Risultati per: Microbiota e steatosi epatica: quali evidenze?

Gastric cancer (GC) is one of the most common malignancies and a prominent cause of cancer mortality worldwide. A distinctive characteristic of GC is its intimate association with commensal microbial community. Although Helicobacter pylori is widely recognised as an inciting factor of the onset of gastric carcinogenesis, increasing evidence has indicated the substantial involvement of microbes that reside in the gastric mucosa during disease progression. In particular, dysregulation in gastric microbiota could play pivotal roles throughout the whole carcinogenic processes, from the development of precancerous lesions to gastric malignancy. Here, current understanding of the gastric microbiota in GC development is summarised. Potential translational and clinical implications of using gastric microbes for GC diagnosis, prognosis and therapeutics are also evaluated, with further discussion on conceptual haziness and limitations at present. Finally, we highlight that modulating microbes is a novel and promising frontier for the prevention and management of GC, which necessitates future in-depth investigations.

Circulation, Volume 150, Issue Suppl_1, Page A4141474-A4141474, November 12, 2024. Background:5-Hydroxytryptophan (5-HTP) has shown positive clinical effects on various neuropsychiatric and metabolic disorders, particularly depression. While it is known to increase serotonin levels in the brain and gastrointestinal tract, its pharmacology remains largely unexplored. Additionally, 5-HTP influences the mouse gut microbiome, which is closely linked to depression through the “microbiota-gut-brain axis.” However, the role of 5-HTP in vascular disease is not well understood. This study aimed to investigate the potential correlation between serum 5-HTP levels and the severity of coronary artery calcification (CAC) in patients with acute coronary syndrome (ACS).Methods and Results:This study included 183 ACS patients who underwent coronary angiography. The severity of coronary calcification was recorded, and serum 5-HTP levels were measured after the coronary event. The study period was from February 4, 2009, to August 9, 2020. The primary exposure variable was 5-HTP levels, and the primary outcome was the severity of coronary calcification assessed through fluoroscopy. Logistic regression was used to determine the association between 5-HTP levels and calcification severity, adjusting for age, gender, smoking status, chronic kidney disease, hyperlipidemia, and diabetes. Odds ratios (OR) and 95% confidence intervals (CI) measured the strength of associations, with statistical significance set at p < 0.05.High 5-HTP levels were significantly associated with more severe calcification (p = 0.04, OR = 3.3, 95% CI = 2.6 to 40686.5). For other factors, the OR for smokers was 0.97 (0.53 to 1.77); dyslipidemia 0.91 (0.5 to 1.63); hypertension 1.57 (0.87 to 2.82); male gender 1.35 (0.45 to 4.01); age 1.07 (1.03 to 1.10); diabetes 1.24 (0.67 to 2.31); chronic kidney disease 1.07 (0.33 to 3.50). After adjusting for conventional risk factors, the association between 5-HTP and calcification remained significant (p < 0.05).Conclusion:Higher 5-HTP levels are positively associated with greater severity of coronary artery calcification. This correlation persists even after adjusting for conventional risk factors.

Circulation, Volume 150, Issue Suppl_1, Page A4141762-A4141762, November 12, 2024. Introduction:Chronic heart failure (HF) is linked to elevated serum TNF-α levels and affects multiple signaling pathways in non-cardiomyocytes, such as immune cells, intestinal epithelial cells, lymphatic endothelial cells, vascular cells, and their interactions. The combined dysbiosis of host transcriptomics and gut microbiota concerning altered TNF-α signaling in older adults with HF remains unknown.Methods:We recruited 10 older adults with heart failure (HF) (6 females) and 16 healthy controls (HCs) (10 females) from the Northeastern U.S. Non-fasting peripheral blood and stool samples were collected. Serum TNF-α was assayed using Enzyme-linked Immunosorbent Assay (ELISA) kits. Differentially expressed genes (DEGs) between HF and HCs were investigated using the R package “DESeq2” after aligning the raw blood RNA sequence data to the reference database and undergoing quality control. The QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the canonical pathways associated with the DEGs. The 16S rRNA V4 gene regions of stool samples were sequenced and processed using the Mothur 1.42.3 pipeline. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the metagenomic functions of different gut microbiota compositions.Results:The mean ages of the HF and HC subjects were 73.50 (SD = 8.33) and 63.19 (SD = 7.75), respectively. HF subjects had significantly higher serum TNF-α levels than HCs (p < 0.05). Among the DEGs, HF subjects had 18 downregulated genes (e.g.,AK5,FAM167A,RGCC, andSARDH) and 3 upregulated genes (SMPD3,TMIGD3, andFRRS1) compared with HCs. TNF signaling (p < 0.01) was one of the significantly different canonical pathways in the DEGs between HF and HCs. HF subjects had significantly enrichedMogibacteriumand diminishedSutterellathan HCs (p < 0.05) and lower P53 signaling pathway activity than HCs (p < 0.05) among the predicted functions in stool samples.Conclusions:By analyzing serum TNF-α, whole transcriptomics, and gut microbiota, we identified higher serum TNF-α, differentially expressed genes (DEGs) and their canonical pathways, and distinct compositions and predicted functions of gut microbiota in older adults with HF compared to healthy controls. These findings suggest that TNF-α signaling may be a potential target for developing precise HF interventions and highlight the need for further large-scale multi-omics analysis in understanding and treating HF.

