RESUMEN

Allosteric modulation is a central mechanism for metabolic regulation but has yet to be described for a gut microbiota-host interaction. Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, has previously been clinically associated with and mechanistically linked to cardiovascular disease (CVD) and heart failure (HF). Here, using cells expressing ß1- versus ß2-adrenergic receptors (ß1AR and ß2AR), PAGln is shown to act as a negative allosteric modulator (NAM) of ß2AR, but not ß1AR. In functional studies, PAGln is further shown to promote NAM effects in both isolated male mouse cardiomyocytes and failing human heart left ventricle muscle (contracting trabeculae). Finally, using in silico docking studies coupled with site-directed mutagenesis and functional analyses, we identified sites on ß2AR (residues E122 and V206) that when mutated still confer responsiveness to canonical ß2AR agonists but no longer show PAGln-elicited NAM activity. The present studies reveal the gut microbiota-obligate metabolite PAGln as an endogenous NAM of a host GPCR.

Asunto(s)

Microbioma Gastrointestinal , Glutamina , Miocitos Cardíacos , Receptores Adrenérgicos beta 2 , Animales , Humanos , Masculino , Ratones , Regulación Alostérica , Glutamina/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/microbiología , Células HEK293 , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/genética

RESUMEN

Heart failure is a multifactorial disease, the percentage of patients with heart failure caused by metabolic syndrome is increasing year by year. The effect of gut flora dysbiosis on metabolic syndrome and heart failure has received widespread attention in recent years. Drugs to treat the condition urgently need to be discovered. C20DM, as a precursor compound of ginsenoside, is a small molecule compound obtained by biosynthetic means and is not available in natural products. In this project, we found that C20DM could improve the diversity of gut flora and elevate the expression of intestinal tight junction proteins-Occludin, Claudin, ZO-1, which inhibited the activity of the TLR4-MyD88-NF-kB pathway, and as a result, reduced myocardial inflammation and slowed down heart failure in metabolic syndrome mice. In conclusion, our study suggests that C20DM can treat heart failure by regulating gut flora, and it may be a candidate drug for treating metabolic syndrome-induced heart failure.

Asunto(s)

Microbioma Gastrointestinal , Insuficiencia Cardíaca , Síndrome Metabólico , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Síndrome Metabólico/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/microbiología , Síndrome Metabólico/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/microbiología , Ratones , Masculino , Ratones Endogámicos C57BL , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal/efectos de los fármacos , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico

RESUMEN

Whipple disease is a rare systemic illness associated with weight loss, diarrhea, and arthralgia. Asymptomatic carriage is common, but the disease can be complicated by cardiac involvement and may result in culture-negative endocarditis. Cardiac manifestations of the disease can lead to death. This report presents the case of a 66-year-old man with Whipple disease and biventricular heart failure with cardiogenic shock. Medical therapy followed by successful replacement of the aortic and mitral valves resulted in substantial improvement.

Asunto(s)

Endocarditis Bacteriana , Insuficiencia Cardíaca , Implantación de Prótesis de Válvulas Cardíacas , Tropheryma , Enfermedad de Whipple , Humanos , Masculino , Anciano , Enfermedad de Whipple/diagnóstico , Enfermedad de Whipple/complicaciones , Enfermedad de Whipple/tratamiento farmacológico , Enfermedad de Whipple/microbiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/etiología , Endocarditis Bacteriana/microbiología , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/terapia , Tropheryma/aislamiento & purificación , Resultado del Tratamiento , Antibacterianos/uso terapéutico , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/microbiología , Válvula Mitral/cirugía , Choque Cardiogénico/etiología , Choque Cardiogénico/terapia , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/microbiología , Válvula Aórtica/microbiología , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/microbiología , Enfermedades de las Válvulas Cardíacas/diagnóstico , Enfermedades de las Válvulas Cardíacas/complicaciones

RESUMEN

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here. METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing. RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats. CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.

