Gut Microbiota-derived Metabolites Research Articles

Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO’s aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe–TMAO pathway.

Unraveling the Gut Microbiota: Implications for Precision Nutrition and Personalized Medicine

Recent studies have shown a growing interest in the complex relationship between the human gut microbiota, metabolism, and overall health. This review aims to explore the gut microbiota–host association, focusing on its implications for precision nutrition and personalized medicine. The objective is to highlight how gut microbiota modulate metabolic and immune functions, contributing to disease susceptibility and wellbeing. The review synthesizes recent research findings, analyzing key studies on the influence of gut microbiota on lipid and carbohydrate metabolism, intestinal health, neurobehavioral regulation, and endocrine signaling. Data were drawn from both experimental and clinical trials examining microbiota–host interactions relevant to precision nutrition. Our findings highlight the essential role of gut microbiota-derived metabolites in regulating host metabolism, including lipid and glucose pathways. These metabolites have been found to influence immune responses and gut barrier integrity. Additionally, the microbiota impacts broader physiological processes, including neuroendocrine regulation, which could be crucial for dietary interventions. Therefore, understanding the molecular mechanisms of dietary–microbiota–host interactions is pivotal for advancing personalized nutrition strategies. Tailored dietary recommendations based on individual gut microbiota compositions hold promise for improving health outcomes, potentially revolutionizing future healthcare approaches across diverse populations.

Heat exposure promotes sarcopenia via gut microbiota-derived metabolites.

The unprecedented rise in global ambient temperatures in the last decade has significantly impacted human health, yet how heat exposure affects the development of sarcopenia remains enigmatic. Here, we demonstrate that chronic heat exposure induces skeletal muscle volume loss, leading to muscle strength and functional decline in mice. The microbiota composition of heat-exposed mice was analyzed using 16S ribosomal DNA analysis. Liquid chromatography-mass spectrometry (LC-MS) was used to explore the effects of heat exposure on the blood metabolome and to further analyze the correlation between blood metabolism and gut microbiota. Transplantation of microbiota from heat-exposed mice to germ-free mice was sufficient to increase adverse effects on skeletal muscle function in the host. Mechanistically, using an untargeted metabolomics strategy, we reveal that altered gut microbiota due to high temperatures is associated with elevated serum levels of homocitrulline. Homocitrulline causes mitochondrial dysfunction in myocytes by exacerbating ferroptosis levels. And Nrf2 activator (Oltipraz) supplementation alleviates muscle atrophy and dysfunction induced by heat exposure. Our findings reveal the detrimental effects of heat exposure on muscle function and provide new strategies for treating sarcopenia.

Effects of Phenolic Acids Produced from Food-Derived Flavonoids and Amino Acids by the Gut Microbiota on Health and Disease.

The gut microbiota metabolizes flavonoids, amino acids, dietary fiber, and other components of foods to produce a variety of gut microbiota-derived metabolites. Flavonoids are the largest group of polyphenols, and approximately 7000 flavonoids have been identified. A variety of phenolic acids are produced from flavonoids and amino acids through metabolic processes by the gut microbiota. Furthermore, these phenolic acids are easily absorbed. Phenolic acids generally represent phenolic compounds with one carboxylic acid group. Gut microbiota-derived phenolic acids have antiviral effects against several viruses, such as SARS-CoV-2 and influenza. Furthermore, phenolic acids influence the immune system by inhibiting the secretion of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. In the nervous systems, phenolic acids may have protective effects against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Moreover, phenolic acids can improve levels of blood glucose, cholesterols, and triglycerides. Phenolic acids also improve cardiovascular functions, such as blood pressure and atherosclerotic lesions. This review focuses on the current knowledge of the effects of phenolic acids produced from food-derived flavonoids and amino acids by the gut microbiota on health and disease.

The gut-microbiome derived phenylacetylglutamine predicts adverse events in patients with acute coronary syndromes

