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The effect of the gut microbiome on the bioavailability and efficacy of orally administered drugs is of considerable importance for personalised medicine.1 We, therefore, read with great interest the ‘GI highlights from the literature’ focussing on gut microbial metabolism of 5-aminosalicylic acid (5-ASA) in inflammatory bowel disease (IBD), originally published in the journal Nature Medicine.2 3 Mehta et al. used metagenomics, metatranscriptomics and metabolomics from the IBD-Integrative Human Microbiome Project (HMP2) to identify 12 microbial acetyltransferase gene families that encode 5-ASA inactivating enzymes and confirmed the results using in vitro analyses. They confirmed that four of these genes—profiled in metagenomic data from stool samples—are associated with 5-ASA treatment failure in two cohorts of patients with IBD, implying that it might be possible to predict 5-ASA treatment outcome by profiling gut microbiota of patients. However, to generalise these findings, they need to be confirmed…

Circulation, Volume 150, Issue Suppl_1, Page A4141474-A4141474, November 12, 2024. Background:5-Hydroxytryptophan (5-HTP) has shown positive clinical effects on various neuropsychiatric and metabolic disorders, particularly depression. While it is known to increase serotonin levels in the brain and gastrointestinal tract, its pharmacology remains largely unexplored. Additionally, 5-HTP influences the mouse gut microbiome, which is closely linked to depression through the “microbiota-gut-brain axis.” However, the role of 5-HTP in vascular disease is not well understood. This study aimed to investigate the potential correlation between serum 5-HTP levels and the severity of coronary artery calcification (CAC) in patients with acute coronary syndrome (ACS).Methods and Results:This study included 183 ACS patients who underwent coronary angiography. The severity of coronary calcification was recorded, and serum 5-HTP levels were measured after the coronary event. The study period was from February 4, 2009, to August 9, 2020. The primary exposure variable was 5-HTP levels, and the primary outcome was the severity of coronary calcification assessed through fluoroscopy. Logistic regression was used to determine the association between 5-HTP levels and calcification severity, adjusting for age, gender, smoking status, chronic kidney disease, hyperlipidemia, and diabetes. Odds ratios (OR) and 95% confidence intervals (CI) measured the strength of associations, with statistical significance set at p < 0.05.High 5-HTP levels were significantly associated with more severe calcification (p = 0.04, OR = 3.3, 95% CI = 2.6 to 40686.5). For other factors, the OR for smokers was 0.97 (0.53 to 1.77); dyslipidemia 0.91 (0.5 to 1.63); hypertension 1.57 (0.87 to 2.82); male gender 1.35 (0.45 to 4.01); age 1.07 (1.03 to 1.10); diabetes 1.24 (0.67 to 2.31); chronic kidney disease 1.07 (0.33 to 3.50). After adjusting for conventional risk factors, the association between 5-HTP and calcification remained significant (p < 0.05).Conclusion:Higher 5-HTP levels are positively associated with greater severity of coronary artery calcification. This correlation persists even after adjusting for conventional risk factors.

Circulation, Volume 150, Issue Suppl_1, Page A4113494-A4113494, November 12, 2024. End-stage ischemic heart disease necessitates heart transplantation, and emerging cell therapy presents a promising solution to address donor scarcity. Disruption of gut microbiota significantly influences various diseases and treatments, including transplantation. However, the impact of immunosuppression and cardiac cell therapy on gut microbiota remains largely unexplored. To elucidate this relationship, we investigated gut microbiota dynamics in response to immunosuppression and cell therapy in a nonhuman primate (NHP) cardiac ischemia/reperfusion (IR) model, with controlled genetic, dietary, and environmental factors. Immunosuppression enriched anaerobes (Faecalibacterium, Streptococcus, Anaerovibrio, Dialister), increasing gut microbiota diversity. These changes correlated with metabolic shifts towards amino acid metabolism and nucleosides/nucleotides biosynthesis. Combined treatment of human induced pluripotent stem cell (iPSC)-derived endothelial cells (EC) and cardiomyocytes (CM) also increased gut microbiota diversity, with specific genera alterations. The EC/CM co-treatment group displayed gut microbiota resembling the pre-injury group, with host metabolism shifting towards amino acid and fatty acid/lipid biosynthesis post-cell therapy. These observed microbiota changes and metabolic shifts could serve as biomarkers for monitoring cell therapy and immunosuppression outcomes, offering potential therapeutic targets to enhance efficacy.

