Inflammation-associated gut microbiome in postacute sequelae of SARS-CoV-2 points towards new therapeutic targets

We read with interest the recent report by Liu et al1 describing faecal microbiome differences with postacute sequelae of SARS-CoV-2 (PASC), commonly referred to as ‘Long-COVID’. We have previously reported elevated levels of SARS-CoV-2-specific T cells with PASC compared with resolved COVID-19 (RC; no lingering symptoms at the time of sample collection) that correlated with increased levels of the inflammatory marker IL-6, suggesting that elevated inflammation in PASC may be related to immune response to residual virus.2 Although several studies have reported gut microbiome differences during acute COVID-19,3 PASC has received less attention. We, thus, sought to characterise gut microbiome differences in PASC versus RC using faecal samples from our study2 and to relate these differences to inflammation. The faecal microbiome was evaluated using 16S rRNA gene sequencing. Plasma levels of inflammatory markers IL-6 and C reactive protein (CRP) were measured…

Leggi
Gennaio 2024

Gut microbiome and dietary fibre intake strongly associate with IgG function and maturation following SARS-CoV-2 mRNA vaccination

The first study to investigate potential associations between gut microbiota composition and SARS-CoV-2 vaccine immunogenicity was recently published in Gut.1 This study demonstrated a statistically significant reduction in alpha diversity and a shift in gut microbiota composition following BNT162b2 vaccination, characterised by reductions in Actinobacteriota, Blautia, Dorea, Adlercreutzia, Asacchaobacter, Coprococcus, Streptococcus, Collinsella and Ruminococcus spp and an increase in Bacteroides cacaae and Alistipes shahii. Our prospective observational study (n=52; figure 1A, ) similarly showed a shift in gut microbiota after the first BNT162b2 vaccine dose (p=0.016; ), including a reduction in Actinobacteria, Blautia spp (p

Leggi
Dicembre 2023

Smart capsules for sensing and sampling the gut: status, challenges and prospects

Smart capsules are developing at a tremendous pace with a promise to become effective clinical tools for the diagnosis and monitoring of gut health. This field emerged in the early 2000s with a successful translation of an endoscopic capsule from laboratory prototype to a commercially viable clinical device. Recently, this field has accelerated and expanded into various domains beyond imaging, including the measurement of gut physiological parameters such as temperature, pH, pressure and gas sensing, and the development of sampling devices for better insight into gut health. In this review, the status of smart capsules for sensing gut parameters is presented to provide a broad picture of these state-of-the-art devices while focusing on the technical and clinical challenges the devices need to overcome to realise their value in clinical settings. Smart capsules are developed to perform sensing operations throughout the length of the gut to better understand the body’s response under various conditions. Furthermore, the prospects of such sensing devices are discussed that might help readers, especially health practitioners, to adapt to this inevitable transformation in healthcare. As a compliment to gut sensing smart capsules, significant amount of effort has been put into the development of robotic capsules to collect tissue biopsy and gut microbiota samples to perform in-depth analysis after capsule retrieval which will be a game changer for gut health diagnosis, and this advancement is also covered in this review. The expansion of smart capsules to robotic capsules for gut microbiota collection has opened new avenues for research with a great promise to revolutionise human health diagnosis, monitoring and intervention.

Leggi
Dicembre 2023

Solutions to Enhance Health with Alternative Treatments (SEHAT) protocol: a double-blinded randomised controlled trial for gut microbiota-targeted treatment of severe acute malnutrition using rice bran in ready-to-use therapeutic foods in Indonesia

Introduction
Current formulations of ready-to-use therapeutic foods (RUTFs) to treat severe acute malnutrition (SAM) in children focus on nutrient density and quantity. Less attention is given to foods targeting gut microbiota metabolism and mucosal barrier functions. Heat-stabilised rice bran contains essential nutrients, prebiotics, vitamins and unique phytochemicals that have demonstrated favourable bioactivity to modulate gut microbiota composition and mucosal immunity. This study seeks to examine the impact of RUTF with rice bran on the microbiota during SAM treatment, recovery and post-treatment growth outcomes in Jember, Indonesia. Findings are expected to provide insights into rice bran as a novel food ingredient to improve SAM treatment outcomes.