Abstract Background and Introduction The gut microbiota-derived metabolite phenylacetylglutamine (PAG) is associated with incident cardiovascular events(1). Acute coronary syndromes (ACS) present a major health challenge, especially as population ages(2). Data from our group show increased PAG levels during aging in humans. However, the predictive potential of PAG for mortality and major adverse cardiovascular events (MACE) in patients (pts) with ACS is unknown. Purpose Here, we investigated the potential of PAG to predict ischemic and fatal events in pts with acute coronary syndromes (ACS). We also compared the predictive potential of PAG to another relevant gut-microbiota derived metabolite involved in CVD, namely Trimethylaminoxyde, (TMAO), and we evaluated their cumulative risk potential. Methods A total of 1’848 patients were enrolled in Cohort I of the SPUM-ACS study – a multi-center prospective ACS cohort study from Switzerland. Overall survival and incident MACE after 1 year follow-up were analyzed using Kaplan-Meier (KM) estimates and compared by log-rank test after patient stratification into PAG tertiles. Uni- and multivariable Cox-regression models were fit to calculate the hazard ratios for 1-year MACE in a crude model and adjusted model (adjusted for established confounders). Healthy controls served as additional controls. PAG plasma levels were quantified using LC-HRMS. Results The median PAG plasma level in the healthy control group was 1.76µM, whereas for the whole ACS patient population it was 1.92µM (Table 1). Pts in the third PAG tertile had a two times higher MACE rate and a four times higher mortality rate compared to pts in the first PAG tertile (p<0.001). (Table 2). PAG levels were significantly higher in pts who presented with MACE (2.63µM) or died (3.1µM) within the 1-year follow-up compared to the healthy control subjects (p<0.0001) (Figure 1A). Spearman correlation analysis revealed that plasma PAG levels were positively associated with age (r=0.43, p<0.0001), while a negative association with eGFR was observed (r=-0.51, p<0.0001) (Figure 1B). KM estimates indicated that pts in the highest PAG tertile had significantly higher 1-year MACE risk relative to those with low levels (Figure 1C; p<0.001 log rank). Following multivariable adjustment, PAG remained an independent predictor for MACE at 1-year follow-up with a hazard ratio (HR) of 1.8 (95% CI, 1.1–3.2, p=0.048) (Figure 1D). KM estimates of both, high levels of PAG and high levels of TMAO together, indicate that the combination of these two detrimental metabolites leads to an even higher risk of 1-year MACE relative to lower levels (Figure 1E). Conclusion PAG is a novel and independent predictor of adverse outcomes in patients with ACS. This study indicates the role of the gut-microbiome and its metabolites in predicting ischemic and fatal outcomes of pts with established CVD.

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p<0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p < 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Gut Microbiota-Derived Metabolites and Their Role in the Pathogenesis of Necrotizing Enterocolitis in Preterm Infants: A Narrative Review

Background: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that occurs predominantly in premature infants and is characterized by the inflammation and necrosis of the intestine, showing high morbidity and mortality rates. Despite decades of research efforts, a specific treatment is currently lacking, and preventive strategies are the mainstays of care. This review aims to help understand the complex interplay between gut microbiota and their metabolites in NEC pathogenesis. In particular, we focused on how these factors can influence gut health, immune responses, and intestinal barrier integrity. Discussion: Current research has increasingly focused on the role of the gut microbiota and their metabolites in NEC pathogenesis, thanks to their involvement in modulating gut health, immune responses, and intestinal barrier integrity. Conclusions: A deeper understanding of the interplay between gut microbiota and their metabolites is essential for developing personalized strategies to prevent NEC. By targeting these microbial interactions, new therapeutic approaches may emerge that offer improved outcomes for preterm infants at a high risk of NEC.

Indole Propionic Acid (IPA), A Gut Microbiota-Derived Metabolite, in Active Pulmonary Tuberculosis (TB) Infection: A Case Control Study

Introduction: A metabolomics study revealed that the tryptophan (Trp) pathway is upregulated in tuberculosis (TB) infection. Indole propionic acid (IPA) is a gut microbiota-derived tryptophan metabolite with antimycobacterial properties through TrpE inhibition and as ligand for AhR in in vitro and in vivo studies. TB infection is associated with gut dysbiosis. However, plasma IPA levels and related factors in active TB patients have not yet been explored. This study aimed to determine the differences and correlations between plasma IPA levels and patient characteristics (age, gender, BMI and GeneXpert result), IPA-producing gut microbiota (Clostridium sporogenes, Lactobacillus sp., and Peptostreptococcus anaerobius), and IFN-γ concentrations in active TB patients and healthy subjects. Materials and methods: A case-control study was performed in 29 active TB patients and 30 healthy controls (HCs) in Aceh, Indonesia. The plasma IPA and IFN-γ levels were measured by ELISA, and the relative abundance of gut microbiota was determined by quantitative PCR (qPCR). The results and discussion: Increased plasma IPA levels (median (IQR) of 22.2 pmol/L (21.3 - 23.9) vs. 18.9 pmol/L (17 - 22.8), p 0.000) were associated with active TB according to the adjusted model (AOR 1.36 (95 % CI 0.37 - 5.1)). Increase of plasma IPA level in higher mycobacterial load patients was found. Higher plasma IPA was positively associated with female, normo- and overweight status, and higher relative abundance of C. sporogenes. The metabolite could be used to discriminate active TB disease at a cutoff of 21.40 pmol/L (72 % sensitivity, 70 % specificity and AUC 0.77). Dysbiosis in IPA-producing bacteria was showed in active TB patients. Conclusion: Plasma IPA could be considered as TB biomarker, and it may also influence disease progression. Future works are needed to validate plasma IPA as biomarker in LTBI and other respiratory infection, as well as its role as biomarker of treatment monitoring response. HIGHLIGHTS The upregulation of the tryptophan (Trp) pathway in tuberculosis infection. Indole propionic acid (IPA) is a Trp metabolite with antimycobacterial properties Higher plasma IPA levels were found in TB patients than in healthy subjects. Dysbiosis of several IPA-producing gut microbiota was revealed in this study. GRAPHICAL ABSTRACT