Circulation, Volume 150, Issue Suppl_1, Page A4140993-A4140993, November 12, 2024. Background:Time-restricted feeding (TRF) is an effective strategy for anti-aging management yet its prophylactic/therapeutic applicability against cardiac aging is unknown.Methods:To assess the effects of TRF on cardiac aging, male mice were randomized into the normal diet+ad libitum feeding (N-ALF), normal diet+TRF (N-TRF), high-fat diet+ALF (H-ALF), high-fat diet+TRF (H-TRF). Metagenomic sequencing was used to investigate the diversity, composition, and evolution of the gut microbiota. The metabolomics was employed to investigate the impact of TRF on the metabolic profile of feces. Using fecal microbiota transplantation, TRF has been validated to delay cardiac aging by optimizing gut microbial composition and function.Results:Compared to the H-ALF group, the H-TRF group showed that the expression of senescence markers p53 and p21 was reduced. In addition, the myocardial interstitial collagen deposition and the expression of collagen I and III were reduced by TRF. Moreover, TRF reduced left ventricular posterior wall dimensions at end-diastole, interventricular septal thickness at end-diastole, and myocardial diastolic function index E/e’ in mice. These suggested that TRF delays high-fat diet-induced cardiac aging. Compared with the H-ALF group, the TRF group exhibited an increase in the alpha diversity of gut microbiota. At the phylum level, the abundance of the Bacteroides was increased by TRF. At the genus level, the abundance of Bacteroides, Parabacteroides, and Akkermansia was increased by TRF. There were 11 characteristic strains in the H-TRF group, six of these strains are closely related to the production of short-chain fatty acids (SCFAs). Function prediction of the differential genes showed an increase in the SCFAs pathway in the H-TRF. LC-MS profiling of feces showed that TRF can reduce the levels of l-tyrosine, l-tryptophan, phenylalanine, valine, indoxyl-sulfate, cholesterol-sulfate, and tetradecanedioic acid in the intestines from high-fat diet mice. TRF increased the levels of 16-oxo-heptadecanoic acid, propionic acid, butyric acid, 2-methylpropionic acid, acetoacetate, succinate, and acetoacetyl-CoA. Using the mice with HFD, those that received gut microbiota from H-TRF showed decreased levels of cardiac senescence markers. It was suggested that gut microbiota plays a crucial role in TRF improving cardiac aging.Conclusions:TRF improves high-fat diet-induced cardiac aging by optimizing the composition and function of gut microbiota.