Asunto(s)

Modelos Animales de Enfermedad , Progresión de la Enfermedad , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Metilaminas , Volumen Sistólico , Función Ventricular Izquierda , Animales , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/metabolismo , Metilaminas/metabolismo , Metilaminas/sangre , Masculino , Obesidad/microbiología , Obesidad/fisiopatología , Obesidad/metabolismo , Oxigenasas/metabolismo , Oxigenasas/genética , Hígado/metabolismo , Biomarcadores/sangre , Heces/microbiología , Ratas , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Bacterias/metabolismo , Disbiosis

RESUMEN

BACKGROUND: Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the mechanisms behind cognitive impairment. METHODS: CHF models in rats were induced by ligation of the left anterior descending coronary artery. Cardiac function was analyzed by cardiac ultrasound and hemodynamics. ELISA, immunofluorescence, Western blot, Golgi staining and transmission electron microscopy were performed on hippocampal tissues. The alterations of intestinal flora under the morbid state were investigated via 16S rRNA sequencing. The connection between neuroinflammation and synapses is confirmed by a co-culture system of BV2 microglia and HT22 cells in vitro. Results: CHF rats exhibited deteriorated cognitive behaviors. CHF induced neuronal structural disruption, loss of Nissl bodies, and synaptic damage, exhibiting alterations in multiple parameters. CHF rats showed increased hippocampal levels of inflammatory cytokines and activated microglia and astrocytes. Furthermore, the study highlights dysregulated PDE4-dependent cAMP signaling and intestinal flora dysbiosis, closely associated with neuroinflammation, and altered synaptic proteins. In vitro, microglial neuroinflammation impaired synaptic plasticity via PDE4-dependent cAMP signaling. CONCLUSIONS: Neuroinflammation worsens CHF-related cognitive impairment through neuroplasticity disorder, tied to intestinal flora dysbiosis. PDE4 emerges as a potential therapeutic target. These findings provide insightful perspectives on the heart-gut-brain axis.

Asunto(s)

Disfunción Cognitiva , Disbiosis , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Enfermedades Neuroinflamatorias , Plasticidad Neuronal , Animales , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/fisiopatología , Disfunción Cognitiva/microbiología , Disbiosis/microbiología , Ratas , Masculino , Hipocampo/metabolismo , Hipocampo/patología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Enfermedad Crónica , Microglía/metabolismo

RESUMEN

The dysbiosis of gut microbiota with aging has been extensively studied, revealing its substantial contribution to variety of diseases. However, the impact of aged microbiota in heart failure (HF) remains unclear. In this study, we employed the method of fecal microbiota transplantation (FMT) from aged donors to investigate its role in the context of HF. Our results demonstrate that FMT from aged donors alters the recipient's gut microbiota composition and abundance. Furthermore, FMT impairs cardiac function and physical activity in HF mice. Aged FMT induces metabolic alterations, leading to body weight gain, impaired glucose tolerance, increased respiratory exchange ratio, and enhanced fat accumulation. The epicardium of aged FMT recipients shows fat accumulation, accompanied by cardiomyocyte hypertrophy, cardiac fibrosis and increased cellular apoptosis. Mechanistically, aged FMT suppresses the PPARα/PGC1α signaling pathway in HF. Notably, activation of PPARα effectively rescues the metabolic changes and myocardial injury caused by aged FMT. In conclusion, our study emphasizes the role of the PPARα/PGC1α signaling pathway in aged FMT-mediated HF.

Asunto(s)

Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Insuficiencia Cardíaca , PPAR alfa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transducción de Señal , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Animales , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/terapia , Ratones , Masculino , Ratones Endogámicos C57BL , Envejecimiento/metabolismo , Humanos , Modelos Animales de Enfermedad

RESUMEN

The gut microbiota, comprising a diverse community of microorganisms, significantly influences various aspects of health. Changes in the composition of the gut microbiota are implicated in adverse effects on host physiology, contributing to the pathogenesis of cardiovascular diseases, among others pathological conditions. Understanding the role of the gut microbiota in the context of heart failure is particularly important. In this regard, the spontaneously hypertensive heart failure (SHHF) rat is an adequate experimental model since exhibits many features in common with heart failure (HF) in humans. Recent advancements in next-generation sequencing (NGS) have greatly improved microbiome analysis. However, standardization and the adoption of best practices are essential to mitigate experimental variations across studies. This manuscript outlines a straightforward methodology for analyzing gut microbiota composition in SHHF rat fecal samples using 16S rRNA sequencing, emphasizing the relevance of gut microbiota in heart failure.

