Risultati per: GUT

Circulation, Volume 148, Issue Suppl_1, Page A13173-A13173, November 6, 2023. Introduction:COVID-19 disproportionately affects older, male obese patients leading to a high prevalence of adverse outcomes. SARS-CoV-2 mediated ACE2 loss may further increase the susceptibility of these patients to adverse outcomes. Loss of ACE2 may be a causative factor in cardiovascular (CV) injury independent of primary viral-mediated injury.Methods:Male, 6-month-old, diabetic, obesedb/db Ace2-/y(double mutant, DM) mice and respective WT,Ace2-/y, anddb/dbcontrols (n=12) were assessed for injury across the gut-heart axis. Cardiovascular parameters were evaluated by echocardiography, pressure-volume loops, and histology. Alterations in gut permeability were determined by measuring plasma peptidoglycan (PGN) levels and immunological staining of microvilli structure. Metagenomics and metatranscriptomics determined the functional and phyla alterations of the gut microbiota.Results:Loss of ACE2 in diabetic obese mice led to increased left atrium diameter (P

Circulation, Volume 148, Issue Suppl_1, Page A13364-A13364, November 6, 2023. Introduction:Perivascular adipose tissue (PVAT) may contribute to atherosclerosis by promoting endothelial dysfunction in aging. Gut microbiota can induce PVAT dysfunction; yet, whether it leads to endothelial cell (EC) senescence requires further investigation. Our studies revealed that gut-derived phenylacetate (PAA) and its derivative PAGln age-dependently increase (TwinsUK Aging Cohort). Yet, it remains unclear whether and how it contributes to PVAT-EC senescence.Methods:To circumvent our limited knowledge of PAA-(peri)vasculature pathway in aging, we performed multi-omics (fecal shotgun metagenomics and targeted metabolomics), and cell-cell (co-culture) interaction and senescence analyses.Results:Our human (TwinsUK, n=7,303) and mouse (24vs.3 months, n=6) studies identified a positive association of plasma PAA and PAGln with higher abundance ofVOR- andPPFOR-harboring bacteria (metabolizing dietary phenylalanine to PAA), particularlyClostridium_ASF356,in gut of old humans and mice that exhibited PVAT and vascular dysfunction. PAA aggravated PVAT dysfunction (reduced UCP1 and Prdm16) by generating excess mitochondrial H2O2and upregulatingNotch1, leading to reduced energy supply and increased senescence-messaging secretome from PVAT. It induced senescence (increased SA-β-galactosidase, telomere attrition, cell-cycle arrest (p16INK4aandp21WAF1/Cip1), and SASP (IL6 and VCAM1)) in co-cultured aortic ECs and reduced angiogenesis (tube formation). We also showed that transplantation ofgenetically-engineeredΔvor, Δppfor C. ASF356double mutantsto old mice (reduces plasma PAA) decreases VCAM1 secretion from PVAT and thereby inhibits senescence in aortic ECs that exhibited eNOS uncoupling.Conclusions:We conclude that age-related increase in microbiota-driven PAA regulates PVAT-mediated EC senescence viaNotch1signaling. Our bacterial engineering approach may represent a novel (peri)vascular senotherapy.

Circulation, Volume 148, Issue Suppl_1, Page A17450-A17450, November 6, 2023. Introduction:Pulmonary arterial hypertension (PAH) is an uncurable cardiopulmonary disease highly incident in women. Infection by the intravascular parasite Schistosoma mansoni recapitulates several aspects of widespread inflammation that leads to PAH (Sch-PAH). Our data indicate that after infection, the S. mansoni eggs translocate within the cardiopulmonary system, disturbing gut-lung microbiome and leading to severe PAH. Hypotheses: S. mansoni eggs disturb the lung microbiome, contributing to vascular inflammation and PAH in a sex-dependent manner.Methods:To test this hypothesis, we induced Sch-PAH in end-Scl.creERT2;Rosamt/mg mice by intraperitoneal sensibilization with 240 eggs/gram body weight (bw; 2 weeks) followed by intravenous injection of 175 eggs/gram bw. After 7 days, we analyzed the Right Ventricular Systolic Pressure and hypertrophy (RVSP; RVH). Lung sections were used for TUNEL stain and for microbiome analysis by shotgun metagenomics.Results:Metagenomic analysis revealed that S. mansoni egg infection disrupted the lung microbiome reducing α-diversity compared to controls. Infection also reduced the Phylum Ascomycota in the lungs, whereas the ratio Firmicutes:Bacteroidetes (F/B) remained similar between groups. No difference was observed in the Simpson and Chao index. In the guts, the infection did not alter the α-diversity or the relative abundance of Deferribacteres and Proteobacteria, but it significantly increased the ratio F/B, indicative of gut dysbiosis. In terms of sex, our preliminary data indicated female mice exhibit a lower lung α-diversity compared to male mice, characterized by a significant reduction in the Firmicutes Phylum (Mean reads: 0.013 and 0.119, respectively; reads normalized by Readcount with Children). Principal coordinate analysis identified a distance in the clustering pattern between sexes, which may account for microbiome differences in Sch-PAH. Finally, our data revealed increased RVH and presence of microvascular apoptosis in female compared to male group.Conclusion:Understanding whether the disrupted gut and lung microbiome composition contributes to the onset and progression of Sch-PAH in a sex-dependent manner opens a novel therapeutic direction.