Circulation, Volume 150, Issue Suppl_1, Page A4141762-A4141762, November 12, 2024. Introduction:Chronic heart failure (HF) is linked to elevated serum TNF-α levels and affects multiple signaling pathways in non-cardiomyocytes, such as immune cells, intestinal epithelial cells, lymphatic endothelial cells, vascular cells, and their interactions. The combined dysbiosis of host transcriptomics and gut microbiota concerning altered TNF-α signaling in older adults with HF remains unknown.Methods:We recruited 10 older adults with heart failure (HF) (6 females) and 16 healthy controls (HCs) (10 females) from the Northeastern U.S. Non-fasting peripheral blood and stool samples were collected. Serum TNF-α was assayed using Enzyme-linked Immunosorbent Assay (ELISA) kits. Differentially expressed genes (DEGs) between HF and HCs were investigated using the R package “DESeq2” after aligning the raw blood RNA sequence data to the reference database and undergoing quality control. The QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the canonical pathways associated with the DEGs. The 16S rRNA V4 gene regions of stool samples were sequenced and processed using the Mothur 1.42.3 pipeline. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the metagenomic functions of different gut microbiota compositions.Results:The mean ages of the HF and HC subjects were 73.50 (SD = 8.33) and 63.19 (SD = 7.75), respectively. HF subjects had significantly higher serum TNF-α levels than HCs (p < 0.05). Among the DEGs, HF subjects had 18 downregulated genes (e.g.,AK5,FAM167A,RGCC, andSARDH) and 3 upregulated genes (SMPD3,TMIGD3, andFRRS1) compared with HCs. TNF signaling (p < 0.01) was one of the significantly different canonical pathways in the DEGs between HF and HCs. HF subjects had significantly enrichedMogibacteriumand diminishedSutterellathan HCs (p < 0.05) and lower P53 signaling pathway activity than HCs (p < 0.05) among the predicted functions in stool samples.Conclusions:By analyzing serum TNF-α, whole transcriptomics, and gut microbiota, we identified higher serum TNF-α, differentially expressed genes (DEGs) and their canonical pathways, and distinct compositions and predicted functions of gut microbiota in older adults with HF compared to healthy controls. These findings suggest that TNF-α signaling may be a potential target for developing precise HF interventions and highlight the need for further large-scale multi-omics analysis in understanding and treating HF.

Circulation, Volume 150, Issue Suppl_1, Page A4141726-A4141726, November 12, 2024. Introduction:Specific ceramides play a crucial role in cellular senescence by upregulating the SASP in the vasculature, leading to atherosclerosis in the aging population. Gut microbiota is emerging as a regulator of circulating ceramides in the host. However, it remains unknown what/how gut bacteria causally regulate ceramide-induced perivascular adipose tissue (PVAT) and endothelial cell (EC) senescence in aging.Methods:To address the knowledge gap in gut-derived ceramides and their regulation of (peri)vascular aging, we performed high-throughput multi-omics (fecal shotgun metagenomics and plasma LC-MS/MS lipidomics) coupled with bacterial colonization, senescence, and cell-cell interaction studies.Results:Our metagenomic and plasma lipidomic studies on human (TwinsUK Aging Cohort, n=900; Aging Heart Zurich Cohort, n >800) and mouse ( >24vs.3 months, n=6) aging cohorts pinpointed a higher abundance ofBacteroides thetaiotaomicron (B. theta)harboring the serine palmitoyltransferase (SPT) gene, synthesizing deleterious ceramides C18:1/16:0 and C18:1/18:0 in old hosts. Importantly, plasma levels of the ceramides were positively associated with major adverse cardiovascular events (MACE) in atherosclerotic CVD patients within the Aging Heart Zurich Cohort (n=105).In vivocolonization of young mice withB. theta(4-weeks) confirmed a marked increase in circulating Cer 18:1/16:0 and 18:1/18:0, accompanied by higher signals of the SASP component IL6 and the proliferative arrest marker p16INK4ain aortic PVAT and ECs. These mice also exhibited reduced vasorelaxation responses and angiogenic incompetence.As a proof of concept, our PVAT-EC co-culture studies demonstrated that addition of the ceramides induces senescence and dysfunction in PVAT by upregulating Notch1 signaling. This upregulation increases IL1β and its downstream IL6, leading to the downregulation of adipocyte function markers UCP1 and adiponectin. The released IL6 also induced a senescence phenotype in ECs, evidenced by increased SA-β-gal activity, DNA damage response (↑ γ-H2A.X), telomere attrition (↓ hTERT), and proliferative arrest (↑ p16INK4a&p19INK4d).Conclusion:This research identifiesB. thetaas a causal contributor to deleterious ceramides in the host circulation, leading to (peri)vascular senescence and dysfunction in aging. TargetingB. thetaoffers a novel microbiome-based approach to decelerate (peri)vascular senescence and extend healthspan, with potential clinical applications.