Asunto(s)

Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Hipertensión , ARN Ribosómico 16S , Animales , Insuficiencia Cardíaca/microbiología , ARN Ribosómico 16S/genética , Microbioma Gastrointestinal/genética , Ratas , Hipertensión/microbiología , Heces/microbiología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Ratas Endogámicas SHR

RESUMEN

Strain TC023T, a Gram-positive, long, rod-shaped, spore-forming anaerobe, was isolated from the faeces of a heart failure mouse model. The strain formed greyish-white coloured colonies with a convex elevation on brain-heart infusion medium supplemented with 0.1 % sodium taurocholate, incubated at 37 °C for 2 days. Taxonomic analysis based on the 16S rRNA gene sequence showed that TC023T belonged to the genus Turicibacter, and was closely related to Turicibacter bilis MMM721T (97.6 %) and Turicibacter sanguinis MOL361T (97.4 %). The whole genome of the strain has a G+C content of 37.3 mol%. The average nucleotide identity and genome-to-genome distance between TC023T and Turicibacter bilis MMM721T were 77.6 % and 24.3 %, respectively, and those with Turicibacter sanguinis MOL361T were 75.4 % and 24.3 %, respectively. These genotypic, phenotypic, and biochemical analyses indicated that the isolate represents a novel species in the genus Turicibacter, and the name Turicibacter faecis sp. nov. is proposed. The type strain is TC023T (RIMD 2002001T=TSD 372T).

Asunto(s)

Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano , Modelos Animales de Enfermedad , Heces , Insuficiencia Cardíaca , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Animales , ARN Ribosómico 16S/genética , Heces/microbiología , Ratones , ADN Bacteriano/genética , Insuficiencia Cardíaca/microbiología , Genoma Bacteriano , Masculino , Ácidos Grasos

RESUMEN

Recent research has revealed that alterations of the gut microbiome (GM) play a comprehensive role in the pathophysiology of HF. However, findings in this field remain controversial. In this study, we focus on differences in GM diversity and abundance between HF patients and non-HF people, based on previous 16 S ribosomal RNA (16rRNA) gene sequencing. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search of PubMed, Web of Science, Embase, Cochrane Library, and Ovid databases using the keyword "Heart failure" and "Gastrointestinal Microbiome". A significant decrease in alpha diversity was observed in the HF patients (Chao1, I2 = 87.5 %, p < 0.001; Shannon index, I2 = 62.8 %, p = 0.021). At the phylum level, the HF group exhibited higher abundances of Proteobacteria (I2 = 92.0 %, p = 0.004) and Actinobacteria (I2 = 82.5 %, p = 0.010), while Bacteroidetes (I2 = 45.1 %, p = 0.017) and F/B ratio (I2 = 0.0 %, p＜0.001) were lower. The Firmicutes showed a decreasing trend but did not reach statistical significance (I2 = 82.3 %, p = 0.127). At the genus level, the relative abundances of Streptococcus, Bacteroides, Alistipes, Bifidobacterium, Escherichia-Shigella, Enterococcus and Klebsiella were increased in the HF group, whereas Ruminococcus, Faecalibacterium, Dorea and Megamona exhibited decreased relative abundances. Dialister, Blautia and Prevotella showed decreasing trends but without statistical significance. This observational meta-analysis suggests that GM changes are associated with HF, manifesting as alterations in GM abundance, disruptions in the production of short-chain fatty acids (SCFAs) bacteria, and an increase in trimethylamine N-oxide (TMAO) producing bacteria.

Asunto(s)

Bacterias , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , ARN Ribosómico 16S/genética , Proteobacteria/genética , Proteobacteria/aislamiento & purificación , Bacteroidetes/genética , Bacteroidetes/aislamiento & purificación

RESUMEN

Epidemiological studies have revealed that hypertensive heart disease is a major risk factor for heart failure, and its heart failure burden is growing rapidly. The need to act in the face of this threat requires first an understanding of the multifactorial origin of hypertensive heart disease and second an exploration of new mechanistic pathways involved in myocardial alterations critically involved in cardiac dysfunction and failure (eg, myocardial interstitial fibrosis). Increasing evidence shows that alterations of gut microbiota composition and function (ie, dysbiosis) leading to changes in microbiota-derived metabolites and impairment of the gut barrier and immune functions may be involved in blood pressure elevation and hypertensive organ damage. In this review, we highlight recent advances in the potential contribution of gut microbiota alterations to myocardial interstitial fibrosis in hypertensive heart disease through blood pressure-dependent and blood pressure-independent mechanisms. Achievements in this field should open a new path for more comprehensive treatment of myocardial interstitial fibrosis in hypertensive heart disease and, thus, for the prevention of heart failure.

