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Microbiome May 2024Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and...
BACKGROUND
Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD.
RESULTS
We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10, for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD.
CONCLUSION
In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. Video Abstract.
Topics: Humans; Gastrointestinal Microbiome; Female; Middle Aged; Male; Hispanic or Latino; Ventricular Dysfunction, Left; United States; Dysbiosis; Aged; Bacteria; Metabolome; Echocardiography
PubMed: 38725043
DOI: 10.1186/s40168-024-01797-x -
Gut Microbes Dec 2023Despite improved cardiometabolic outcomes following bariatric surgery, its long-term impact on colorectal cancer (CRC) risk remains uncertain. In parallel, the influence...
Despite improved cardiometabolic outcomes following bariatric surgery, its long-term impact on colorectal cancer (CRC) risk remains uncertain. In parallel, the influence of bariatric surgery on the host microbiome and relationships with disease outcomes is beginning to be appreciated. Therefore, we investigated the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on the patterns of sulfide-reducing and butyrate-producing bacteria, which are hypothesized to modulate CRC risk after bariatric surgery. In this single-center, cross-sectional study, we included 15 pre-surgery subjects with severe obesity and patients who are at a median (range) of 25.6 (9.9-46.5) months after RYGB ( = 16) or VSG ( = 10). The DNA abundance of fecal bacteria and enzymes involved in butyrate and sulfide metabolism were identified using metagenomic sequencing. Differences between pre-surgery and post-RYGB or post-VSG cohorts were quantified using the linear discriminant analysis (LDA) effect size (LEfSe) method. Our sample was predominantly female (87%) with a median (range) age of 46 (23-71) years. Post-RYGB and post-VSG patients had a higher DNA abundance of fecal sulfide-reducing bacteria than pre-surgery controls (LDA = 1.3-4.4, < .05). The most significant enrichments were for fecal , and after RYGB, and for , after VSG. As for butyrate-producing bacteria, was more abundant, whereas and were lower post-RYGB vs. pre-surgery. was also lower in post-VSG vs. pre-surgery. Consistent with these findings, our analysis showed a greater enrichment of sulfide-reducing enzymes after bariatric surgery, especially RYGB, vs. pre-surgery. The DNA abundance of butyrate-producing enzymes was lower post-RYGB. In conclusion, the two most used bariatric surgeries, RYGB and VSG, are associated with microbiome patterns that are potentially implicated in CRC risk. Future studies are needed to validate and understand the impact of these microbiome changes on CRC risk after bariatric surgery.
Topics: Humans; Female; Middle Aged; Aged; Male; Butyrates; Cross-Sectional Studies; Escherichia coli; Gastrointestinal Microbiome; Bariatric Surgery; Bacteria; Colorectal Neoplasms
PubMed: 37702461
DOI: 10.1080/19490976.2023.2255345 -
Molecular Neurobiology Nov 2023Depression is one of the complications in patients with polycystic ovary syndrome (PCOS) that leads to considerable mental health. Accumulating evidence suggests that...
Depression is one of the complications in patients with polycystic ovary syndrome (PCOS) that leads to considerable mental health. Accumulating evidence suggests that human gut microbiomes are associated with the progression of PCOS and depression. However, whether microbiota influences depression development in PCOS patients is still uncharacterized. In this study, we employed metagenomic sequencing and transcriptome sequencing (RNA-seq) to profile the composition of the fecal microbiota and gene expression of peripheral blood mononuclear cells in depressed women with PCOS (PCOS-DP, n = 27) in comparison to mentally healthy women with PCOS (PCOS, n = 18) and compared with healthy control (HC, n = 27) and patients with major depressive disorder (MDD, n = 29). Gut microbiota assessment revealed distinct patterns in the relative abundance in the PCOS-DP compared to HC, MDD, and PCOS groups. Several gut microbes exhibited uniquely and significantly higher abundance in the PCOS-DP compared to PCOS patients, inducing EC Ruminococcus torques, Coprococcus comes, Megasphaera elsdenii, Acidaminococcus intestini, and Barnesiella viscericola. Bacteroides eggerthii was a potential gut microbial biomarker for the PCOS-DP. RNA-seq profiling identified that 35 and 37 genes were significantly elevated and downregulated in the PCOS-DP, respectively. The enhanced differential expressed genes (DEGs) in the PCOS-DP were enriched in pathways involved in signal transduction and endocrine and metabolic diseases, whereas several lipid metabolism pathways were downregulated. Intriguingly, genes correlated with the gut microbiota were found to be significantly enriched in pathways of neurodegenerative diseases and the immune system, suggesting that changes in the microbiota may have a systemic impact on the expression of neurodegenerative diseases and immune genes. Gut microbe-related DEGs of CREB3L3 and CCDC173 were possible molecular biomarkers and therapeutic targets of women with PCOS-DP. Our multi-omics data indicate shifts in the gut microbiome and host gene regulation in PCOS patients with depression, which is of possible etiological and diagnostic importance.
