Risultati per: Microbiota e barriera intestinale distanti ma non troppo: implicazioni metaboliche sistemiche

Circulation, Volume 148, Issue Suppl_1, Page A13116-A13116, November 6, 2023. Introduction:The gut derived trimethylamine-N-oxide (TMAO) is correlated with increased atrial inflammation and fibrosis and associated with atrial fibrillation, heart failure, and stroke. However, the mechanisms mediating these links remain unresolved.Hypothesis:TMAO and its precursor metabolite L-carnitine (LCART) induce the transformation of atrial fibroblasts into pro-fibrotic phenotypes.Aim:To characterise the association between TMAO and cardiac fibrosis.Methods:Primary human cardiac (atrial) fibroblasts (hCFs) were sourced from healthy donors. hCFs were starved for 24 h and treated with PBS (control), 20 ng/mL transforming growth factor beta 1 (TGFβ1), 10 mM TMAO, or 1.0 mM LCART for 72 h (n=6 in each), then analysed by flow cytometry for α-smooth muscle actin (αSMA) expression. Unbiased proteomics was performed using LC-MS/MS to determine protein expression profile.Results:Analysis of αSMA expression revealed 3 hCF states: quiescent (Fbs), quiescent-to-myofibroblast (intermediate [Fbs-myoFbs]), and fully activated myofibroblast (myoFbs), (Fig-A). Compared to controls, there was no difference in the intermediate state after TGFβ1, TMAO, or LCART treatment (p=0.30). TMAO and LCART resulted in a significant induction of myofibroblast states compared to controls and TGFβ1 group. Unbiased proteomics identified 92, 65, and 43 proteins to be overexpressed and 84, 46, and 78 proteins downregulated following TGFβ1, TMAO, and LCART treatments (Fig-B). Both TGFβ1 and TMAO demonstrated shared enrichment for oxidative stress-regulated ferroptosis pathway (fold enrichment [FE] 31.8 and 22.2, p

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.

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.

Introduction
Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson’s disease (PD) via the gut–brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy.

Methods and analysis
We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor–recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months.

Ethics and dissemination
This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences.

Trial registration number
International Clinical Trial Registry Platform: NL9438.

I ricercatori dell’Istituto Humanitas hanno identificato un ceppo di batteri in grado di produrre molecole che rendono “visibili” le cellule tumorale al sistema immunitario

Background
Hashimoto’s thyroiditis (HT) is a common endocrine autoimmune disease affecting roughly 5% of the general population and involves life-long treatment with levothyroxine, as no curative treatment yet exists. Over the past decade, the crosstalk between gut microbiota and the host immune system has been well-recognised, identifying the gut microbiome as an important factor in host health and disease, including susceptibility to autoimmune diseases. Previous observational studies yielded a link between disruption of the gut microbiome composition and HT. This is the first study that investigates the potential of restoring a disrupted gut microbiome with faecal microbiota transplantations (FMTs) to halt disease progression and dampen autoimmunity.

Methods and analysis
The IMITHOT trial is a randomised, double-blinded, placebo-controlled study evaluating either autologous or allogenic FMTs in medication-naïve patients with subclinical autoimmune hypothyroidism. In total, 34 patients will be enrolled to receive either three allogenic or autologous FMTs. FMT will be made of fresh stool and directly administered into the duodenum. Patients will be evaluated at baseline before the first FMT is administered and at 6, 12 and 24 months post-intervention to assess efficacy and adverse events. The primary outcome measure will be the net incremental increase (incremental area under the curve) on thyrotropin-stimulated free thyroxine and free triiodothyronine release at 6 and 12 months compared with baseline. Results will be disseminated via peer-reviewed journals and international conferences. The recruitment of the first patient and donor occurred on 18 December 2019.

Ethics and dissemination
Ethics approval was obtained from the hospital Ethics Committee (Medical Ethics Committee) at Amsterdam University Medical Center. The trial’s outcomes offer high-quality evidence that aids in unveiling distinct patterns within the gut microbiota potentially associated with improved thyroid function. Consequently, this may open avenues for the future clinical applications of microbial-targeted therapy in individuals at risk of developing overt HT.

Trial registration number
NL7931.

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.

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,…

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…

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…

Pien-Tze-Huang (PZH) is a well-established Traditional Medicine with beneficial effects against inflammation and cancer. We aim to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota.

Circulation, Volume 148, Issue 8, Page 701-702, August 22, 2023.

Background
Several randomised clinical trials (RCTs) performing faecal microbiota transplantation (FMT) for the management of inflammatory bowel disease (IBD), particularly for ulcerative colitis, have recently been published, but with major variations in study design. These include differences in administered dose, route and frequency of delivery, type of placebo and evaluated endpoints. Although the overall outcomes appear to be promising, they are highly dependent on both donor and recipient factors.

Objective
To develop concensus-based statements and recommendations for the evaluation, management and potential treatment of IBD using FMT in order to move towards standardised practices.

Design
An international panel of experts convened several times to generate evidence-based guidelines by performing a deep evaluation of currently available and/or published data. Twenty-five experts in IBD, immunology and microbiology collaborated in different working groups to provide statements on the following key issues related to FMT in IBD: (A) pathogenesis and rationale, (B) donor selection and biobanking, (C) FMT practices and (D) consideration of future studies and perspectives. Statements were evaluated and voted on by all members using an electronic Delphi process, culminating in a plenary consensus conference and generation of proposed guidelines.

Results and conclusions
Our group has provided specific statements and recommendations, based on best available evidence, with the end goal of providing guidance and general criteria required to promote FMT as a recognised strategy for the treatment of IBD.