Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg -1 ·d -1 ). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined. Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation. Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.

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Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽

10.1007/s10753-021-01507-x ◽

2021 ◽

Author(s):

Shangrila Parvin ◽

Clintoria R. Williams ◽

Simone A. Jarrett ◽

Sandra M. Garraway

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Inflammatory Cytokine ◽

Cardiovascular Health ◽

Mrna Levels ◽

Post Injury ◽

Cord Injury ◽

And Function ◽

The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

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The Impact of Maternal Preeclampsia and Hyperglycemia on the Cardiovascular Health of the Offspring: A Systematic Review and Meta-Analysis

American Journal of Perinatology ◽

10.1055/s-0041-1728823 ◽

2021 ◽

Author(s):

Zahra Hoodbhoy ◽

Nuruddin Mohammed ◽

Karim Rizwan Nathani ◽

Saima Sattar ◽

Devyani Chowdhury ◽

...

Keyword(s):

Systematic Review ◽

Body Composition ◽

Birth Weight ◽

Vascular Function ◽

Cardiovascular Health ◽

Meta Analysis ◽

The Body ◽

Cochrane Library ◽

And Function ◽

The Impact

Objectives The objective of this review was to assess the impact of maternal preeclampsia or hyperglycemia on the body composition and cardiovascular health in the offspring. Study Design We conducted a systematic review utilizing PubMed, EBSCO, CINAHLPlus, Cochrane Library, and Web of Science to include all studies assessing the impact of preeclampsia/eclampsia and/or gestational/pregestational diabetes mellitus on the health of the offspring (children <10 years of age). The health measures included anthropometry, cardiac dimensions and function, and vascular function. We performed a meta-analysis using Review Manager software and computed net risk ratio (RR) with 95% confidence interval (CI) for dichotomous data and mean difference (MD) with 95% CI for continuous data. Results There were 6,376 studies in total, of which 45 were included in the review and 40 in the meta-analysis. The results demonstrated higher birth weight (MD: 0.12 kg; 95% CI: 0.06–0.18) and systolic and diastolic blood pressure (BP; MD: 5.98 mmHg; 95% CI: 5.64–6.32 and MD: 3.27 mmHg; 95% CI: 0.65–5.89, respectively) in the offspring of mothers with gestational diabetes compared to controls. In contrast, the offspring of mothers with preeclampsia had lower birth weight (MD: −0.41 kg; 95% CI: −0.7 to −0.11); however, they had increased systolic (MD: 2.2 mmHg; 95% CI: 1.28–3.12) and diastolic BP (MD: 1.41 mmHg; 95% CI: 0.3–2.52) compared to controls. There is lack of data to conduct a meta-analysis of cardiac morphology, functional, and vascular imaging parameters. Conclusion These findings suggest that the in-utero milieu can have a permanent impact on the body composition and vascular health of the offspring. Future work warrants multicenter prospective studies to understand the mechanism and the actual effect of exposure to maternal hyperglycemia and high BP on the cardiovascular health of the offspring and long-term outcomes. Key Points

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Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study

Cardiovascular Diabetology ◽

10.1186/s12933-020-01199-x ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Stephen J. Nicholls ◽

◽

Gregory G. Schwartz ◽

Kevin A. Buhr ◽

Henry N. Ginsberg ◽

...

Keyword(s):

Heart Failure ◽

Acute Coronary Syndrome ◽

Secondary Analysis ◽

Cardiovascular Death ◽

Major Adverse Cardiovascular Events ◽

Double Blind ◽

Coronary Syndrome ◽

Patients With Diabetes ◽

And Function ◽

The Impact

Abstract Background Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known. Methods The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. Results Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38–0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27–0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53–0.98], P = 0.04). Conclusion Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.

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The Microbiome as a Therapeutic Target for Multiple Sclerosis: Can Genetically Engineered Probiotics Treat the Disease?

Diseases ◽

10.3390/diseases8030033 ◽

2020 ◽

Vol 8 (3) ◽

pp. 33

Author(s):

Hannah M. Kohl ◽

Andrea R. Castillo ◽

Javier Ochoa-Repáraz

Keyword(s):

Multiple Sclerosis ◽

Intestinal Microbiota ◽

Genetically Engineered ◽

Brain Inflammation ◽

Protective Effects ◽

Neuroinflammatory Disease ◽

Initial Work ◽

And Function ◽

Work Done ◽

The Impact

There is an increasing interest in the intestinal microbiota as a critical regulator of the development and function of the immune, nervous, and endocrine systems. Experimental work in animal models has provided the foundation for clinical studies to investigate associations between microbiota composition and function and human disease, including multiple sclerosis (MS). Initial work done using an animal model of brain inflammation, experimental autoimmune encephalomyelitis (EAE), suggests the existence of a microbiota–gut–brain axis connection in the context of MS, and microbiome sequence analyses reveal increases and decreases of microbial taxa in MS intestines. In this review, we discuss the impact of the intestinal microbiota on the immune system and the role of the microbiome–gut–brain axis in the neuroinflammatory disease MS. We also discuss experimental evidence supporting the hypothesis that modulating the intestinal microbiota through genetically modified probiotics may provide immunomodulatory and protective effects as a novel therapeutic approach to treat this devastating disease.