PubMed: 37995075
DOI: 10.1007/s12035-023-03744-7 -
Applied Microbiology and Biotechnology Dec 2023Type 2 diabetes mellitus (T2DM) has a major comorbidity known as diabetes-associated cognitive dysfunction (DACD). Studies have demonstrated that the gut microbiota is...
Type 2 diabetes mellitus (T2DM) has a major comorbidity known as diabetes-associated cognitive dysfunction (DACD). Studies have demonstrated that the gut microbiota is crucial in mediating the cognitive abnormalities that occur in diabetic individuals. Additionally, changes in dietary fatty acid intake levels, inflammatory cytokines, and microRNAs (miRs) have an effect on cognitive performance. However, further studies are needed to identify the link between gut microbiota and cognition in T2DM patients and the role that the above indicators play in this process. In order to provide a new rationale for the treatment of cognitive dysfunction in diabetes, this study was conducted in the middle-aged and elderly Beijing population to examine the differences in gut microbiota between DACD and T2DM patients as well as to further explore the role of erythrocyte membrane fatty acids, inflammatory cytokines, and miRs in gut microbiota-mediated cognitive impairment. According to the results, the abundance of norank_f_Eubacterium_coprostanoligenes_group, Acidaminococcus, Enterorhabdus, and norank_f_Clostridium_methylpentosum_group was higher in DACD patients compared to T2DM patients at the genus level. Compared with T2DM patients, plasma interleukin-12 (IL-12) concentrations were significantly higher in DACD patients than in T2DM patients, and IL-12 was significantly positively correlated with norank_f_Eubacterium_coprostanoligenes_group. In addition, plasma miR-142-5p was significantly positively correlated with Enterorhabdus and norank_f_Eubacterium_coprostanoligenes_group. We therefore hypothesize that cognitive impairment in T2DM patients is associated with altered gut microbial composition and that the effect of microbiota on cognition may be mediated through IL-12 and miR-142-5p. KEY POINTS: • Type 2 diabetes with or without cognitive impairment differs in gut microbiota. • Differential genera of gut microbiota were associated with inflammatory cytokines. • Differential genera of gut microbiota were associated with plasma microRNAs.
Topics: Middle Aged; Aged; Humans; MicroRNAs; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Cytokines; Cognitive Dysfunction; Fatty Acids; Interleukin-12
PubMed: 37733050
DOI: 10.1007/s00253-023-12754-3 -
Scientific Reports Jul 2023The fecal microbiome of 55 obese children and adolescents (BMI-SDS 3.2 ± 0.7) and of 25 normal-weight subjects, matched both for age and sex (BMI-SDS...
The fecal microbiome of 55 obese children and adolescents (BMI-SDS 3.2 ± 0.7) and of 25 normal-weight subjects, matched both for age and sex (BMI-SDS - 0.3 ± 1.1) was analysed. Streptococcus, Acidaminococcus, Sutterella, Prevotella, Sutterella wadsworthensis, Streptococcus thermophilus, and Prevotella copri positively correlated with obesity. The inferred pathways strongly associated with obesity concern the biosynthesis pathways of tyrosine, phenylalanine, tryptophan and methionine pathways. Furthermore, polyamine biosynthesis virulence factors and pro-inflammatory lipopolysaccharide biosynthesis pathway showed higher abundances in obese samples, while the butanediol biosynthesis showed low abundance in obese subjects. Different taxa strongly linked with obesity have been related to an increased risk of multiple diseases involving metabolic pathways related to inflammation (polyamine and lipopolysaccharide biosynthesis). Cholesterol, LDL, and CRP positively correlated with specific clusters of microbial in obese patients. The Firmicutes/Bacteroidetes-ratio was lower in obese samples than in controls and differently from the literature we state that this ratio could not be a biomarker for obesity.
