The prevalence of obesity and diabetes, and their complicating mental disorders, severely affect public health. This study aimed to investigate the long-term effects of an Akkermansia muciniphila subtype (A. muciniphilasub) on high-fat diet-induced obesity and diabetes, and to evaluate whether this subtype can alleviate their complicated mental disorders. Whole genome sequencing and short chain fatty acid production analysis in supernatant of pure culture were performed. Female adult C57BL/6 mice were fed a high-fat diet or a normal chow diet and were gavaged with A. muciniphilasub or phosphate-buffered saline daily for 10 months. Body weight, food consumption and blood glucose were measured. At the end of the treatment period, all mice were subjected to the Y-maze test, sucrose preference test, analyses of serum, fecal microbiota analysis and histological examination. This A. muciniphilasub had 278 unique genes compared to the type strain (A. muciniphila ATCC BAA-835) and produced short chain fatty acids both. A. muciniphilasub administration significantly reduced body weight gain and improved the spatial memory of high-fat diet-fed mice. A. muciniphilasub increased Nissl bodies in neurons of the hippocampus, and restored the high-fat diet-inhibited tryptophan metabolism. The high-fat diet led to decreased serum 5-hydroxytryptamine and induced depression, which were not alleviated by A. muciniphilasub. A. muciniphilasub increased the relative fecal abundance of Bifidobacterium, and was negatively correlated with the fecal abundance of Bacteroides. The present study demonstrated the beneficial effects of this A. muciniphilasub on body weight, blood glucose control and the alleviation of the memory decay caused by a high-fat diet in mice.

Genome sequencing of 39 Akkermansia muciniphila isolates reveals its population structure, genomic and functional diverisity, and global distribution in mammalian gut microbiotas.

BACKGROUND: Akkermansia muciniphila is one of the most dominant bacteria that resides on the mucus layer of intestinal tract and plays key role in human health, however, little is known about its genomic content. RESULTS: Herein, we for the first time characterized the genomic architecture of A. muciniphila based on whole-genome sequencing, assembling, and annotating of 39 isolates derived from human and mouse feces. We revealed a flexible open pangenome of A. muciniphila currently consisting of 5644 unique proteins. Phylogenetic analysis identified three species-level A. muciniphila phylogroups exhibiting distinct metabolic and functional features. Based on the comprehensive genome catalogue, we reconstructed 106 newly A. muciniphila metagenome assembled genomes (MAGs) from available metagenomic datasets of human, mouse and pig gut microbiomes, revealing a transcontinental distribution of A. muciniphila phylogroups across mammalian gut microbiotas. Accurate quantitative analysis of A. muciniphila phylogroups in human subjects further demonstrated its strong correlation with body mass index and anti-diabetic drug usage. Furthermore, we found that, during their mammalian gut evolution history, A. muciniphila acquired extra genes, especially antibiotic resistance genes, from symbiotic microbes via recent lateral gene transfer. CONCLUSIONS: The genome repertoire of A. muciniphila provided insights into population structure, evolutionary and functional specificity of this significant bacterium.

DNA methylation dysregulations in valvular atrial fibrillation.

BACKGROUND: The epigenetic changes underlying the development of atrial fibrillation (AF) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of AF. In the present study, we evaluated the methylation status of genomic DNA from myocardial tissue in AF patients and sinus rhythm (SR) patients systematically. HYPOTHESIS: DNA methylation dysregulations will be associated with valvular AF. METHODS: Right atrial myocardial tissue was obtained from rheumatic valvular patients who had undergone valve replacement surgery (SR group, n = 10; AF group, n = 10). The global DNA methylation level, the promoter methylation level of the natriuretic peptide receptor-A gene (NPRA), and its correlation with the mRNA expression level of DNA methyltransferase genes were detected. RESULTS: The global DNA methylation level was significantly higher in the AF group than in the SR group (P < 0.05). The NPRA mRNA expression was decreased and the NPRA gene was hypermethylated in the AF group (P < 0.05). Meanwhile, the NPRA mRNA expression level has a negative correlation with the mean methylation level in the promoter region of the NPRA gene. CONCLUSIONS: DNA methylation dysregulations may be relevant in the pathogenesis of AF. DNA methyltransferase 3B likely plays an essential role in the DNA methylation dysregulations in AF.

DNA methylation dysregulations in rheumatic heart valve disease.

BACKGROUND: The epigenetic changes underlying the development of rheumatic heart valve disease (RHVD) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of RHVD. In the present study, we evaluated the DNA methylation dysregulations from myocardial tissue in RHVD patients systematically. METHODS: Right atrial myocardial tissue obtained from rheumatic valvular patients who had undergone valve replacements surgery (n = 73) and were compared to healthy controls (n = 4). the promoter methylation level of Intercellular adhesion molecule-1 (ICAM-1) gene and its correlation with ICAM-1 mRNA expression level, the global DNA methylation level and its correlation with age and mRNA expression level of DNA methyltransferase (DNMT) genes were detected. RESULTS: The ICAM-1 mRNA expression was increased (healthy control vs. NHYA III, 0.70 ± 0.19 vs. 4.38 ± 3.19, p = 0.011; NYHA IIvs. NHYA III, 2.60 ± 1.99 vs. 4.38 ± 3.19, p = 0.008) and the ICAM-1 gene was hypomethylated in RHVD patients (healthy controls vs. NYHA II, 0.120 ± 0.011 vs. 0.076 ± 0.057, p = 0.039; healthy control vs. NHYA III, 0.120 ± 0.011 vs. 0.041 ± 0.022, p < 0.001; NYHA IIvs. NHYA III, 0.076 ± 0.057 vs. 0.041 ± 0.022, p < 0.001). Meanwhile, The ICAM-1 mRNA expression level has negative correlation with the mean methylation level in the promoter region of ICAM-1 gene (r = -0.459, p < 0.001). The global DNA methylation levels was significantly increased in RHVD patients than in healthy controls (healthy control vs. NHYA III, 0.77 ± 0.28 vs. 2.09 ± 1.20, p = 0.017; NYHA IIvs. NHYA III, 1.57 ± 0.78 vs. 2.09 ± 1.20, p = 0.040) and had positive correlation with age (r = 0.326, p = 0.005), especially for older age group (≥ 60 years). DNMT1 likely plays an essential role in the DNA dysregulations in RHVD patients. CONCLUSIONS: Our analysis revealed that DNA methylation dysregulations may be relevant in the pathogenesis of RHVD.