Circulation, Volume 148, Issue Suppl_1, Page A18307-A18307, November 6, 2023. Background:Considerable evidence has shown that alterations in gut microbiota composition are associated with atrial fibrillation (AF). However, the causal associations remain largely unresolved. This study aims to reveal the causality between gut microbiota and AF.Method:We incorporated data from the largest genome-wide association studies (GWASs) of gut microbiota composition including a sample of 18,304 individuals and AF compared a total of 60,620 cases and 970,216 controls of European ancestry. A two-sample Mendelian randomization framework was designed to investigate the involvement of gut microbiota in AF.Results:Among all gut microbiota, four microbial taxa, namely Lachnospiraceae FCS020 group (OR: 1.077; 95% CI: 1.011- 1.148; P= 0.021), Rikenellaceae_ RC9_ gut_ group (OR: 1.047; 95% CI: 1.010- 1.086; P= 0.012), Catenibacterium (OR: 1.060; 95% CI: 1.002-1.122; P= 0.043), Victivallis (OR: 1.038; 95% CI: 1.001- 1.077; P= 0.044), and Erysipelatoclostridium (OR: 1.344; 95% CI:1.095-1.649; P= 0.014), were identified to be causally associated with the higher risk of AF. Besides, genetically predicted five microbial taxa, namely Lachnospiraceae NK4A136 group (OR: 0.918; 95% CI: 0.865- 0.973; P= 0.004), Howardella (OR: 0.948; 95% CI: 0.910- 0.989; P= 0.012), Intestinibacter bartlettii (OR: 0.933; 95% CI: 0.879- 0.991; P= 0.024), Alloprevotella (OR: 0.942; 95% CI: 0.896-0.992; P= 0.022), Anaerostipes (OR: 0.922; 95% CI: 0.857-0.992; P= 0.030), Odoribacter (OR: 0.910; 95% CI: 0.831- 0.996; P= 0.041), Ruminococcus (gnavus group) (OR: 0.952; 95% CI: 0.908- 0.999; P= 0.044), and Ruminiclostridium 5 (OR: 0.678; 95% CI: 0.486- 0.947; P= 0.046), can prevent AF.Conclusions:Our study provides evidence of the causal effect of the gut microbiota on AF, highlighting causal microbial taxa. Our results may offer novel insights into gut microbiota-mediated mechanisms and interventions of AF.

Does AD change the gut microbiome, or does the gut microbiome influence risk for developing AD?

Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice.

The gut contains approximately 100 trillion commensal microorganisms, including viruses, archaea, bacteria, and unicellular eukaryotes that influence the development and function of the human neurological, immunological, and digestive systems from birth through adulthood. These collective microbes and their genes comprise the gut microbiome, which has gained clinical interest in many specialties as a diagnostic and potential therapeutic tool for several diseases and malignant neoplasms. The bacterial component of the gut microbiome is the most well-characterized and can be studied in a culture-independent manner using 16S ribosomal RNA sequencing. Alpha diversity describes the richness (number of unique species) in a single sample. Beta diversity describes differences between population samples. Dysbiosis describes a deviation from normal composition or metabolic activity.

This case-control study compares differences in the fecal microbiota—including overall diversity, composition, and putative function—between control participants and patients with melanoma and between patients with early- and late-stage melanoma.

Introduction
Excess body weight is associated with a state of low-grade chronic inflammation and alterations of the gut microbiome. Powdered meal replacements (PMR) have been shown to be an effective strategy for weight management; however, their effect on inflammation and the gut microbiome remains unclear. The aim of this 12-week randomised control clinical trial is to investigate the effects of PMR consumption, here given as a soy-yoghurt-honey formula, on inflammation, gut microbiome and overall metabolism in individuals with excessive body weight.