Methods and analysis
A total of 200 children aged 6–59 months with uncomplicated SAM (weight-for-height z-scores (WHZ)

Leggi
Novembre 2023

Correction: Mucus barrier, mucins and gut microbiota: the expected slimy partners?

Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 2020;69:2232-43.
There is a misspelling of the Cftr gene in this article. The article has Ctfr instead of Cftr in the following sentence, which should read as:
For example, during high-fat diet feeding, there is an impairment in mucus production and secretion, an enrichment in barrier-disrupting species, and a decrease in the expression of the Cftr gene in mouse ileal enterocytes, causing a reduction in viscosity and density of the mucus and an increase in intestinal permeability.
doi:10.1136/gutjnl-2020-322260corr1

Leggi
Novembre 2023

Abnormal gastrointestinal motility is a major factor in explaining symptoms and a potential therapeutic target in patients with disorders of gut-brain interaction

The objective of this article is to review the evidence of abnormal gastrointestinal (GI) tract motor functions in the context of disorders of gut–brain interaction (DGBI). These include abnormalities of oesophageal motility, gastric emptying, gastric accommodation, colonic transit, colonic motility, colonic volume and rectal evacuation. For each section regarding GI motor dysfunction, the article describes the preferred methods and the documented motor dysfunctions in DGBI based on those methods. The predominantly non-invasive measurements of gut motility as well as therapeutic interventions directed to abnormalities of motility suggest that such measurements are to be considered in patients with DGBI not responding to first-line approaches to behavioural or empirical dietary or pharmacological treatment.

Leggi
Novembre 2023

World Gastroenterology Organisation – Gut commentary series on digestive health and climate change

Introducing a commentary series related to digestive health and climate change We are delighted to introduce to the Gut readership a compendium of nine commentaries, each summarising one, or a hybrid, of the nine educational webinars organised by the World Gastroenterology Organisation. The webinars covered the why, what and how in terms of climate change (CC) as related to digestive health hazards, disease implications and actionable interventions.1 These 1-hour webinars were held every 2 weeks, 8 March to 28 June 2023, and will remain freely available for anyone to view any or all of them depending on the topic of interest to the viewer. Each webinar included presentations by two content experts and ended with a question-and-answer segment.1 The webinars were viewed live by 987 participants from 117 countries, including gastroenterologists, trainees, nurses, general practitioners, paediatricians, surgeons, dietitians and pharmacists, and the freely available videos…

Leggi
Novembre 2023

Abstract 13116: Profiling the Role of Gut Microbiota-Derived Trimethylamine-N-Oxide in Cardiac Fibrosis — Evidence From a Primary Human in vitro Model

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

Leggi
Novembre 2023

Abstract 16444: Gut Microbiota Derived Metabolite, Ursodeoxycholic Acid, and the Risk of Cardiovascular Disease

