Fecal Microbiome Transplantation and Butyrate Improves Early Cardiac Dysfunction and Modifies the BCAA Metabolic pathway in a Diet induced pre-HFpEF Mouse Model.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221195 | GEO | 2023/03/01
REPOSITORIES: GEO
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Project description:More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement. Cardiac RNAseq analysis showed butyrate to significantly upregulate ppm1k gene that encodes protein phosphatase 2Cm (PP2Cm) which dephosphorylates and activates branched-chain α-keto acid dehydrogenase (BCKDH) enzyme, and in turn increases the catabolism of branched chain amino acids (BCAAs). Following both FMT and butyrate treatment, the level of inactive p-BCKDH in the heart was reduced. These findings show that gut microbiome modulation can alleviate early cardiac mechanics dysfunction seen in the development of obesity associated HFpEF.
| S-EPMC9944585 | biostudies-literature
Project description:Fecal Microbiome Transplantation and Butyrate Improves Early Cardiac Dysfunction and Modifies the BCAA Metabolic pathway in a Diet induced pre-HFpEF Mouse Model.
| PRJNA913181 | ENA
Project description:Gut microbiota are recognized to be important for anticancer therapy, yet the underlying mechanism is not clear. Herein, we demonstrate that gut microbial metabolite butyrate improves anticancer therapy efficacy by regulating intracellular calcium homeostasis. Butyrate metabolism is activated in hepatocellular carcinoma (HCC) patients. Butyrate supplementation or depletion of short-chain Acyl-CoA dehydrogenase (ACADS), a key enzyme for butyrate metabolism, significantly inhibit HCC proliferation and metastasis. Profiling analysis of genes upregulated by butyrate supplementation or ACADS knockdown reveal that calcium signaling pathway is activated, leading to dysregulation of intracellular calcium homeostasis and production of reactive oxygen species (ROS). Butyrate supplementation improves the therapy efficacy of a tyrosine kinase inhibitor sorafenib. Butyrate and sorafenib co-encapsulated monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-poly(L-lysine)-glypican 3 (PEAL-GPC3) nanoparticles significantly reduce HCC progression. Our findings provide new insight into the mechanisms that the gut microbial metabolites inhibit HCC progression and suggest a translatable therapeutics approach to enhance the clinical targeted therapeutic efficacy.
2025-07-20 | GSE210156 | GEO
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
2024-03-05 | PXD045677 | Pride
Project description:Datasets to accompany the manuscript "Fecal butyrate and deoxycholic acid quantitation for rapid assessment of the gut microbiome" Michael W. Mullowney, Angelica Moran, Antonio Hernandez, Mary McMillin, Amber R. Rose, David Moran, Jessica Little, Ann B. Nguyen, Bhakti K. Patel, Christopher J. Lehmann, Matthew A. Odenwald, Eric G. Pamer, Kiang-Teck J. Yeo, Ashley M. Sidebottom.
2025-06-17 | MSV000098238 | MassIVE
Project description:Fecal microbiota transplantation (FMT) has become an effective strategy to treat metabolic diseases, including type 2 diabetes mellitus (T2DM). We previously reported that the intestinal microbiome had significant difference between individuals with normal glucose tolerance and T2DM in Chinese Kazak ethnic group. In this study, we investigated the effects of transplanted fecal bacteria from Kazaks with normal glucose tolerance (KNGT) in db/db mice. The mice were treated with 0.2?mL of fecal bacteria solution from KNGT daily for 10 weeks. We showed that the fecal bacteria from KNGT successfully colonized in the intestinal tract of db/db mice detected on day 14. In the FMT-treated db/db mice, the levels of fasting blood glucose, postprandial glucose, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol were significantly downregulated, whereas high-density lipoprotein-cholesterol levels were upregulated. In the FMT-treated db/db mice, Desulfovibrio and Clostridium coccoides levels in gut were significantly decreased, but the fecal levels of Akkermansia muciniphila and colon histone deacetylase-3 (HDAC3) protein expression were increased. At 8 weeks, both intestinal target bacteria and HDAC3 were correlated with glycolipid levels; Akkermansia muciniphila level was positively correlated with HDAC3 protein expression (r?= +0.620, P?=?0.037). Our results suggest that fecal bacteria from KNGT could potentially be used to treat diabetic patients.
| S-EPMC7468362 | biostudies-literature
Project description:Background: HFpEF is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of HFpEF patients showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment specific-patterns. Methods: We performed single cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) of HFpEF patients (n=6), HFrEF patients (n=8) and healthy controls (n=7) taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in a HFpEF mouse model (induced by a high-fat diet plus L-NAME), with one group additionally administered the anti-inflammatory agent nitro-oleic acid (NO₂-OA). Results: Analysis of human PBMCs revealed a HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (e.g. CCL2, TNF) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with NO₂-OA leading to a partial normalization of immunological signatures and a significant improvement in diastolic function. Conclusion: Our results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with HFrEF. The conserved immunological signatures between humans and mice, and the beneficial effect of NO₂-OA in a preclinical model, provide important translational insights and generate hypotheses for personalized interventions in HFpEF.
2025-07-28 | GSE298172 | GEO
Project description:Background: HFpEF is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of HFpEF patients showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment specific-patterns. Methods: We performed single cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) of HFpEF patients (n=6), HFrEF patients (n=8) and healthy controls (n=7) taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in a HFpEF mouse model (induced by a high-fat diet plus L-NAME), with one group additionally administered the anti-inflammatory agent nitro-oleic acid (NO₂-OA). Results: Analysis of human PBMCs revealed a HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (e.g. CCL2, TNF) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with NO₂-OA leading to a partial normalization of immunological signatures and a significant improvement in diastolic function. Conclusion: Our results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with HFrEF. The conserved immunological signatures between humans and mice, and the beneficial effect of NO₂-OA in a preclinical model, provide important translational insights and generate hypotheses for personalized interventions in HFpEF.
2025-07-28 | GSE298173 | GEO
Project description:Background: HFpEF is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of HFpEF patients showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment specific-patterns. Methods: We performed single cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) of HFpEF patients (n=6), HFrEF patients (n=8) and healthy controls (n=7) taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in a HFpEF mouse model (induced by a high-fat diet plus L-NAME), with one group additionally administered the anti-inflammatory agent nitro-oleic acid (NO₂-OA). Results: Analysis of human PBMCs revealed a HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (e.g. CCL2, TNF) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with NO₂-OA leading to a partial normalization of immunological signatures and a significant improvement in diastolic function. Conclusion: Our results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with HFrEF. The conserved immunological signatures between humans and mice, and the beneficial effect of NO₂-OA in a preclinical model, provide important translational insights and generate hypotheses for personalized interventions in HFpEF.
2025-07-28 | GSE298171 | GEO