Circulation, Volume 150, Issue Suppl_1, Page A4140993-A4140993, November 12, 2024. Background:Time-restricted feeding (TRF) is an effective strategy for anti-aging management yet its prophylactic/therapeutic applicability against cardiac aging is unknown.Methods:To assess the effects of TRF on cardiac aging, male mice were randomized into the normal diet+ad libitum feeding (N-ALF), normal diet+TRF (N-TRF), high-fat diet+ALF (H-ALF), high-fat diet+TRF (H-TRF). Metagenomic sequencing was used to investigate the diversity, composition, and evolution of the gut microbiota. The metabolomics was employed to investigate the impact of TRF on the metabolic profile of feces. Using fecal microbiota transplantation, TRF has been validated to delay cardiac aging by optimizing gut microbial composition and function.Results:Compared to the H-ALF group, the H-TRF group showed that the expression of senescence markers p53 and p21 was reduced. In addition, the myocardial interstitial collagen deposition and the expression of collagen I and III were reduced by TRF. Moreover, TRF reduced left ventricular posterior wall dimensions at end-diastole, interventricular septal thickness at end-diastole, and myocardial diastolic function index E/e’ in mice. These suggested that TRF delays high-fat diet-induced cardiac aging. Compared with the H-ALF group, the TRF group exhibited an increase in the alpha diversity of gut microbiota. At the phylum level, the abundance of the Bacteroides was increased by TRF. At the genus level, the abundance of Bacteroides, Parabacteroides, and Akkermansia was increased by TRF. There were 11 characteristic strains in the H-TRF group, six of these strains are closely related to the production of short-chain fatty acids (SCFAs). Function prediction of the differential genes showed an increase in the SCFAs pathway in the H-TRF. LC-MS profiling of feces showed that TRF can reduce the levels of l-tyrosine, l-tryptophan, phenylalanine, valine, indoxyl-sulfate, cholesterol-sulfate, and tetradecanedioic acid in the intestines from high-fat diet mice. TRF increased the levels of 16-oxo-heptadecanoic acid, propionic acid, butyric acid, 2-methylpropionic acid, acetoacetate, succinate, and acetoacetyl-CoA. Using the mice with HFD, those that received gut microbiota from H-TRF showed decreased levels of cardiac senescence markers. It was suggested that gut microbiota plays a crucial role in TRF improving cardiac aging.Conclusions:TRF improves high-fat diet-induced cardiac aging by optimizing the composition and function of gut microbiota.

Circulation, Volume 150, Issue Suppl_1, Page A4113494-A4113494, November 12, 2024. End-stage ischemic heart disease necessitates heart transplantation, and emerging cell therapy presents a promising solution to address donor scarcity. Disruption of gut microbiota significantly influences various diseases and treatments, including transplantation. However, the impact of immunosuppression and cardiac cell therapy on gut microbiota remains largely unexplored. To elucidate this relationship, we investigated gut microbiota dynamics in response to immunosuppression and cell therapy in a nonhuman primate (NHP) cardiac ischemia/reperfusion (IR) model, with controlled genetic, dietary, and environmental factors. Immunosuppression enriched anaerobes (Faecalibacterium, Streptococcus, Anaerovibrio, Dialister), increasing gut microbiota diversity. These changes correlated with metabolic shifts towards amino acid metabolism and nucleosides/nucleotides biosynthesis. Combined treatment of human induced pluripotent stem cell (iPSC)-derived endothelial cells (EC) and cardiomyocytes (CM) also increased gut microbiota diversity, with specific genera alterations. The EC/CM co-treatment group displayed gut microbiota resembling the pre-injury group, with host metabolism shifting towards amino acid and fatty acid/lipid biosynthesis post-cell therapy. These observed microbiota changes and metabolic shifts could serve as biomarkers for monitoring cell therapy and immunosuppression outcomes, offering potential therapeutic targets to enhance efficacy.

