Risultati per: GUT

Circulation, Volume 146, Issue Suppl_1, Page A13266-A13266, November 8, 2022. Introduction:Pulmonary arterial hypertension (PAH) patients exhibit sexual dimorphism in pulmonary vascular remodeling and right ventricular (RV) dysfunction. While female PAH patients have severe pulmonary vascular remodeling, male PAH patients have worse RV function. Inflammation, a key component of PAH pathobiology, has been implicated as a potential mechanism for sexual dimorphism. Gut dysbiosis causes systemic inflammation. However, it is unknown whether gut dysbiosis contributes to sexual dimorphism in PAH.Hypothesis:There are sex-specific differences in the gut microbiome and microbial metabolites of PAH patients.Methods:16S ribosomal ribonucleic acid gene sequencing was performed on stool samples from PAH patients (n=73). Markers of inflammation and circulating microbial metabolites were measured using plasma samples.Results:There was no significant difference in the Shannon diversity indices or species richness (Chao1 indices) between the gut microbiomes of male and female PAH patients. Moreover, principal component analysis of pairwise Bray-Curtis dissimilarity indices revealed no distinct microbiome compositions dependent on sex. There was no difference in serum claudin-3, a marker of gut permeability, and serum interleukin 6 levels between male and female PAH patients. When examining microbial metabolites, including trimethylamine N-oxide, short chain fatty acids, and secondary bile acids, no sex-specific differences were observed. Linear discriminant analysis of effect size revealed that there were no taxonomic differences based on sex.Conclusions:Male and female PAH patients do not possess distinct differences in their gut microbiomes or metabolites. There are also no sex-specific taxonomic differences. These findings do not support our hypothesis that gut dysbiosis may serve as a possible explanation for the sexual dimorphism observed in PAH.

Circulation, Volume 146, Issue Suppl_1, Page A11851-A11851, November 8, 2022. Introduction:Age-related gut microbiota alteration may underpin vascular disease. Yet, little is known about the role of cardiovascular disease-linked gut microbial metabolite phenylacetyl glutamine (PAG) in vascular aging.Hypothesis:1)PAG promotes endothelial senescence via epigenetic and SASP modulation;2)Acetate rescues PAG-induced endothelial senescence and impaired angiogenesis.Methods:We quantitated plasma concentrations of PAG and its precursor phenylacetic acid (PAA) in old and young healthy humans ( >65vs.18-35 years, n=41-45) and mice (24vs.3 months, n=6) by LC-MS/MS. Fecal acetate was measured by HPLC-RI. We then treated proliferating human aortic endothelial cells (PEC) with PAA+Glutamine (for PAG production) to examine its effects on cellular senescence, epigenetic and SASP state, mitochondrial respiration, and angiogenesis.Results:We showed markedly higher plasma PAA and PAG concentrations in old humans and micevs.young ones. Yet, fecal acetate level was significantly lower in oldvs.young mice. PAG significantly induced senescence (increased SA-β-gal positive cells and transcripts p16, p19, p21) and mitochondrial ROS production in PEC associated with upregulated SASP (IL1α, IL1β, TNF-α and adhesion molecule VCAM-1), and reduced mitochondrial respiration. PAG markedly reduced angiogenesis (endothelial sprouting and tube formation) accompanied by decreases in CaMKKβT286and histone deacetylase 4 (HDAC4S632) phosphorylation, histone 3 (H3) acetylation, and the subsequent Mef2A-mediated eNOSS1177phosphorylation. By contrast, acetate (3 μM) rescued senescence and impaired angiogenesis and mitochondrial function and reversed SASP and epigenetic alteration induced by PAG in PEC.Conclusions:We conclude that acetate regulates the aging gut microbial metabolite PAG-induced SASP and epigenetic alteration, by which rescues endothelial senescence and represents a potential vascular regenerative strategy.

Circulation, Volume 146, Issue Suppl_1, Page A12294-A12294, November 8, 2022. Introduction:Modest experimental and human evidence implicate a role for physical activity or sedentary lifestyle in the perturbation of the gut microbiome, yet large human studies are lacking.Methods:This study included 1846 US Hispanic/Latino adults without diabetes aged 23-82 years (mean age 48 years, 49% women) with gut microbiome data by shotgun sequencing of stools and accelerometer-measured moderate-to-vigorous physical activity (MVPA) and sedentary time from the HCHS/SOL population based cohort (2014-2017). We examined associations of MVPA and sedentary time with gut microbial features – Bray-Curtis dissimilarity by PERMANOVA, and alpha diversity and centered log ratio transformed relative abundance of species and KEGG pathway modules by a linear regression accounting for the complex survey design.Results:Prolonged sedentary time was associated with higher Shannon index (0.03 per 1 hr of sedentary time, SE=0.02, P=0.077) and Bray-Curtis dissimilarity (R2=0.32%, P