Methods and analysis
Healthy adults with excess body weight (n=88) are being recruited and randomly assigned to one of the following groups: (1) Control group (CON): maintaining usual diet for 12 weeks, or (2) PMR group: replacing morning and afternoon snacks daily with a PMR for 12 weeks. Participants are asked to maintain body weight throughout the study and fill out a journal with information about PMR consumption, body weight, food intake, appetite sensations and medications. Three study visits are required: baseline, week 6 and week 12. Outcome measures include systemic inflammatory biomarkers, gut microbiome composition, metabolic blood markers, host energy metabolism, body composition, appetite sensations and host gene expression profile.

Ethics and dissemination
This research protocol was approved by the University of Alberta Ethics Board (Pro00070712) and adheres to the Canadian Tri-Council Policy statement on the use of human participants in research. Procedures and potential risks are fully discussed with participants. Study findings will be disseminated in peer-reviewed journals, conference presentations and social media.

Trial registration number
NCT03235804.

Objective
Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability (‘leaky gut’) in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive.

Design
In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism.

Results
We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA-miR-101a-3p by enhancing ARID3a binding on the miR promoter. Increased miR-101a-3p decreased the stability of zona occludens-1 (Zo1) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/miR-101a/Zo1 axis.

Conclusion
Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities.

Trial registration number
NCT02869659 and NCT03269032.

Microbiota are a source of low-grade inflammation during obesity and contribute to insulin resistance and poor blood glucose control among other mechanisms in the progression of type 2 diabetes.1 Nearly all bacteria that reside within the host are found in the intestine, but it is not yet clear how microbiota are a source of inflammation in the circulation or metabolic tissues during obesity. A key knowledge gap is understanding how obesity or certain diets promote gut barrier dysfunction that allows increased permeability for bacteria or bacterial components that can engage immune response and promote inflammation-induced metabolic dysfunction. Metabolic endotoxaemia is the key example of a bacterial source of inflammation. Obesity or diet-induced increases in lipopolysaccharides (LPS or endotoxin), that escape the gut lumen, penetrate the intestinal barrier and enter into the host circulation, cells and tissues. This low-level increase in LPS activate toll-like receptor 4, increase inflammation…

We read with interest the study by Kartal et al1 showing that the gut-microbiota-derived biomarkers for disease stratification are often shared by subjects across disease cohorts. Here, we confirmed their observations with findings from a newly diagnosed natural killer/T-cell lymphoma (NKTCL) cohort, in which the gut biomarkers were significantly overlapped with those of multiple disease cohorts and consistently enriched/depleted in subjects with those diseases. Importantly, many of the shared biomarkers were remarkably associated with patient outcomes in our cohort, implying that they may have broad prognostic values in multiple diseases. ‘Microbiota-gut-lymphoma axis’ represents a fascinating avenue of microbiota-mediated lymphomagenesis and intervention opportunity,2 but the implications of gut microbiota in NKTCL remain enigmatic. To identify gut microbiota-derived diagnostic biomarkers for NKTCL, we recruited a discovery cohort consisting of 30 treatment-naïve patients and 20 healthy controls (HCs), and a validation cohort, including 12 patients and 13 HCs,…

A Southeast Asian man in his early 20s with no medical history presented with persistent abdominal pain and nausea for 3 weeks. He reported no recent sick contacts and no travel in the past 5 years since arrival to the USA. Physical examination was notable for right lower quadrant tenderness. CT of the abdomen and pelvis showed hyperaemia and fat stranding near the terminal ileum and cecum, concerning for appendicitis. He underwent laparoscopic appendectomy with pathology showing acute granulomatous appendicitis. Bacterial, fungal and acid-fast bacilli (AFB) stains were negative. Given the presence of granulomas, interferon gamma release assay and ACE levels were obtained which were unremarkable. HIV-1/2 testing was negative. He unfortunately developed recurrent abdominal pain 4 weeks postoperatively. CT imaging at that time showed pelvic fluid collections, treated empirically with amoxicillin–clavulanic acid for presumed abscesses. The collections persisted despite additional antibiotic rounds, and he eventually presented to the…

Recently, we read the article by Ng et al with great interest,1 which identified several gut microbiota harbour the potential to improve immune response and reduce adverse events following COVID-19 vaccines, and demonstrated that gut microbiota has the potential to complement the effectiveness of vaccines. Together with several recent studies, gut microbiota plays a key role in modulating immune responses of vaccination2–4 and is related to the severity of COVID-19 patients,5 6 however, the comprehensive assessment of host’s response, particularly the role of gut microbiota in antibodies production is limited and should be seriously considered because the vaccination of SARS-CoV-2 is the most promising approach for curbing the COVID-19 pandemic.4 7 Therefore, we recruited 30 young volunteers (20–23 years old), including 15 male and 15 female volunteers, and collected 143 faecal and 120…