Risultati per: GUT

Objective
The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC.

Design
We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results.

Results
Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome–metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls.

Conclusion
Our large-sample multiomics data suggest that altered microbiome–metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

We recently published in Gut to show that gut dysbiosis persisted for at least 6 months in patients with post-acute COVID-19 syndrome (PACS).1 Murine and human studies have also reported microbial alterations associated with different PACS symptoms.2 3 With the pandemic entering its third year, PACS could potentially affect recovered individuals for over 1 year.4 It remains unknown whether PACS-associated gut dysbiosis would also linger for such a long time. Here, we conducted a prospective study to determine long-term alterations in the gut microbiome of patients with COVID-19 using shotgun metagenomic sequencing (). A total of 155 patients with COVID-19 in Hong Kong were followed up for an average of 14 months after SARS-CoV-2 viral clearance, and 155 age-matched, sex-matched and body mass index-matched subjects without COVID-19 were recruited as controls. Patients with COVID-19 were infected with the original or earlier variants…

The abundance of certain bacterial groups correlated significantly with eating disorder scores on validated questionnaires.

Elevated intestinal permeability has long been appreciated as a pathophysiological marker of gut inflammatory disease, in particular in inflammatory bowel disease (IBD). In addition to the association of IBD risk genetic variants with multiple aspects of intestinal permeability and barrier dysfunction, increased permeability has been identified as a predictor of IBD onset in healthy first-degree relatives of patients with Crohn’s disease, and of relapse in patients with Crohn’s disease.1–4 However, despite extensive investigation of the role of inflammation in disease-associated permeability, development of barrier-restoring agents beyond broad-acting anti-inflammatory agents has proven extremely challenging. In GUT, Zuo et al present an innovative study identifying that the tacrolimus-binding protein FKBP8 is a specific binding partner for the tight junction regulatory mediator, myosin light-chain kinase 1 (MLCK1).5 MLCK1 is one of two splice variants of the canonical tight junction regulatory protein, MLCK….

Circulation, Volume 147, Issue 14, Page 1079-1096, April 4, 2023. Background:Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.Methods:TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor–deficient (Ldlr−/−) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3−/−). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.Results:Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition,Fmo3−/−mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells–augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.Conclusions:These results define a role for gut microbiota–generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress–related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

Introduction
The gut microbiota develops from birth and matures significantly during the first 24 months of life, playing a major role in infant health and development. The composition of the gut microbiota is influenced by several factors including mode of delivery, gestational age, feed type and treatment with antibiotics. Alterations in the pattern of gut microbiota development and composition can be associated with illness and compromised health outcomes.
Infants diagnosed with ‘congenital heart disease’ (CHD) often require surgery involving cardiopulmonary bypass (CPB) early in life. The impact of this type of surgery on the integrity of the gut microbiome is poorly understood. In addition, these infants are at significant risk of developing the potentially devastating intestinal condition necrotising enterocolitis.

Methods and analysis
This study will employ a prospective cohort study methodology to investigate the gut microbiota and urine metabolome of infants with CHD undergoing surgery involving CPB. Stool and urine samples, demographic and clinical data will be collected from eligible infants based at the National Centre for Paediatric Cardiac Surgery in Ireland. Shotgun metagenome sequencing will be performed on stool samples and urine metabolomic analysis will identify metabolic biomarkers. The impact of the underlying diagnosis, surgery involving CPB, and the influence of environmental factors will be explored. Data from healthy age-matched infants from the INFANTMET study will serve as a control for this study.

Ethics and dissemination
This study has received full ethical approval from the Clinical Research Ethics Committee of Children’s Health Ireland, GEN/826/20.

Variation in clinical response to 5-aminosalicylic acid (5-ASA) has been attributed in part to its inactivation by gut microbes. Recently, in the Inflammatory Bowel Disease (IBD) Multi’omics Database (IBDMDB), a multicenter year-long cohort of 100+ participants with IBD, we identified 12 gut microbial enzymes from two protein families that convert 5-ASA to N-acetyl 5-ASA, a compound that lacks anti-inflammatory effects. Within the IBDMDB, we then found that a subset of these enzymes was cross-sectionally linked with greater risk of treatment failure, defined by corticosteroid use.