Circulation, Volume 146, Issue Suppl_1, Page A12300-A12300, November 8, 2022. Introduction:Phenylacetylglutamine (PAGln) has been recently discovered as a gut-microbiota-related metabolite, and circulating PAGln may be related to risks of cardiometabolic abnormalities. Gut microbiota-related dietary intakes and high-protein foods may affect circulating PAGln levels.Hypothesis:We assessed whether circulating PAGln levels may be related to intakes of gut-microbiota-related food intakes, and higher levels of PAGln may be associated with greater degrees of cardiometabolic abnormalities. We also tested a hypothesis that higher levels of circulating PAGln may be related to higher risk of the incident coronary heart disease (CHD).Methods:Circulating levels of PAGln, diet assessed using 7-day dietary records, and cardiometabolic abnormalities were assessed in the Women’s Lifestyle Validation Study (WLVS) (n=723). The associations between plasma PAGln levels and risk of incident CHD were analyzed in a prospective nested case-control of 1520 women (760 incident cases of fatal CHD and nonfatal myocardial infarction and 760 controls) from the Nurses’ Health Study (NHS). We identified incident cases of CHD over 10-14 years of follow-up time.Results:Higher levels of PAGln were associated with higher levels of circulating insulin, triglycerides, as well as lower levels of HDL cholesterol. We found that greater intakes of red meat and processed meat (p=0.01), but not of poultry or fish (p >0.05), and lower intakes of vegetables (p=0.03) were significant factors associated with higher levels of circulating PAGln. In the prospective nested case-control study setting, higher levels of PAGln were associated with higher risk of the incident CHD. Every 1 unit increment of log-transformed PAGln was associated with a relative risk of 1.21 (95% CI: 1.01, 1.45) for the incident CHD.Conclusions:Gut-microbiota-affecting diet quality were related to circulating levels of PAGln. Circulating PAGln levels may be associated with cardiometabolic abnormalities and risk of incident CHD among women.

Circulation, Volume 146, Issue Suppl_1, Page A11083-A11083, November 8, 2022. BackgroundThe gut microbiota and their metabolites have been shown to contribute to the development of coronary artery diseases. However, little is known about their roles in post-injury cardiac repair. Here, we investigated the gut microbiota and plasma metabolomes distinct in patients with ST-elevation myocardial infarction (STEMI), and explored their roles on adaptive responses, using germ-free (GF) mice and nonhuman primate models.MethodsWe recruited 70 controls and 77 coronary angiogram-confirmed STEMI patients, and collected their stool and plasma. The stool and plasma of STEMI patients were collected immediately following percutaneous coronary intervention (PCI, STEMIT1) and again at 28 days after PCI (STEMIT2). We used 16S V3-V4 rRNA NGS and shotgun metagenomics to map the gut microbiota and both NMR and LC-MS metabolomics to profile the plasma metabolites. To determine therole of the gut microbiota and their metabolites on post-injury cardiac repair, we inoculated identified bacteria in GF mice and treated specific pathogen free mice with candidate metabolites. Moreover, we validated the microbiome and metabolomics findings in a nonhuman primate coronary ischemia-reperfusion (IR) injury model.ResultsThe 16S V3-V4 rRNA NGS and shotgun metagenomic analysis revealed an enrichment of butyrate-producing bacteria in STEMIT1, as compared to STEMIT2 or to control cases. Fecal microbiome transplantation of STEMI samples in GF mice deteriorated host post-injury cardiac function, showing reduced left ventricle ejection fraction and cardiac mechanics. Moreover, plasma ketogenesis increased in the STEMI patients using NMR and LC-MS metabolomics. The protective effect of butyrate was more profound with intact commensal gut flora. Furthermore, inoculation of butyrate-producers in GF mice elevated plasma ketone body and better preserved post-injury cardiac function. Agreed with the clinical finding, we observed injury-induced elevation of gut butyrate-producers and plasma ketone bodies in the nonhuman primate IR model.ConclusionThis study demonstrates the pivotal role of gut butyrate-producers and the derived ketogenesis in post-injury cardiac repair, which may lead to new prevention strategies and treatment for heart failure.

Accumulating evidence not only supports the functional role of the gut microbiome in cancer development and progression but also its role in defining the efficacy and toxicity of chemotherapeutic agents (5-fluorouracil, CTX, Irinotecan, Oxaliplatin, Gemcitabine, Methotrexate) and immunotherapeutic (anti-PD-L1/ anti-PD-1 and anti-CTLA-4) compounds. This evidence is supported in numerous in-vitro, animal and clinical studies which highlight the importance of microbial mechanisms in defining therapeutic responses.