Circulation, Volume 150, Issue Suppl_1, Page A4146466-A4146466, November 12, 2024. Background:Without timely intervention, pressure-overloading left ventricular (poLV) remodeling may become progressive and readily degenerate into heart failure. The relative risk is especially high in children with congenital heart disease who are awaiting surgical correction.Aims:The aims of this study were to identify a plasma metabolite that is clinically and mechanically linked to poLV remodeling and heart failure in children and investigate a safe, efficacious treatment that blocks its action.Methods:We used multi-omics including untargeted metabolomics on the plasma of poLV children and neonatal ascending aorta constriction (nAAC) mice, whole-transcriptome resequencing and single-nucleus RNA sequencing of mouse and human LV samples, and metagenomics analysis of mouse gut microbiota to disclose the gut microbiota-kynurenine (Kyn)-remodeling axis. Aryl hydrocarbon receptor (AHR) knockout mice and germ-free (GF) mice as well as fecal microbiota transplantation were used to clarify its mechanism.Results:Abnormally elevated plasma kynurenine (Kyn) was detected in both the patient cohort and the mouse model. Plasma Kyn levels were clinically associated with the cardiac functions and the degree of remodeling. Excessive Kyn induced the hypertrophy and fibrosis phenotypes both in vitro and in vivo, which was blocked by AHR inhibitors and by AHR knockout, respectively. It was demonstrated that Kyn affected both cardiomyocytes and cardiac fibroblasts by promoting AHR nuclear translocation, initiating ADAMTS2 transcription which accelerates hypertrophy, and inducing FN1 and COL1A1 which exacerbate fibrosis. There were significant alterations in the gut microbiota of nAAC mice.Transplantation of nAAC mouse feces to GF mice augmented their Kyn level, indicating the existence of a gut microbiota-Kyn relationship. Oral probiotic supplementation reconstructed the gut microbiota in the nAAC mice, modulated the Kyn-AHR axis, and alleviated poLV remodeling.Conclusions:Plasma Kyn levels were strongly correlated with cardiac remodeling and function in pediatric patients and mice with poLV. Kyn is a pathological signal from an altered gut microbiota to activates AHR and its gene targets in poLV remodeling heart, promoting hypertrophy and fibrosis in respective cells. Oral probiotics reshaped the gut microbiota, lowered Kyn levels, and showed great potential at delaying cardiac remodeling and preventing heart failure.

Circulation, Volume 150, Issue Suppl_1, Page A4141332-A4141332, November 12, 2024. Background:Diabetic cardiomyopathy (DCM) is one of the most serious complications of diabetes mellitus (DM). However, studies exploring the roles of gut microbiome in DM and cardiovascular disease remain limited.Hypothesis:Gut microbiota dysbiosis is associated with the development of DCM.Methods:We collected fecal and serum samples from 18 DCM patients and 13 matched control subjects for metagenomic and metabolomic analysis. Fecal microbiota transplantation (FMT) with samples from both groups was performed on the pseudo-germ-free (PGF) rats. Then, we analyzed rat gut microbiota by 16S rDNA sequencing, and examined cardiac parameters and blood glucose indicators of PGF rats. Serum and myocardium metabolomic analysis was performed on DCM rats and compared with human samples.Results:Linear Discriminant Analysis Effect Size (p＜0.05, LDA≥2.0) of the metagenomics data identified 11 gut microbiota, which can be used as the DCM patient’s biomarkers. After FMT, compared to control-PGF rats, DCM-PGF rats showed significant differences in the composition of gut microbiota (α-diversity, simpsonp=0.015, shannonp=0.011; β-diversity p= 0.005). Moreover, DCM-PGF rats had higher fasting blood glucose levels (p=0.036), intraperitoneal glucose tolerance test showed higher blood glucose levels at 15 and 30 minutes (p=0.000, 0.030), left ventricular (LV) end systolic diameter was larger (p=0.009), diastolic and systolic LV anterior wall thickness, and systolic LV posterior wall thickness were thicker (p=0.011, 0.035, 0.036), fibrosis area was larger (p=0.022). When comparing metabolic profiles of serum of DCM patients, serum of DCM rats and the myocardium of DCM model with the corresponding controls, we identified 2 shared differential metabolites:Hydroxybutyric acidand15,16-DiHODE. Spearman correlation analysis of these two metabolites with differential gut microbiota species in DCM patientsvs.control subjects showed thatHydroxybutyric acidand15,16-DiHODEare strongly correlated with 7 species (p＜0.05, r＞|0.5|) and with 23 species (p＜0.05, r＞|0.5|) respectively.Conclusions:Our study found that DCM patients have their characteristic altered gut microbiota and serum metabolites, which may be responsible for the development of DCM. Gut microbiota is expected to be a potential target for therapeutic intervention in DCM.

This systematic anatomization of gut microbiota revealed the microbial characteristics of PCOS patients, particularly those with different testosterone level, thus laying the foundations for further research into pathogenesis of PCOS, and the development of effective diagnostic, treatment, and intervention strategies.

Objective
Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction.

Design
We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder.