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Development of a self-limiting model of methotrexate-induced mucositis reinforces butyrate as a potential therapy

Scientific Reports ◽

10.1038/s41598-021-02308-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. R. da Silva Ferreira ◽

S. A. J. van der Aa ◽

T. Wehkamp ◽

H. R. Wardill ◽

J. P. ten Klooster ◽

...

Keyword(s):

Folinic Acid ◽

Metabolic Activity ◽

Mucosal Injury ◽

Short Chain Fatty Acids ◽

Optimal Dosage ◽

Protective Effects ◽

Chemokine Production ◽

In Vitro Systems ◽

The Impact

AbstractGastrointestinal mucositis is a complication of anticancer treatment, with few validated in vitro systems suitable to study the complex mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX). Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. The protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005–50 µg/mL) folinic acid. The impact of microbial-derived short-chain fatty acids was evaluated by supplementation with butyrate in the organoid model. MTX caused a dose-dependent reduction in cell metabolic activity and citrulline production that was salvaged by folinic acid treatment. Overall, MTX causes significant organoid damage, which can be reversed upon removal of MTX. The protective effect of folinic acid suggest that the organoids respond in a clinical relevant manner. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

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Cardiovascular Health and The Intestinal Microbial Ecosystem: The Impact of Cardiovascular Therapies on The Gut Microbiota

Microorganisms ◽

10.3390/microorganisms9102013 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2013

Author(s):

Noora Alhajri ◽

Rubiya Khursheed ◽

Mohammad Taher Ali ◽

Tareq Abu Izneid ◽

Oumaima Al-Kabbani ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Gut Microbiota ◽

Cardiovascular Health ◽

Critical Role ◽

Short Chain Fatty Acids ◽

Therapeutic Interventions ◽

Ecosystem Functions ◽

Microbial Ecosystem ◽

Host Interaction ◽

The Impact

It has become evident over the past several years that the intestinal microbial ecosystem plays a critical role in the development and prevention of cardiovascular diseases (CVDs) and other metabolic disorders, such as hypertension, obesity, diabetes mellitus, and metabolic syndrome. The intestinal microbiota ecosystem functions as a major virtual endocrine organ that interacts and responds to molecules’ signals within the host. Several meta-organismal pathways are involved in the gut–host interaction, including trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFA). Host phenotype and cardiovascular diseases (CVDs) varying from hypertension, insulin resistance, and obesity to more specific inflammatory processes, such as atherosclerosis and hypercoagulability, have shown to be affected by the gut–host interaction. Additionally, several studies that involved animals and humans demonstrated a striking connection between the development of new CVDs and an imbalance in the gut microbiota composition along with the presence of their derived metabolites. Through this review article, we aim to evaluate the role of the normal gut microbiota ecosystem, its association with CVDs, effects of the therapies used to control and manage CVDs in the gut microbiota environment and explore potential therapeutic interventions to amplify disease outcomes in patients with CVDs.

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Development of a self-limiting model of Methotrexate-induced mucositis reinforces butyrate as a potential therapy

10.21203/rs.3.rs-25140/v1 ◽

2020 ◽

Author(s):

Ana Rita da Silva Ferreira ◽

Stijn A.J. van der Aa ◽

Tjalling Wehkamp ◽

Hannah R. Wardill ◽

Jean Paul Ten Klooster ◽

...

Keyword(s):

Folinic Acid ◽

Metabolic Activity ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Optimal Dosage ◽

Protective Effects ◽

Clinical Practices ◽

Chemokine Production ◽

The Impact

Abstract Background: Gastrointestinal mucositis remains a significant complication of anticancer treatment, with limited anti-mucositis interventions. Currently, there are few validated in vitro systems suitable to study the mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Methods: Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX), ranging from 0-1000 ng/ml. Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. To link the model to clinical practices, the protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. Given the impact of microbial-derived short-chain fatty acids in epithelial health, we also evaluated the impact of short-chain fatty acid supplementation on MTX toxicity in the organoid model. Results: MTX treatment caused a dose-dependent reduction in cell metabolic activity and citrulline production. Folinic acid treatment reduced MTX toxicity when applied simultaneously or up to 24 hours after treatment. Supplementation of the growth medium with butyrate reduced MTX toxicity. Analysis of organoid gene expression suggests that butyrate may reduce intracellular MTX concentrations by increasing the expression of MTX transporters, including the ABCC1 transporter.Conclusion: MTX causes significant organoid damage, which can be reversed upon removal of MTX. The specific readouts and the protective effects of folinic acid suggest that the model is clinically relevant, and can be used in the future to study mucositis, diminishing the need for animal models. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