We read with great interest the recent article by Yeoh et al, demonstrating an altered stool microbiome composition in patients with COVID-19 compared with controls, with greater dysbiosis correlating with elevated inflammatory markers.1 Additionally, dysbiosis was seen after disease resolution.1 To our knowledge, gut microbiome studies in young children with COVID-19 have not been reported. Critically, the developing gut microbiome of very young children differs from adults and establishes immune and inflammatory pathways.2 3 Moreover, children with COVID-19 can subsequently develop autoimmune and autoinflammatory diseases including Multisystem Inflammatory Syndrome in Children (MIS-C)4 5, which may in part be microbiome mediated, given recent findings by Yeoh et al.1 It is difficult to study this in young children, as many with SARS-CoV-2 infection are asymptomatic and rarely tested.6 To address this, knowing that SARS-CoV-2 can…

Objective
This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis.

Design
We analysed the gut microbiota composition of 3xTg mice in an age-dependent manner. We generated germ-free 3xTg mice and recolonisation of germ-free 3xTg mice with fecal samples from both patients with AD and age-matched healthy donors.

Results
Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3xTg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3xTg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3xTg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants.

Conclusions
These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

We read with interest the work by Camilleri and Vella1 reporting the potential role of ‘leaky gut’ or reduced barrier function in some pathophysiological states. The detrimental effects of dietary emulsifiers on host intestinal barrier have also been evaluated.1–3 However, their role on promoting skin-related diseases and whether modulation of the microbiota can reversibly impact their underlying chemical effects are unknown. Herein, we showed that a common emulsifier, polysorbate-80 (P80), together with a soybean-deprived diet, promoted alopecia in mice. Importantly, the pathogenic process was exacerbated by antibiotics through aggravating gut dysbiosis and reversed following faecal microbiota transplantation (FMT) or administration of a targeted probiotic (Bifidobacterium longum HK003) isolated from faeces of healthy subjects (figures 1A–C and 2A,B). P80 and antibiotics-treated mice developed severe alopecia with large balding patches. Antibiotics exacerbated the microbial compositions induced by P80 including…

Objective
Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis.

Design
Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses.

Results
SQLE messenger RNA and protein expression was upregulated in CRC (p

We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and validate the results with follow-up, Japanese 4D microbiome cohort, and non-Japanese datasets.

Introduction
Gut microbiota (GM) appears critical for gastrointestinal symptoms, but whether alterations in GM are associated with increased risk of postoperative gastrointestinal dysfunction (POGID) in older patients with colon cancer (CC) undergoing elective colon resection remains unclear.

Methods and analysis
This study aims to prospectively recruit 284 elderly patients with CC undergoing elective colon resection. GM of fresh faeces specimens is characterised using 16S rRNA gene sequencing. Data are collected preoperatively, daily postoperatively during the in-hospital stay, and follow-up visits are scheduled four times within 30 days after discharge. Associations with POGID will be investigated using logistic regression models to calculate ORs with 95% CIs. The models include the adjustment for age, sex, frequency of spicy diet, coffee drinking and tea drinking, tobacco and alcohol history, diabetes, obesity, gastroenteritis, preoperative gut microbial composition. Furthermore, we will use joint modelling for longitudinal data to study several outcome variables simultaneously.

Ethics and dissemination
This study was approved by the Institutional Review Board of West China Hospital, Sichuan University (IRB Number: 20201334). The results will be disseminated through peer-reviewed publications or conference presentations.

Trial registration number
It has been registered in PROSPERO, number CRD42019145032. It has been registered in the Chinese clinical trial registry, number ChiCTR2100043646.

Objective
Using faecal shotgun metagenomic sequencing, we identified the depletion of Lactobacillus gallinarum in patients with colorectal cancer (CRC). We aimed to determine the potential antitumourigenic role of L. gallinarum in colorectal tumourigenesis.

Design
The tumor-suppressive effect of L. gallinarum was assessed in murine models of CRC. CRC cell lines and organoids derived from patients with CRC were cultured with L. gallinarum or Escherichia coli MG1655 culture-supernatant to evaluate cell proliferation, apoptosis and cell cycle distribution. Gut microbiota was assessed by 16S ribosomal DNA sequencing. Antitumour molecule produced from L. gallinarum was identified by liquid chromatography mass spectrometry (LC-MS/MS) and targeted mass spectrometry.

Results
L. gallinarum significantly reduced intestinal tumour number and size compared with E. coli MG1655 and phosphate-buffered saline in both male and female murine intestinal tumourigenesis models. Faecal microbial profiling revealed enrichment of probiotics and depletion of pathogenic bacteria in L. gallinarum-treated mice. Culturing CRC cells with L. gallinarum culture-supernatant (5%, 10% and 20%) concentration-dependently suppressed cell proliferation and colony formation. L. gallinarum culture-supernatant significantly promoted apoptosis in CRC cells and patient-derived CRC organoids, but not in normal colon epithelial cells. Only L. gallinarum culture-supernatant with fraction size