Topics: Child; Adolescent; Humans; Pediatric Obesity; Lipopolysaccharides; Gastrointestinal Microbiome; Microbiota; Algorithms
PubMed: 37438382
DOI: 10.1038/s41598-023-36533-2 -
Biomolecules Apr 2024In recent years, CRISPR-Cas toolboxes for editing have rapidly accelerated natural product discovery and engineering. However, Cas efficiencies are oftentimes...
In recent years, CRISPR-Cas toolboxes for editing have rapidly accelerated natural product discovery and engineering. However, Cas efficiencies are oftentimes strain-dependent, and the commonly used Cas9 (SpCas9) is notorious for having high levels of off-target toxicity effects. Thus, a variety of Cas proteins is required for greater flexibility of genetic manipulation within a wider range of strains. This study explored the first use of sp. Cas12j, a hypercompact Cas12 subfamily, for genome editing in and its potential in activating silent biosynthetic gene clusters (BGCs) to enhance natural product synthesis. While the editing efficiencies of Cas12j were not as high as previously reported efficiencies of Cas12a and Cas9, Cas12j exhibited higher transformation efficiencies compared to SpCas9. Furthermore, Cas12j demonstrated significantly improved editing efficiencies compared to Cas12a in activating BGCs in sp. A34053, a strain wherein both SpCas9 and Cas12a faced limitations in accessing the genome. Overall, this study expanded the repertoire of Cas proteins for genome editing in actinomycetes and highlighted not only the potential of recently characterized Cas12j in but also the importance of having an extensive genetic toolbox for improving the editing success of these beneficial microbes.
Topics: Streptomyces; Gene Editing; CRISPR-Cas Systems; Acidaminococcus; CRISPR-Associated Protein 9; Multigene Family; Bacterial Proteins; CRISPR-Associated Proteins; Genome, Bacterial
PubMed: 38672502
DOI: 10.3390/biom14040486 -
Scientific Reports Oct 2023Type 2 Diabetes Mellitus has reached epidemic levels globally, and several studies have confirmed a link between gut microbial dysbiosis and aberrant glucose homeostasis...
Uncovering the relationship between gut microbial dysbiosis, metabolomics, and dietary intake in type 2 diabetes mellitus and in healthy volunteers: a multi-omics analysis.
Type 2 Diabetes Mellitus has reached epidemic levels globally, and several studies have confirmed a link between gut microbial dysbiosis and aberrant glucose homeostasis among people with diabetes. While the assumption is that abnormal metabolomic signatures would often accompany microbial dysbiosis, the connection remains largely unknown. In this study, we investigated how diet changed the gut bacteriome, mycobiome and metabolome in people with and without type 2 Diabetes.1 Differential abundance testing determined that the metabolites Propionate, U8, and 2-Hydroxybutyrate were significantly lower, and 3-Hydroxyphenyl acetate was higher in the high fiber diet compared to low fiber diet in the healthy control group. Next, using multi-omics factor analysis (MOFA2), we attempted to uncover sources of variability that drive each of the different groups (bacterial, fungal, and metabolite) on all samples combined (control and DM II). Performing variance decomposition, ten latent factors were identified, and then each latent factor was tested for significant correlations with age, BMI, diet, and gender. Latent Factor1 was the most significantly correlated. Remarkably, the model revealed that the mycobiome explained most of the variance in the DM II group (12.5%) whereas bacteria explained most of the variance in the control group (64.2% vs. 10.4% in the DM II group). The latent Factor1 was significantly correlated with dietary intake (q < 0.01). Further analyses of the impact of bacterial and fungal genera on Factor1 determined that the nine bacterial genera (Phocaeicola, Ligilactobacillus, Mesosutterella, Acidaminococcus, Dorea A, CAG-317, Caecibacter, Prevotella and Gemmiger) and one fungal genus (Malassezia furfur) were found to have high factor weights (absolute weight > 0.6). Alternatively, a linear regression model was fitted per disease group for each genus to visualize the relationship between the factor values and feature abundances, showing Xylose with positive weights and Propionate, U8, and 2-Hydroxybutyrate with negative weights. This data provides new information on the microbially derived changes that influence metabolic phenotypes in response to different diets and disease conditions in humans.