Asunto(s)

Fibrosis , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Hipertensión , Miocardio , Humanos , Microbioma Gastrointestinal/fisiología , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/complicaciones , Miocardio/patología , Miocardio/metabolismo , Disbiosis/microbiología , Disbiosis/complicaciones , Animales

RESUMEN

BACKGROUND: Sarcopenia, characterized by loss of muscle mass and function, is prevalent in heart failure (HF) and predicts poor outcomes. We investigated alterations in sarcopenia index (SI), a surrogate for skeletal muscle mass, in HF, left ventricular assist device (LVAD), and heart transplant (HT), and assessed its relationship with inflammation and digestive tract (gut and oral) microbiota. METHODS: We enrolled 460 HF, LVAD, and HT patients. Repeated measures pre/post-procedures were obtained prospectively in a subset of LVAD and HT patients. SI (serum creatinine/cystatin C) and inflammatory biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) were measured in 271 and 622 blood samples, respectively. Gut and saliva microbiota were assessed via 16S ribosomal ribonucleic acid sequencing among 335 stool and 341 saliva samples. Multivariable regression assessed the relationship between SI and (1) New York Heart Association class; (2) pre- versus post-LVAD or HT; and (3) biomarkers of inflammation and microbial diversity. RESULTS: Median (interquartile range) natural logarithm (ln)-SI was -0.13 (-0.32, 0.05). Ln-SI decreased across worsening HF class, further declined at 1 month after LVAD and HT, and rebounded over time. Ln-SI was correlated with inflammation (r = -0.28, p < 0.01), gut (r = 0.28, p < 0.01), and oral microbial diversity (r = 0.24, p < 0.01). These associations remained significant after multivariable adjustment in the combined cohort but not for all individual cohorts. The presence of the gut taxa Roseburia inulinivorans was associated with increased SI. CONCLUSIONS: SI levels decreased in symptomatic HF and remained decreased long-term after LVAD and HT. In the combined cohort, SI levels covaried with inflammation in a similar fashion and were significantly related to overall microbial (gut and oral) diversity, including specific taxa compositional changes.

Asunto(s)

Microbioma Gastrointestinal , Insuficiencia Cardíaca , Trasplante de Corazón , Corazón Auxiliar , Inflamación , Sarcopenia , Humanos , Femenino , Masculino , Sarcopenia/microbiología , Corazón Auxiliar/efectos adversos , Corazón Auxiliar/microbiología , Persona de Mediana Edad , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/fisiopatología , Microbioma Gastrointestinal/fisiología , Estudios Prospectivos , Microbiota , Anciano , Biomarcadores/metabolismo , Boca/microbiología

RESUMEN

BACKGROUND: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals. METHODS: We performed a matched nationwide cohort study (Denmark, 1993-2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease. RESULTS: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7-10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8-4.8, aHR 1.13, 95 % CI: 1.11-1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members. CONCLUSIONS: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure.

Asunto(s)

Anticuerpos Antibacterianos , Insuficiencia Cardíaca , Enfermedad de Lyme , Humanos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/microbiología , Masculino , Femenino , Persona de Mediana Edad , Enfermedad de Lyme/epidemiología , Enfermedad de Lyme/microbiología , Anciano , Estudios de Cohortes , Anticuerpos Antibacterianos/sangre , Adulto , Grupo Borrelia Burgdorferi/inmunología , Sistema de Registros , Factores de Riesgo , Adulto Joven , Borrelia burgdorferi/inmunología , Adolescente , Anciano de 80 o más Años

Asunto(s)

Neoplasias Colorrectales , Progresión de la Enfermedad , Disbiosis , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/microbiología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/metabolismo , Animales , Factores de Riesgo , Cardiooncología

RESUMEN

AIMS: Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation. METHODS AND RESULTS: C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice. CONCLUSION: We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.

Asunto(s)

Colon , Modelos Animales de Enfermedad , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Insuficiencia Cardíaca , Ratones Endogámicos C57BL , Infarto del Miocardio , Animales , Infarto del Miocardio/patología , Infarto del Miocardio/microbiología , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/etiología , Masculino , Colon/microbiología , Colon/patología , Ribotipificación , Neoplasias del Colon/patología , Neoplasias del Colon/microbiología , Bacterias/genética , Heces/microbiología , Interacciones Huésped-Patógeno