Results
Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species Blautia wexlerae was observed in addicted humans and of Blautia genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour Blautia growth, led to increased relative abundance of Blautia in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of Blautia wexlerae as a beneficial microbe.

Conclusion
By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.

Objective
To decipher the mechanisms by which the major human milk oligosaccharide (HMO), 2’-fucosyllactose (2’FL), can affect body weight and fat mass gain on high-fat diet (HFD) feeding in mice. We wanted to elucidate whether 2’FL metabolic effects are linked with changes in intestinal mucus production and secretion, mucin glycosylation and degradation, as well as with the modulation of the gut microbiota, faecal proteome and endocannabinoid (eCB) system.

Results
2’FL supplementation reduced HFD-induced obesity and glucose intolerance. These effects were accompanied by several changes in the intestinal mucus layer, including mucus production and composition, and gene expression of secreted and transmembrane mucins, glycosyltransferases and genes involved in mucus secretion. In addition, 2’FL increased bacterial glycosyl hydrolases involved in mucin glycan degradation. These changes were linked to a significant increase and predominance of bacterial genera Akkermansia and Bacteroides, different faecal proteome profile (with an upregulation of proteins involved in carbon, amino acids and fat metabolism and a downregulation of proteins involved in protein digestion and absorption) and, finally, to changes in the eCB system. We also investigated faecal proteomes from lean and obese humans and found similar changes observed comparing lean and obese mice.

Conclusion
Our results show that the HMO 2’FL influences host metabolism by modulating the mucus layer, gut microbiota and eCB system and propose the mucus layer as a new potential target for the prevention of obesity and related disorders.

Objective
Probiotic Lactococcus lactis is known to confer health benefits to humans. Here, we aimed to investigate the role of L. lactis in colorectal cancer (CRC).

Design
L. lactis abundance was evaluated in patients with CRC (n=489) and healthy individuals (n=536). L. lactis was isolated from healthy human stools with verification by whole genome sequencing. The effect of L. lactis on CRC tumourigenesis was assessed in transgenic Apc Min/+ mice and carcinogen-induced CRC mice. Faecal microbiota was profiled by metagenomic sequencing. Candidate proteins were characterised by nano liquid chromatography-mass spectrometry. Biological function of L. lactis conditioned medium (HkyuLL 10-CM) and functional protein was studied in human CRC cells, patient-derived organoids and xenograft mice.

Results
Faecal L. lactis was depleted in patients with CRC. A new L. lactis strain was isolated from human stools and nomenclated as HkyuLL 10. HkyuLL 10 supplementation suppressed CRC tumourigenesis in Apc Min/+ mice, and this tumour-suppressing effect was confirmed in mice with carcinogen-induced CRC. Microbiota profiling revealed probiotic enrichment including Lactobacillus johnsonii in HkyuLL 10-treated mice. HkyuLL 10-CM significantly abrogated the growth of human CRC cells and patient-derived organoids. Such protective effect was attributed to HkyuLL 10-secreted proteins, and we identified that α-mannosidase was the functional protein. The antitumourigenic effect of α-mannosidase was demonstrated in human CRC cells and organoids, and its supplementation significantly reduced tumour growth in xenograft mice.

Conclusion
HkyuLL 10 suppresses CRC tumourigenesis in mice through restoring gut microbiota and secreting functional protein α-mannosidase. HkyuLL 10 administration may serve as a prophylactic measure against CRC.

Introduction
The observed alteration of the intestinal microbiota in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the effect of transferring a healthy gut flora from a faecal donor using a faecal microbiota transplantation (FMT) will be explored in this trial.

Methods and analysis
This is a protocol for a randomised, double-blind, placebo-controlled, parallel-group, single-centre trial, with 12 months follow-up. 80 participants will be included and randomised (1:1:2) to either donor FMT (from two different donors) or placebo (autologous FMT). Participants will be included by the International Clinical Criteria for ME/CFS. The clinical measures of ME/CFS and disease activity include Modified DePaul Questionnaire, Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS), 36-Item Short Form Health Survey (SF-36), ROMA IV criteria, Food Frequency Questionnaire, Repeatable Battery for the Assessment of Neuropsychological Status, heart rate variability testing and reports on the use of antibiotics and food supplements, as well as biobanking of blood, urine and faeces.
The primary endpoint is proportion with treatment success in FSS score in donor versus autologous FMT group 3 months after treatment. Treatment success is defined as an FSS improvement of more than 1.2 points from baseline at 3 months after treatment. Adverse events will be registered throughout the study.

Ethics and dissemination
The Regional Committee for Medical Research Ethics Northern Norway has approved the study. The study has commenced in May 2019. Findings will be disseminated in international peer-reviewed journal(s), submitted to relevant conferences, and trial participants will be informed via phone calls.

Trial registration number
NCT03691987.