Topics: Humans; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Dysbiosis; Propionates; Multiomics; Metabolomics; Bacteria; Eating; Hydroxybutyrates
PubMed: 37863978
DOI: 10.1038/s41598-023-45066-7 -
Journal of Dairy Science Nov 2023The aim of this study was to assess the potential consequences on calf intake, performance, behavior, ruminal microbiome, and ruminal epithelium development of combining...
The aim of this study was to assess the potential consequences on calf intake, performance, behavior, ruminal microbiome, and ruminal epithelium development of combining the inclusion of chopped barley straw and alfalfa hay during the pre- and postweaning periods keeping concentrate to forage ratio constant among dietary treatments. Forty-five Holstein calves (44 ± 5.7 kg of body weight [BW] and 3 ± 1.5 d of age) individually penned were blocked by BW and randomly assigned to a common pellet concentrate fed ad libitum along with one of following forage feeding strategies: barley straw before and after weaning (S-S), barley straw before and alfalfa hay after weaning (S-A), or alfalfa hay before and after weaning (A-A). All calves received the same milk replacer regimen. Forage was supplied in a separated bucket at the rate of 7.5% (preweaning) and 15% (postweaning) of total solid feed intake of the previous day. Feed intake and BW were recorded daily and weekly, respectively. Rumen samples were obtained via a stomach tube at 53, 66, and 87 d and were composite in 3 samples of 5 animals each for subsequent rumen microbiome analysis. A rumen epithelium sample was taken by endoscopy at 90 d to assess gene expression of OCLN, CLDN4, SLC9A1, SLC9A3, SLC16A1, SLC16A4, IL6, and TGFB1. Data were analyzed with a mixed-effects model accounting for the fixed effects of block, forage, week of study, and their interaction, and calf as a random effect. The type of forage fed did not affect concentrate feed, forage, or total DM intake before weaning. However, S-A and A-A calves consumed less concentrate feed and S-A calves grew at a lower rate after weaning than S-S calves. Expression of the gene coding for SLC16A1 in the rumen epithelium was greatest in S-S among treatments. Rumen microbiome did not differ among treatments, while the relative abundance of Acidaminococcus and Selenomas genera increased, while Alloprevotella, Bifidobaterium, Olsenella, and Succiclasticum genera decreased with age. In conclusion, feeding barley straw before and after weaning was more effective than feeding alfalfa hay in promoting concentrate feed intake after weaning and fostering an increase in the expression of SLC16A1 in the rumen epithelium.
PubMed: 37558048
DOI: 10.3168/jds.2023-23401 -
Nature Biotechnology May 2024Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting,...
Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting one to three genomic sites per cell. We engineer an Acidaminococcus Cas12a (AsCas12a) variant, multiplexed transcriptional interference AsCas12a (multiAsCas12a), that incorporates R1226A, a mutation that stabilizes the ribonucleoprotein-DNA complex via DNA nicking. The multiAsCas12a-KRAB fusion improves CRISPRi activity over DNase-dead AsCas12a-KRAB fusions, often rescuing the activities of lentivirally delivered CRISPR RNAs (crRNA) that are inactive when used with the latter. multiAsCas12a-KRAB supports CRISPRi using 6-plex crRNA arrays in high-throughput pooled screens. Using multiAsCas12a-KRAB, we discover enhancer elements and dissect the combinatorial function of cis-regulatory elements in human cells. These results instantiate a group testing framework for efficiently surveying numerous combinations of chromatin perturbations for biological discovery and engineering.
PubMed: 38760567
DOI: 10.1038/s41587-024-02224-0 -
Journal of Gastroenterology Apr 2024Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this...
BACKGROUND/AIM
Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy.
SUBJECTS/METHODS
110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis.
RESULTS
Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity.
CONCLUSIONS
We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Obesity, Morbid; Ethanol; Fibrosis; Succinates
PubMed: 38265508
DOI: 10.1007/s00535-023-02075-7