Circulation, Volume 150, Issue Suppl_1, Page A4143104-A4143104, November 12, 2024. Background:Gut microbiota have been suggested as a causative agent of atherosclerosis mainly by converting dietary and endogenous molecules into active metabolites like the trimethylamine N-oxide (TMAO). Nevertheless, the relationship between gut microbiota and plaque features has not been well documented. In this study, we tested the hypothesis that gut microbial transplantation can transmit atherosclerotic plaque characteristics.Methods and Results:In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from patients with acute coronary syndrome (ACS, n=9), chronic coronary syndrome (CCS, n=11) and control subjects (CTRL, n=8) was evaluated and plaque features of stability were assessed. Transplantation was performed into ApoE KO mice fed a diet containing 1% choline or a standard diet. Initially, resident intestinal microbes were suppressed using antibiotics, followed by the administration of fecal oral gavages from human donors over a period of 12 weeks. Firstly, a significant positive correlation was detected between TMAO serum levels assessed by UPLC-MS/MS system and atherosclerotic lesion formation measured by Oil Red O staining of aortic root cross-sections; however, no correlations were identified with plaque instability. Plaque composition was analyzed using necrotic core area and fibrous cap thickness as primary readouts of plaque vulnerability. Interestingly, microbiota from ACS patients significantly decreased plaque stability as showed by increased necrotic core and fibrous cap thinning. Further, it decreased α-SMA+cell population and increased MMP2 staining, indicating intraplaque metalloprotease activity.Gut microbiota composition was evaluated using 16S rRNA sequencing of ApoE KO mice fecal samples. In ACS transplanted mice, 14 bacterial genera were positively associated with larger necrotic core and 6 bacterial genera with MMP2. In CCS transplanted mice, 6 bacterial genera showed negative correlations with necrotic core size and 2 bacterial genera positively correlated with α-SMA+cells.Conclusions:In conclusion, we identified bacteria significantly associated with the vulnerable plaque phenotype, which provides potential insights to modulate atherosclerotic plaque composition by influencing the gut microbiota.

Circulation, Volume 150, Issue Suppl_1, Page A4146466-A4146466, November 12, 2024. Background:Without timely intervention, pressure-overloading left ventricular (poLV) remodeling may become progressive and readily degenerate into heart failure. The relative risk is especially high in children with congenital heart disease who are awaiting surgical correction.Aims:The aims of this study were to identify a plasma metabolite that is clinically and mechanically linked to poLV remodeling and heart failure in children and investigate a safe, efficacious treatment that blocks its action.Methods:We used multi-omics including untargeted metabolomics on the plasma of poLV children and neonatal ascending aorta constriction (nAAC) mice, whole-transcriptome resequencing and single-nucleus RNA sequencing of mouse and human LV samples, and metagenomics analysis of mouse gut microbiota to disclose the gut microbiota-kynurenine (Kyn)-remodeling axis. Aryl hydrocarbon receptor (AHR) knockout mice and germ-free (GF) mice as well as fecal microbiota transplantation were used to clarify its mechanism.Results:Abnormally elevated plasma kynurenine (Kyn) was detected in both the patient cohort and the mouse model. Plasma Kyn levels were clinically associated with the cardiac functions and the degree of remodeling. Excessive Kyn induced the hypertrophy and fibrosis phenotypes both in vitro and in vivo, which was blocked by AHR inhibitors and by AHR knockout, respectively. It was demonstrated that Kyn affected both cardiomyocytes and cardiac fibroblasts by promoting AHR nuclear translocation, initiating ADAMTS2 transcription which accelerates hypertrophy, and inducing FN1 and COL1A1 which exacerbate fibrosis. There were significant alterations in the gut microbiota of nAAC mice.Transplantation of nAAC mouse feces to GF mice augmented their Kyn level, indicating the existence of a gut microbiota-Kyn relationship. Oral probiotic supplementation reconstructed the gut microbiota in the nAAC mice, modulated the Kyn-AHR axis, and alleviated poLV remodeling.Conclusions:Plasma Kyn levels were strongly correlated with cardiac remodeling and function in pediatric patients and mice with poLV. Kyn is a pathological signal from an altered gut microbiota to activates AHR and its gene targets in poLV remodeling heart, promoting hypertrophy and fibrosis in respective cells. Oral probiotics reshaped the gut microbiota, lowered Kyn levels, and showed great potential at delaying cardiac remodeling and preventing heart failure.