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Microbiome–host systems interactions: Protective effects of propionate upon the blood–brain barrier

10.1101/170548 ◽

2017 ◽

Cited By ~ 2

Author(s):

Lesley Hoyles ◽

Tom Snelling ◽

Umm-Kulthum Umlai ◽

Jeremy K. Nicholson ◽

Simon R. Carding ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Protective Effects ◽

Microbial Metabolites ◽

Blood Brain ◽

Microbial Infections ◽

Pathway Regulation ◽

And Function ◽

The Impact

AbstractBackgroundGut microbiota composition and function are symbiotically linked with host health, and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognized mechanisms exist by which the microbiome influences the gut-brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesized interactions between circulating gut–derived microbial metabolites and the blood–brain barrier (BBB) also contribute to the gut–brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed.ResultsAfter demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signaling.ConclusionsTogether, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut–brain axis that warrants further attention.

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Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review

Nutrients ◽

10.3390/nu11061231 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1231 ◽

Cited By ~ 8

Author(s):

Allison S. Bardagjy ◽

Francene M. Steinberg

Keyword(s):

Dietary Patterns ◽

Cardiovascular Health ◽

Synergistic Effects ◽

Density Lipoprotein ◽

Functional Changes ◽

Beneficial Effects ◽

The Individual ◽

And Function ◽

The Impact ◽

Selected Functions

Cardiovascular disease is a leading cause of death around the world. Overall diet quality and dietary behaviors are core contributors to metabolic health. While therapeutic targets have traditionally focused on levels of lipoprotein cholesterol when evaluating cardiovascular risk, current perspectives on high-density lipoprotein (HDL) have shifted to evaluating the functionality of this lipoprotein particle. Effects of diet on cardiovascular health are mediated through multiple pathways, but the impact on HDL composition and function deserves greater attention. Potential areas of investigation involve changes in particle characteristics, distribution, microRNA cargo, and other functional changes such as improvements to cholesterol efflux capacity. Various dietary patterns like the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet have beneficial effects on cardiovascular health and may prevent cardiovascular events. These healthful dietary patterns tend to be rich in plant-based foods, with cardiovascular benefits likely resulting from synergistic effects of the individual dietary components. The purpose of this review is to summarize current perspectives on selected functions of HDL particles and how various dietary patterns affect cardiovascular health biomarkers, with a focus on HDL functionality.

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160 The obesity paradox in atrial fibrillation

European Heart Journal Supplements ◽

10.1093/eurheartj/suab127.024 ◽

2021 ◽

Vol 23 (Supplement_G) ◽

Author(s):

Marco Favilli ◽

Doralisa Morrone ◽

Francesco Gentile ◽

Giacinta Guarini ◽

Riccardo Morganti ◽

...

Keyword(s):

Atrial Fibrillation ◽

Meta Analysis ◽

Obesity Paradox ◽

Cardiovascular Death ◽

World Health ◽

Extensive Literature ◽

Protective Effects ◽

Randomized Controlled ◽

Pubmed Database ◽

The Impact

Abstract Aims The World Health Organization (WHO) defines obesity as a body mass index (BMI) of ≥ 30 kg/m2. Obesity has been established as an independent risk factor for new-onset atrial fibrillation (AF). Despite the association between obesity and major cardiovascular risk factors and outcomes, some studies showed that obesity may have a protective effect on AF-related outcomes, leading to the controversial concept of the ‘obesity paradox’. We carried out a systematic review to explore the ‘obesity paradox’, providing an overview of the randomized controlled trials (RCTs) and the impact of BMI on AF-related outcomes. Methods and results We performed an extensive literature search, from 2000 up to 2021, using the PubMed database, with two independent reviewers (M. F. and F.G.). Discrepancies were resolved by consensus with a senior researcher (D.M.). Studies were eligible if they were RCTs and included outcome comparisons (cardiovascular death, all death, stroke, and major bleeding) with allocation to BMI. We excluded from the analysis trials in which the number of events was not reported. The effect measures of each included study were calculated and reported as hazard ratio (HR) with 95% confidence interval (CI), visually presented in forest plots. A total of 683 studies were available for the analysis; 74 records were included after reading the title; after full reading 8 studies were eligible to be analysed. The meta-analysis of the eight selected randomized controlled clinical trials demonstrated a significantly lower risk of stroke or systemic embolism and all causes of death in obese patient (Figures 1 and 2). A meta-analysis on cardiovascular mortality was not conducted because this was reported only for three trials. Conclusions This meta-analysis demonstrated lower stroke and death risk with increasing BMI. Our meta-analysis included only data from RCTs. Observational studies rendered more conflicting results. Because of the few studies included, these apparently protective effects of obesity on the risk of stroke in patients with atrial fibrillation should still be interpreted with caution.

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