Bile acids at the cross-roads of gut microbiome–host cardiometabolic interactions

This work is supported in part by the APC Microbiome Institute (under Science Foundation Ireland [SFI] Grant Number: SFI/12/RC/2273) and by Enterprise Ireland Commercialization Fund (Contract Reference: CF/2013/3030A/B).peer-reviewedWhile basic and clinical research over the last several decades has recognized a number of modifiable risk factors associated with cardiometabolic disease progression, additional and alternative biological perspectives may offer novel targets for prevention and treatment of this disease set. There is mounting preclinical and emerging clinical evidence indicating that the mass of metabolically diverse microorganisms which inhabit the human gastrointestinal tract may be implicated in initiation and modulation of cardiovascular and metabolic disease outcomes. The following review will discuss this gut microbiome–host metabolism axis and address newly proposed bile-mediated signaling pathways through which dysregulation of this homeostatic axis may influence host cardiovascular risk. With a central focus on the major nuclear and membrane-bound bile acid receptor ligands, we aim to review the putative impact of microbial bile acid modification on several major phenotypes of metabolic syndrome, from obesity to heart failure. Finally, attempting to synthesize several separate but complementary hypotheses, we will review current directions in preclinical and clinical investigation in this evolving field.Enterprise IrelandScience Foundation Irelan

Is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in COVID-19?

Coronavirus disease 2019 (COVID-19), the worst pandemic in more than a century, has claimed >125,000 lives worldwide to date. Emerging predictors for poor outcome include advanced age, male gender, pre-existing cardiovascular disease and risk factors including hypertension, diabetes and more recently obesity. Herein, we posit new obesity-driven predictors of poor COVID-19 outcome, over and above the more obvious extant risks associated with obesity including cardiometabolic disease and hypoventilation syndrome in intensive care patients. We outline a theoretical mechanistic framework whereby adipose tissue in subjects with obesity may act as a reservoir for more extensive viral spread with increased shedding, immune activation and cytokine amplification. We propose studies to test this reservoir concept with a focus on specific cytokine pathways that might be amplified in subjects with obesity and COVID-19. Finally, we underscore emerging therapeutic strategies that might benefit subsets of patients in which cytokine amplification is excessive and potentially fatal

Intravascular cell delivery device for therapeutic VEGF-induced angiogenesis in chronic vascular occlusion

AbstractSite specific targeting remains elusive for gene and stem cell therapies in the cardiovascular field. One promising option involves use of devices that deliver larger and more sustained cell/gene payloads to specific disease sites using the versatility of percutaneous vascular access technology. Smooth muscle cells (SMCs) engineered to deliver high local concentrations of an angiogenic molecule (VEGF) were placed in an intravascular cell delivery device (ICDD) in a porcine model of chronic total occlusion (CTO) involving ameroid placement on the proximal left circumflex (LCx) artery. Implanted SMC were retained within the ICDD and were competent for VEGF production in vitro and in vivo. Following implantation, micro-CT analyses revealed that ICDD-VEGF significantly enhanced vasa vasora microvessel density with a concomitant increase in tissue VEGF protein levels and formation of endothelial cell colonies suggesting increased angiogenic potential. ICDD-VEGF markedly enhanced regional blood flow determined by microsphere and contrast CT analysis translating to a functional improvement in regional wall motion and global left ventricular (LV) systolic and diastolic function. Our data indicate robust, clinically relevant angiogenesis can be achieved in a human scale porcine chronic vascular occlusion model following ICDD-VEGF-based delivery of angiogenic cells. This may have implications for percutaneous delivery of numerous therapeutic factors promoting creation of microvascular bypass networks in chronic vaso-occlusive diseases

Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E-/- mice

Background: There is strong evidence indicating that gut microbiota have the potential to modify, or be modified by the drugs and nutritional interventions that we rely upon. This study aims to characterize the compositional and functional effects of several nutritional, neutraceutical, and pharmaceutical cardiovascular disease interventions on the gut microbiome, through metagenomic and metabolomic approaches. Apolipoprotein-E-deficient mice were fed for 24 weeks either high-fat/cholesterol diet alone (control, HFC) or high-fat/cholesterol in conjunction with one of three dietary interventions, as follows: plant sterol ester (PSE), oat β-glucan (OBG) and bile salt hydrolase-active Lactobacillus reuteri APC 2587 (BSH), or the drug atorvastatin (STAT). The gut microbiome composition was then investigated, in addition to the host fecal and serum metabolome. Results: We observed major shifts in the composition of the gut microbiome of PSE mice, while OBG and BSH mice displayed more modest fluctuations, and STAT showed relatively few alterations. Interestingly, these compositional effects imparted by PSE were coupled with an increase in acetate and reduction in isovalerate (p < 0.05), while OBG promoted n-butyrate synthesis (p < 0.01). In addition, PSE significantly dampened the microbial production of the proatherogenic precursor compound, trimethylamine (p < 0.05), attenuated cholesterol accumulation, and nearly abolished atherogenesis in the model (p < 0.05). However, PSE supplementation produced the heaviest mice with the greatest degree of adiposity (p < 0.05). Finally, PSE, OBG, and STAT all appeared to have considerable impact on the host serum metabolome, including alterations in several acylcarnitines previously associated with a state of metabolic dysfunction (p < 0.05). Conclusions: We observed functional alterations in microbial and host-derived metabolites, which may have important implications for systemic metabolic health, suggesting that cardiovascular disease interventions may have a significant impact on the microbiome composition and functionality. This study indicates that the gut microbiome-modifying effects of novel therapeutics should be considered, in addition to the direct host effects