RESUMEN

Food-derived oligosaccharides show promising therapeutic potential in lowering blood pressure (BP), but the mechanism is poorly understood. Recently, the potential role of gut microbiota (GM) in hypertension has been investigated, but the specific GM signature that may participate in hypertension remains unclear. To test the potassium alginate oligosaccharides (PAO) mechanism in lowering BP and specific microbial signature changes in altering GM, we administered various dosages of PAO in 40 spontaneously hypertensive rats for a duration of six weeks. We analyzed BP, sequenced the 16S ribosomal DNA gene in the cecum content, and gathered RNA-seq data in cardiac tissues. We showed that the oral administration of PAO could significantly decrease systolic BP and mean arterial pressure. Transcriptome analyses demonstrated that the protective effects of developing heart failure were accompanied by down-regulating of the Natriuretic Peptide A gene expression and by decreasing the concentrations of angiotensin II and atrial natriuretic peptide in plasma. In comparison to the Vehicle control, PAO could increase the microbial diversity by altering the composition of GM. PAO could also decrease the ratio of Firmicutes to Bacteroidetes by decreasing the abundance of Prevotella and Phascolarctobacterium bacteria. The favorable effect of PAO may be added to the positive influence of the abundance of major metabolites produced by Gram-negative bacteria in GM. We suggest that PAO caused changes in GM, and thus, they played an important role in preventing the development of cardiovascular disease.

Asunto(s)

Alginatos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Insuficiencia Cardíaca , Hipertensión , Oligosacáridos/farmacología , Animales , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Hipertensión/sangre , Hipertensión/microbiología , Hipertensión/fisiopatología , Hipertensión/prevención & control , Masculino , Ratas , Ratas Endogámicas SHR

RESUMEN

Background Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial-derived metabolites such as short-chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. Methods and Results We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α-diversity (eg, number of microbes) and ß-diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF (P=0.001). We did not find an association between ß-diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so (P=0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short-chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P=0.016). Conclusions We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.

Asunto(s)

Bacterias/metabolismo , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Insuficiencia Cardíaca/microbiología , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Bacterias/clasificación , Estudios de Casos y Controles , Disbiosis , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Ribotipificación , Medición de Riesgo , Factores de Riesgo , Victoria

RESUMEN

BACKGROUND: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). METHODS: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. FINDINGS: We enrolled a total of 151 patients. After three months' treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. INTERPRETATION: Three months' treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF. FUNDING: The trial was funded by the Norwegian Association for Public Health, the Blix foundation, Stein Erik Hagen's Foundation for Clinical Heart Research, Ada og Hagbart Waages humanitære og veldedige stiftelse, Alfasigma, and Biocodex.

Asunto(s)

Antibacterianos/uso terapéutico , Microbioma Gastrointestinal , Insuficiencia Cardíaca/microbiología , Probióticos/uso terapéutico , Rifaximina/uso terapéutico , Saccharomyces boulardii/patogenicidad , Anciano , Gasto Cardíaco , Prueba de Esfuerzo , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Persona de Mediana Edad , Nivel de Atención

RESUMEN

BACKGROUND: The potential role of the gut microbiome (GM) in heart failure (HF) had recently been revealed. However, the underlying mechanisms of the GM and fecal metabolome in HF have not been characterized. The Dahl salt-sensitive rat model of hypertensive heart failure (H-HF) was used to study the clinical symptoms and characteristics. To elucidate the pathogenesis of HF, we combined 16S rRNA gene sequencing and metabolomics to analyze gut microbial compositions and fecal metabolomic profiles of rats with H-HF. RESULTS: PCoA of beta diversity shown that the gut microbiome composition profiles among the three groups were separated. Gut microbial composition was significantly altered in H-HF rats, the ratio of Firmicutes to Bacteroidetes(F/B) increased and the abundance of Muribaculaceae, Lachnospiraceae, and Lactobacillaceae decreased. Significantly altered levels of 17 genera and 35 metabolites were identified as the potential biomarker of H-HF. Correlation analysis revealed that specific altered genera were strongly correlated with changed fecal metabolites. The reduction in short-chain fatty acids (SCFA)-producing bacteria and trimethylamine N-oxide (TMAO) might be a notable characteristic for H-HF. CONCLUSIONS: This is the first study to characterize the fecal microbiome of hypertensive heart failure by integrating 16S rRNA gene sequencing and LC-MS-based metabolomics approaches. Collectively, the results suggesting changes of gut microbiome composition and metabolites are associated with hypertensive heart failure rats.