Fiber under-consumption in the American population has been associated with a rise in several gastrointestinal diseases. In this study, we focused on Ulcerative Colitis (UC) which currently affects 1 million Americans needing effective preventive and treatment strategies. Short-chain fatty acid (SCFA) production by fiber fermentation is linked to an improved gut barrier function. However, physicochemical properties of fibers such as rate of fermentability, solubility, and structure complexity can influence SCFA levels and fiber tolerance by UC patients.

Inflammatory bowel disease (IBD) is a disorder marked by chronic, relapsing inflammation of the gastrointestinal tract. Although the precise etiology of IBD is unclear, pathogenic immune response to the gut microbiota is considered a contributing factor. The importance of the gut microbiota in the development of intestinal inflammation has been previously shown through associative studies that correlate dysbiosis of the gut microbiota with active IBD, particularly through the loss of fiber-fermenting obligate anaerobes, an increased presence of pathobionts, and an overall decrease in microbial species diversity.

Inflammatory bowel disease (IBD) causes T cell infiltration of the intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The drug vedolizumab is believed to treat IBD by blocking the entry of circulating integrin α4β7+ T cells into the intestinal mucosa.

Joint inflammation, or spondyloarthritis (SpA), is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD), but the specific role for therapies targeting SpA is not well defined. One of the earliest medications used for the treatment of IBD is sulfasalazine (SAS). SAS is a prodrug composed of two chemical moieties, the anti-inflammatory 5-aminosalicilate and the antibiotic sulfapyridine. The efficacy of SAS in peripheral arthritis is thought to depend on its “antibacterial” properties, however the impact of SAS on the IBD-SpA microbiome and how it may improve extra-intestinal symptoms is unknown.

Patients with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) have decreased production of endogenous aryl hydrocarbon receptor (AhR) ligands in colon tissue. Activation of the AhR is a potential novel therapeutic target for ulcerative colitis and may play an important role in promoting immune homeostasis through increased IL-22 production, downregulation of proinflammatory mediators, and improved epithelial barrier function. Indigo naturalis, a botanical extract containing potent AhR agonists, has been effective for the treatment of moderate-to-severe and treatment-refractory ulcerative colitis in multiple clinical studies.

Gut microbiome plays a crucial role in modulation of inflammatory and immune pathways. Diverse bacterial species from gut microbiota feed on specific prebiotics (non-digestible dietary fibers) producing metabolites, such as short chain fatty acids (SCFA). These metabolites beneficially affect the intestinal mucosa with their role in metabolic and immunologic homeostasis, and gut barrier integrity. Recently gut-biome modulation and use of metabolites gained interest as potential targets for therapeutic development, for instance in Inflammatory Bowel Disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC).

A normal gastrointestinal (GI) tract biopsy result might not eliminate an inflammatory bowel disease (IBD) diagnosis, according to a population-based, sibling-controlled study published in PLOS Medicine.

Objective
First decompensation development is a critical milestone that needs to be predicted. Transkingdom gut microbial interactions, including archaeal methanogens, may be important targets and predictors but a longitudinal approach is needed.

Design
Cirrhosis outpatients who provided stool twice were included. Group 1: compensated, group 2: 1 decompensation (decomp), group 3: >1 decompensationwere followed and divided into those who remained stable or decompensated. Bacteria, viral and archaeal presence, α/β diversity and taxa changes over time adjusted for clinical variables were analysed. Correlation networks between kingdoms were analysed.

Results
157 outpatients (72 group 1, 33 group 2 and 52 group 3) were followed and 28%–47% developed outcomes. Baseline between those who remained stable/developed outcome: While no α/β diversity differences were seen, commensals were lower and pathobionts were higher in those who decompensated. After decompensation: those experiencing their first decompensation showed greater decrease in α/β-diversity, bacterial change (Lactobacillus spp, Streptococcus parasanguinis and beneficial Lachnospiraceae and Eubacterium hallii) and viral change (Siphoviridae, Myoviridae) versus those with further decompensation. Archaea: 19% had Methanobacter brevii, which was similar between/within groups. Correlation networks: Baseline archaeal-viral-bacterial networks were denser and more homogeneous in those who decompensated versus the rest. Archaea-bacterial correlations collapsed post first decompensation. Lactobacillus phage Lc Nu and C2-like viruses were negatively linked with beneficial bacteria.

Conclusion
In this longitudinal study of cirrhosis outpatients, the greatest transkingdom gut microbial changes were seen in those reaching the first decompensation, compared with subsequent decompensating events. A transkingdom approach may refine prediction and provide therapeutic targets to prevent cirrhosis progression.