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Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

ABSTRACT: Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA amplicon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.

SUBMITTER: Jama HA

PROVIDER: S-EPMC7578080 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

Jama Hamdi A HA Fiedler April A Tsyganov Kirill K Nelson Erin E Horlock Duncan D Nakai Michael E ME Kiriazis Helen H Johnson Chad C Du Xiao-Jun XJ Mackay Charles R CR Marques Francine Z FZ Kaye David M DM

Scientific reports 20201021 1

Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. ...[more]

PMID: 33087738

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Project description:Abstract Background Neurocognitive impairment is increasingly recognized as a fundamental symptomatology in schizophrenia with more than 80% of patients exhibiting significant deficits, even at first episode of illness. Current pharmacotherapies do not alleviate cognitive symptoms, and often cause severe metabolic dysfunction and weight gain that readily become major health concerns. Identifying adjunctive interventions that improve cognition without disrupting the therapeutic actions of anti-psychotic medications, and can mitigate the metabolic side-effects of these drugs, would be highly beneficial to patients and improve prognosis. We have recently demonstrated that the manipulation of the rat gut microbiota with a prebiotic (dietary fibre that grows beneficial enteric bacteria) improves cognitive flexibility and prevents olanzapine-mediated weight gain. We therefore aim to explore whether these actions of the prebiotic translate to medicated stable patients with schizophrenia. Methods A total of 40 patients with psychosis aged 18–65 will be enrolled in a 24-week maltodextrin-controlled cross-over experimental medicine study. Participants will receive either a 12-week treatment with a prebiotic (active compound) followed by a 12-week maltodextrin supplement (placebo), or in the reverse order. The order of supplements that participants receive is randomized. The primary outcome is to examine the influence of prebiotic supplementation on neurocognitive functioning, which is measured using a tablet-based neuropsychometric test battery. We will also examine the impact on clinical metabolic measures such as total weight and visceral adiposity. The concentration of immune-related serum proteins as well as neuroendocrine hormones will be evaluated. All measurements will take place at baseline, at 12-week cross-over, and at the end of the 24-week study. A within-subjects repeated measures analysis will be performed, and co-variates (gender, weight, medication) identified. This trial is registered with ClinicalTrials.gov, identifier number NCT03153046. Results We have currently screened 36 patients, of whom 30 were eligible for the study (67% male). At baseline, the average age of all recruited was 36.41 ± 11.42. The overall cognitive score was -2.03 ± 0.53 where the subtests included verbal memory (29.09 ± 8.75), digit sequencing (15.41 ± 2.77), token motor (55.74 ± 24.14), semantic fluency (8.83 ± 3.46), letter fluency (11.39 ± 3.65), symbol coding (35.61 ± 9.22) and tower of London (15.1 ± 4.06). There was no difference in overall cognitive between male (14.29 ± 2.46) and female (17.22 ± 2.30) patients. However, long-term associative learning as measured by the digit sequencing subtest appeared to show a significant difference between male (14.29 ± 2.46) and female (17.22 ± 2.33; p=0.008) participants. No significant differences between clinical metabolic measures were observed in baseline BMI (32.25 ± 6.79) and abdominal obesity as measured by hip-to-waist ratio (0.94 ± 0.11). The serum concentrations of immune and endocrine markers will also be presented. Discussion This investigation, to our knowledge, is the first clinical study to provide medicated schizophrenia patients with a prebiotic, as a potential means of improving cognition and managing secondary metabolic dysfunction. Although a potential link between commensal enteric bacteria and schizophrenia have been suggested, earlier work with probiotics (live cultures) did not support this association. However, since the current study uses a prebiotic that proliferates multiple species of gut bacteria, it will provide more robust data that will support, or refute, the validity of manipulating the gut microbiome in the treatment of schizophrenia.

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Project description:ObjectivesThe rat model of heart failure (HF) induced by doxorubicin (DOX), a broad spectrum and highly effective chemotherapeutic anthracycline with high-affinity to myocardial tissue that causes severe dose-dependent irreversible cardiotoxicity has been widely recognized and applied in HF pathogenesis and drug therapy studies. The gut microbiota (GM) has attracted significant attention due to its potential role in HF, and research in this area may provide beneficial therapeutic strategies for HF. Considering the differences in the route, mode, and total cumulative dose of DOX administration used to establish HF models, the optimal scheme for studying the correlation between GM and HF pathogenesis remains to be determined. Therefore, focusing on establishing the optimal scheme, we evaluated the correlation between GM composition/function and DOX-induced cardiotoxicity (DIC).MethodsThree schemes were investigated: DOX (at total cumulative doses of 12, 15 or 18 mg/kg using a fixed or alternating dose via a tail vein or intraperitoneal injection) was administered to Sprague Dawley (SD) for six consecutive weeks. The M-mode echocardiograms performed cardiac function evaluation. Pathological changes in the intestine were observed by H&E staining and in the heart by Masson staining. The serum levels of N-terminal pre-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured by ELISA. The GM was analysed by 16S rRNA gene sequencing.Key findingsStrikingly, based on the severity of cardiac dysfunction, there were marked differences in the abundance and grouping of GM under different schemes. The HF model established by tail vein injection of DOX (18 mg/kg, alternating doses) was more stable; moreover, the degree of myocardial injury and microbial composition were more consistent with the clinical manifestations of HF.ConclusionsThe model of HF established by tail vein injection of doxorubicin, administered at 4mg/kg body weight (2mL/kg) at weeks 1, 3 and 5, and at 2mg/kg body weight (1mL/kg) at weeks 2, 4 and 6, with a cumulative total dose of 18mg/kg, is a better protocol to study the correlation between HF and GM.

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Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

Publications

Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

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