Asunto(s)

Microbioma Gastrointestinal/genética , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/microbiología , Hipertensión/complicaciones , Animales , Cromatografía Liquida , Modelos Animales de Enfermedad , Heces/química , Espectrometría de Masas , Metabolómica , ARN Ribosómico 16S/genética , Ratas , Ratas Endogámicas Dahl

RESUMEN

Background Small intestinal bacterial overgrowth (SIBO) is a common pathological condition of intestinal microbiota. The prevalence of SIBO and its prognostic value in patients with heart failure (HF) are unknown. Methods and Results A total of 287 patients tested for SIBO using lactulose hydrogen-methane breath test were evaluated. At least 1 of the following criteria fulfilled was SIBO positive: patients with fasting hydrogen level ≥20 parts per million (ppm) or a ≥20 ppm rise in hydrogen by 90 minutes were diagnosed with SIBO (H2) positive; and patients with methane levels ≥10 ppm at any test point were diagnosed with SIBO (CH4) positive. The association between SIBO and the composite of cardiovascular death and HF rehospitalization was investigated. In 287 consecutive patients with HF, 128 (45%) were positive for SIBO. Our result showed SIBO increased the risk of HF rehospitalization in patients with HF with reduced ejection fraction (P<0.001), and the risk of cardiovascular death in patients with HF with preserved EF (P=0.011). SIBO was an independent risk factor of primary end point in patients with HF (hazard ratio [HR], 2.13; 95% CI; 1.26-3.58; P=0.005). In addition, SIBO (CH4) showed a prognostic value on adverse outcomes (HR, 2.35; 95% CI, 1.38-4.02; P<0.001), whereas the association between SIBO (H2) and outcomes was not statistically significant. Conclusions There was high prevalence of SIBO in patients with HF, and SIBO was independently associated with poor outcomes. Proactive treatment for SIBO may provide extra benefit for patients with HF.

Asunto(s)

Síndrome del Asa Ciega , Pruebas Respiratorias/métodos , Insuficiencia Cardíaca , Síndrome del Asa Ciega/diagnóstico , Síndrome del Asa Ciega/epidemiología , Síndrome del Asa Ciega/microbiología , China/epidemiología , Técnicas de Diagnóstico del Sistema Digestivo , Femenino , Microbioma Gastrointestinal , Factores de Riesgo de Enfermedad Cardiaca , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/mortalidad , Humanos , Hidrógeno/análisis , Masculino , Metano/análisis , Persona de Mediana Edad , Mortalidad , Valor Predictivo de las Pruebas , Prevalencia , Pronóstico , Volumen Sistólico

RESUMEN

In patients with heart failure (HF), the exhaled concentrations of hydrogen after a breath test-a non-invasive assessment of small intestinal overgrowth- has been related to HF severity and higher risk of adverse outcomes. Indeed, two intestinal bacterial metabolites-blood Trimethylamine N-Oxide (TMAO) and butyrate-have been related to a worse prognosis in HF. However, the relationship between the exhaled concentrations of hydrogen after a breath test and these two metabolites remains unknown. Thus, in this post-hoc analysis, we sought to evaluate whether these two metabolites are associated with the exhaled concentrations of hydrogen after a breath test in patients with a recent admission for HF. We included 60 patients with a recent hospitalization for HF. Cumulative hydrogen over time was integrated into a single measurement by the area under the concentration curve (AUC-H2). A linear regression multivariable analysis was used to evaluate the associations. A 2-sided p-value < 0.05 was considered to be statistically significant. The median (p25-p75) amino-terminal pro-brain natriuretic peptide, AUC-H2, TMAO, and Butyrate were 4789 pg/ml (1956-11149), 1615 (700-2585), 0.68 (0.42-1.12), and 0.22 ± 13, respectively. After multivariate adjustment, TMAO and butyrate were significantly associated with AUC-H2 (p = 0.027 and p = 0.009, respectively). For TMAO, this association was positive and for butyrate, negative. Bacterial-origin metabolites TMAO and Butyrate were independently related to AUC-H2 in patients with a recent hospitalization for acute HF.

Asunto(s)

Bacterias/metabolismo , Síndrome del Asa Ciega/metabolismo , Butiratos/metabolismo , Insuficiencia Cardíaca/metabolismo , Intestino Delgado/microbiología , Metilaminas/metabolismo , Anciano , Biomarcadores/metabolismo , Síndrome del Asa Ciega/microbiología , Pruebas Respiratorias , Femenino , Insuficiencia Cardíaca/microbiología , Insuficiencia Cardíaca/terapia , Humanos , Masculino