Lactobacillus mucosae DPC 6426 as a bile-modifying and immunomodulatory microbe.

BACKGROUND: Lactobacillus mucosae DPC 6426 has previously demonstrated potentially cardio-protective properties, in the form of dyslipidaemia and hypercholesterolemia correction in an apolipoprotein-E deficient mouse model. This study aims to characterise the manner in which this microbe may modulate host bile pool composition and immune response, in the context of cardiovascular disease. Lactobacillus mucosae DPC 6426 was assessed for bile salt hydrolase activity and specificity. The microbe was compared against several other enteric strains of the same species, as well as a confirmed bile salt hydrolase-active strain, Lactobacillus reuteri APC 2587. RESULTS: Quantitative bile salt hydrolase assays revealed that enzymatic extracts from Lactobacillus reuteri APC 2587 and Lactobacillus mucosae DPC 6426 demonstrate the greatest activity in vitro. Bile acid profiling of porcine and murine bile following incubation with Lactobacillus mucosae DPC 6426 confirmed a preference for hydrolysis of glyco-conjugated bile acids. In addition, the purified exopolysaccharide and secretome of Lactobacillus mucosae DPC 6426 were investigated for immunomodulatory capabilities using RAW264.7 macrophages. Gene expression data revealed that both fractions stimulated increases in interleukin-6 and interleukin-10 gene transcription in the murine macrophages, while the entire secretome was necessary to increase CD206 transcription. Moreover, the exopolysaccharide elicited a dose-dependent increase in nitric oxide and interleukin-10 production from RAW264.7 macrophages, concurrent with increased tumour necrosis factor-α secretion at all doses. CONCLUSIONS: This study indicates that Lactobacillus mucosae DPC 6426 modulates both bile pool composition and immune system tone in a manner which may contribute significantly to the previously identified cardio-protective phenotype

Randomized placebo controlled trial evaluating the safety and efficacy of single low dose intracoronary insulin like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI)

Background: Residual and significant post-infarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models low dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodelling effects. We studied the safety and efficacy of immediate post PCI low dose intracoronary IGF1 infusion in STEMI patients. Methods: Using a double-blind, placebo controlled, multi-dose study design, we randomized 47 STEMI patients with significantly reduced (≤ 40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n=15), 1.5ng IGF1 (n=16) or 15ng IGF1 (n=16). All received optimal medical therapy. Safety endpoints were freedom from hypoglycaemia, hypotension or significant arrhythmias within 1 hour of therapy. The primary efficacy endpoint was LVEF and secondary endpoints were LV volumes, mass, stroke volume, and infarct size at 2 months follow up, all assessed by MRI. Treatment effects were estimated by analysis of covariance adjusted for baseline (24hrs) outcome. Results: No significant differences in safety endpoints occurred between treatment groups out to 30 days (chi squared test, p-value = 0.77).There were no statistically significant differences in baseline (24 hrs post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5ng IGF1, treatment with 15ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (p=0.018), LV mass (p=0.004) and stroke volume (p=0.016). Late gadolinium enhancement (±SD) at 2 months was lower in 15ng IGF1 (34.5±29.6g) compared to placebo (49.1±19.3g) or 1.5ng IGF1 (47.4±22.4g) treated patients, though the result was not statistically significant (p = 0.095). Conclusion: In this pilot trial, low dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose dependent benefit on post MI remodeling that may warrant further study. Despite timely reperfusion by primary PCI (PPCI) a significant cohort of patients develop adverse left ventricular remodelling with clinical sequelae such as arrhythmia and heart failure[1].Therapeutic approaches to avert such remodeling, including a variety of cell therapy and ischemia- reperfusion-injury mitigation trials have achieved modest success 2.;3. Thus, there remains a significant opportunity for novel therapies in this field