Circulation, Volume 148, Issue Suppl_1, Page A16444-A16444, November 6, 2023. Introduction:Gut microbial metabolites have been recognized as risk factors for cardiometabolic diseases. The associations between plasma levels of the gut microbiota derived metabolites with cardiovascular disease (CVD) have not been comprehensively examined. Our objective was to investigate the association between 6 secondary bile acids including ursodeoxycholic acid and CVD. Ursodeoxycholic acid is used to dissolve cholesterol gall stones to treat cholestatic liver diseases.Hypothesis:Gut microbiota derived metabolites are associated with CVD.Methods:We performed a secondary analysis of data from the cross-sectional Metabolic Syndrome in Men (METSIM) cohort. Our study included 915 men aged 45-73 years (age = 54.94 ± 5.04 years, BMI = 27.31 ± 3.44), randomly selected from the population register of Kuopio, Eastern Finland, from 2005 to 2010. The associations between 6 secondary bile acids (ursodeoxycholic acid, glycoursodeoxycholate, glycolithocholate sulfate, taurocholenate sulfate, taurochenodeoxycholate, and glycocholenate sulfate) and the risk of CVD were investigated. Kaplan-Meier analysis with Cox proportional-hazards regressions were conducted for the time-to-event analysis to determine hazard ratios (HR) and 95% confidence intervals (CI) for CVD. Adjustments were made for traditional cardiovascular risk factors (age, systolic blood pressure, low-density and high-density lipoprotein cholesterol levels, triglyceride levels, smoking status, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and alcohol consumption).Results:Participants were stratified into groups according to quartile metabolites levels and CVD. During a median follow-up of 16 years, n = 62 (7%) of patients experienced CVD. Only ursodeoxycholic acid was significantly associated with CVD risk. Cox regression analyses showed that the adjusted HR for CVD was higher in patients in quartile 4 (HR: 2.8, 95% [CI]: 1.35-4.6; p =0.008) than in quartile 1. The Kaplan-Meier analysis indicated that patients in quartile 4 had a significantly lower event-free survival (p = 0.037) compare to quartile 1.Conclusions:Ursodeoxycholic acid, a secondary bile acid, was positively associated with an increased risk of CVD.

Leggi
Novembre 2023

Abstract 13173: Loss of ACE2 in a Diabetic Obese Setting Exacerbates Cardiovascular Dysfunction in the Setting of Gut Dysbiosis

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

Leggi
Novembre 2023

Abstract 17450: Sex Influences the Gut-Lung Microbiome Composition in Schistosomiasis-Associated Pulmonary Arterial Hypertension

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.

Leggi
Novembre 2023

Abstract 13364: Transplantation of Mutant Clostridium_ASF356 Rescues Aging Gut-Derived Phenylacetate-Mediated Perivascular Adipose Tissue and Endothelial Senescence

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.

Leggi
Novembre 2023

Abstract 13063: Gut Microbiota-Derived Metabolites and Cardiometabolic Traits: Findings From a Monozygotic Twin Study

Circulation, Volume 148, Issue Suppl_1, Page A13063-A13063, November 6, 2023. Introduction:Microbial metabolites are small chemical compounds produced by gut microbiota when it breaks down food, chemicals, or other environmental exposures. These metabolites serve as signaling molecules between the host and gut microbiota and regulate numerous aspects of host physiology, immunity, and metabolism.Hypothesis:Gut dysbiosis is associated with cardiometabolic disorders via alterations in microbial metabolites.Aims:To identify gut-microbiota-derived metabolites associated with cardiometabolic traits.Methods:Using hydrophilic interaction liquid chromatography (HILIC), we measured the relative abundances of 62 food and gut-microbiota-derived metabolites in plasma sample of 46 complete monozygotic twin pairs (34 female-female pairs, 12 male-male pairs, mean age 36.2) enrolled in the Mood and Methylation Study (MMS), an observational study designed to identify biomarkers associated with depressive symptoms using a twin design. Information for cardiometabolic traits, including body mass index, waist circumference, blood glucose, HbA1c, insulin, triglycerides, total cholesterol, HDL and LDL, was collected using standard questionnaires or laboratory methods. The association of each metabolite with cardiometabolic trait was examined by a linear mixed-effects model, adjusting for age, sex, smoking, drinking, and depressive symptoms. The co-twin correlation was accounted for by including twin pair as a random effect in the model.Results:After correction for multiple testing by false discovery rate (FDR

Leggi
Novembre 2023

Abstract 18307: Causal Association Between Gut Microbiota Composition and the Risk of Atrial Fibrillation

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.

Leggi
Novembre 2023