Circulation, Volume 150, Issue Suppl_1, Page A4141332-A4141332, November 12, 2024. Background:Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes mellitus (DM). However, studies exploring the roles of gut microbiome in DM and cardiovascular disease remain limited.Hypothesis:Gut microbiota dysbiosis is associated with the development of DCM.Methods:We collected fecal and serum samples from 18 DCM patients and 13 matched control subjects for metagenomic and metabolomic analysis. Fecal microbiota transplantation (FMT) with samples from both groups was performed on the pseudo-germ-free (PGF) rats. Then, we analyzed rat gut microbiota by 16S rDNA sequencing, and examined cardiac parameters and blood glucose indicators of PGF rats. Serum and myocardium metabolomic analysis was performed on DCM rats and compared with human samples.Results:Linear Discriminant Analysis Effect Size (p＜0.05, LDA≥2.0) of the metagenomics data identified 11 gut microbiota, which can be used as the DCM patient’s biomarkers. After FMT, compared to control-PGF rats, DCM-PGF rats showed significant differences in the composition of gut microbiota (α-diversity, simpsonp=0.015, shannonp=0.011; β-diversity p= 0.005). Moreover, DCM-PGF rats had higher fasting blood glucose levels (p=0.036), intraperitoneal glucose tolerance test showed higher blood glucose levels at 15 and 30 minutes (p=0.000, 0.030), left ventricular (LV) end systolic diameter was larger (p=0.009), diastolic and systolic LV anterior wall thickness, and systolic LV posterior wall thickness were thicker (p=0.011, 0.035, 0.036), fibrosis area was larger (p=0.022). When comparing metabolic profiles of serum of DCM patients, serum of DCM rats and the myocardium of DCM model with the corresponding controls, we identified 2 shared differential metabolites:Hydroxybutyric acidand15,16-DiHODE. Spearman correlation analysis of these two metabolites with differential gut microbiota species in DCM patientsvs.control subjects showed thatHydroxybutyric acidand15,16-DiHODEare strongly correlated with 7 species (p＜0.05, r＞|0.5|) and with 23 species (p＜0.05, r＞|0.5|) respectively.Conclusions:Our study found that DCM patients have their characteristic altered gut microbiota and serum metabolites, which may be responsible for the development of DCM. Gut microbiota is expected to be a potential target for therapeutic intervention in DCM.

Circulation, Volume 150, Issue Suppl_1, Page A4141398-A4141398, November 12, 2024. Background:Hypertension is the most common cardiovascular disease risk factor of which African Americans have a greater burden. Gut microbial production of short chain fatty acids (SCFA) has been associated with blood pressure status in animals, with limited evidence in humans. The complex and diverse gut microbial ecosystem contributes to synthesizing the SCFA butyrate. Aim: The goal of the study is to determine if butyrate production in the gut is associated with hypertension and how the microbial composition differs in normal and hypertensive participants.Methods:Fecal samples from 20 participants diagnosed with normal (n = 10) or high (n = 10) blood pressure were sequenced via the 16S rRNA gene. Inference-based modeling generated functional (PICRUSt2) and metabolic (MICOM) models of microbial communities focusing on carbohydrate fermentation pathways. Supervised learning was conducted to identify significant (p < 0.05) differences in predicted functional genes and microbial communities.Results:Microbial dominance was inversely correlated with increasing systolic blood pressure (Pearson, p < 0.05, R = -0.44); however, no significant correlation was measured for beta diversity between the two groups. More importantly, inference modeling showed differences in microbial function and metabolism between groups. Functional pathways associated with carbohydrate fermentation were significantly (ANOVA, p < 0.05) lower for hypertensive compared to normal participants. Carbohydrate fermentation accounted for only 8.05% of the predicted functions of the identified pathways. Within this subset, pyruvate fermentation to isobutanol was the most abundant pathway (12.6%), followed by starch degradation (9.6%) and glycolysis III (9.34%). Additionally, metabolic flux models revealedCatenibacterium, Subdoligranulum, andRoseburiawere predicted as butyrate producers.CatenibacteriumandSubdoligranulumproduced 51% and 44% butyrate, respectively, in the normal group. In contrast, a different distribution was observed in the hypertensive group, withCatenibacteriumaccounting for 97% andRoseburiacontributing 3% of the butyrate production.Conclusion:Our preliminary investigation elucidates the potential relationship between SCFA producers (as well as butyrate producers) and blood pressure status among minority participants, providing insights into how gut microbiota may influence or be influenced by blood pressure.

Circulation, Volume 150, Issue Suppl_1, Page A4141296-A4141296, November 12, 2024. Background:Recent animal studies connect high sodium intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions and hypertension. However, the relationship between sodium intake on the gut-immune axis in humans is largely unknown. We previously showed that dietary sodium reduction increased circulating levels of gut-produced short-chain fatty acids (SCFAs), in persons with untreated hypertension. Therefore, we examined whether dietary sodium intake is associated with gut microbial taxonomic features.Methods:The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a recently completed randomized, double-blind, placebo-controlled, 2×2 factorial trial of a multivitamin and cocoa extract supplement (containing 500 mg/d flavanols, including 80 mg/day (-)-epicatechin) in 21,442 older adults. Dietary intake was assessed by a validated Food Frequency Questionnaires at baseline and year 2. We previously conducted a deep shotgun metagenomic sequencing in a pilot study of 30 COSMOS participants using fecal samples collected at baseline and year 2 to explore whether the interventions affected gut microbial composition and function. We leveraged available taxonomic profiling data and analyzed the association between energy-adjusted sodium intake and microbial features at baseline.Results:We did not observe significant associations between sodium intake and alpha diversity parameters including Shannon Diversity Index and Inverse Simpson Index (P >0.05). The PERMANOVA analysis showed that sodium intake was significantly associated with the overall taxonomic beta diversity (Bray-Curtis dissimilarity) (R2= 0.067, p=0.031), suggesting 6.7% of the variation in beta diversity was explained by sodium intake. The Spearman’s rank-order correlation test showed several nominally significant associations (P

Circulation, Volume 150, Issue Suppl_1, Page A4147927-A4147927, November 12, 2024. Background:Recent studies have reported associations between alterations in gut microbiome composition (GMC) and cardiovascular disease risk factors (CVR). However, data regarding the use of GMC as a biomarker of CVR is scarce.Aims:The current study was designed to assess the distinct patterns in GMC among patients with varying degrees of CVR and/or atherosclerotic cardiovascular disease (ASCVD).Methods:Patients with a range of CVR including hypertension (HTN), hyperlipidemia (HLD), diabetes (DM), and/or ASCVD referring to Mayo Clinic from 2013 to 2018 were prospectively enrolled. DNA extracted from stool samples was analyzed using the V3-V5 region of the 16s data. Microbial α-diversity was assessed by the observed taxonomic units, Shannon, and Chao1 indices. β-diversity was assessed using Bray-Curtis dissimilarity and plotted using principal coordinates analysis. Hierarchical clustering was used to identify patterns in the GMC samples. Random Forest analysis was used to identify the most important clinical factors differentiating the clusters.Results:A total of 211 patients with a median age of 60 [IQR: 50,70] years and with 90 (42.7%) males were included. Two clusters of GMC were identified(Figure 1A). Cluster 1 and 2 had 104 (49.3%) and 107 (50.7%) patients, respectively. Among CVRs, age and body mass index were the most prominent factors contributing to the difference in GMC among clusters (Figure 1B). Cluster 2 had a better α diversity profile than Cluster 1(Figure 1C-E). There was no significant difference in TMAO between clusters (P=0.6). Cluster 2 patients were younger (P

This systematic anatomization of gut microbiota revealed the microbial characteristics of PCOS patients, particularly those with different testosterone level, thus laying the foundations for further research into pathogenesis of PCOS, and the development of effective diagnostic, treatment, and intervention strategies.