Scutellarin alleviated ulcerative colitis through gut microbiota-mediated cAMP/PKA/NF-κB pathway

PurposeUlcerative colitis (UC) is a chronic, non-specific inflammatory condition of the colon, characterized by recurrent episodes and a notable lack of effective pharmacological treatments. Scutellarin, a natural component, exhibits appreciable pharmacological effects and therapeutic potential for various diseases. However, its effects on UC are not fully understood, and the precise mechanisms remain to be deciphered. This study aimed to assess the therapeutic efficacy of scutellarin and elucidate its underlying mechanisms in treating UC. MethodsThis study utilized dextran sulfate sodium (DSS)-induced mice to evaluate the therapeutic potential of scutellarin against UC and to elucidate the mechanisms involving the gut microbiota. An antibiotics cocktail (ABX) and fecal microbiota transplantation (FMT) were also used to determine the mechanistic role of the gut microbiota. An integrative approach combining fecal metabolomics and network pharmacology analysis was used to explore the gut microbiota-directed molecular mechanism. ResultsThe results showed that scutellarin provided various therapeutic benefits in UC management, including alleviating weight loss, slowing disease progression, and reducing inflammatory damage in colon structures. The improved gut microbiota after scutellarin administration contributed to these effects. Fecal metabolome revealed that scutellarin selectively mitigated DSS-induced dysregulation of gut microbiota-derived metabolites, including glycolic acid, γ-aminobutyric acid, glutamate, tryptophan, xanthine, and β-hydroxypyruvate. Network pharmacology analysis, along with in vivo experimental verification, implicated the cAMP/PKA/NF-κB pathway in the action of these metabolites in treating UC, which may be the mechanism responsible for scutellarin's curative effects on UC. ConclusionThis study demonstrates the potential of scutellarin in alleviating UC by activating the cAMP/PKA/NF-κB pathway through gut microbiota-derived metabolites, highlighting scutellarin as a promising therapeutic agent for UC.

Clostridium sporogenes-derived metabolites protect mice against colonic inflammation

ABSTRACT Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3+ regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes-derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Gut microbiota-related modulation of immune mechanisms in post-infarction remodelling and heart failure.

The immune system has long been recognized as a key driver in the progression of heart failure (HF). However, clinical trials targeting immune effectors have consistently failed to improve patient outcome across different HF aetiologies. The activation of the immune system in HF is complex, involving a broad network of pro-inflammatory and immune-modulating components, which complicates the identification of specific immune pathways suitable for therapeutic targeting. Increasing attention has been devoted to identifying gut microbial pathways that affect cardiac remodelling and metabolism and, thereby impacting the development of HF. In particular, gut microbiota-derived metabolites, absorbed by the host and transported to the peripheral circulation, can act as signalling molecules, influencing metabolism and immune homeostasis. Recent reports suggest that the gut microbiota plays a crucial role in modulating immune processes involved in HF. Here, we summarize recent advances in understanding the contributory role of gut microbiota in (auto-)immune pathways that critically determine the progression or alleviation of HF. We also thoroughly discuss potential gut microbiota-based intervention strategies to treat or decelerate HF progression.

The potential influence and intervention measures of gut microbiota on sperm: it is time to focus on testis-gut microbiota axis.

As the global male infertility rate continues to rise, there is an urgent imperative to investigate the underlying causes of sustained deterioration in sperm quality. The gut microbiota emerges as a pivotal factor in host health regulation, with mounting evidence highlighting its dual influence on semen. This review underscores the interplay between the Testis-Gut microbiota axis and its consequential effects on sperm. Potential mechanisms driving the dual impact of gut microbiota on sperm encompass immune modulation, inflammatory responses mediated by endotoxins, oxidative stress, antioxidant defenses, gut microbiota-derived metabolites, epigenetic modifications, regulatory sex hormone signaling. Interventions such as probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and Traditional natural herbal extracts are hypothesized to rectify dysbiosis, offering avenues to modulate gut microbiota and enhance Spermatogenesis and motility. Future investigations should delve into elucidating the mechanisms and foundational principles governing the interaction between gut microbiota and sperm within the Testis-Gut microbiota Axis. Understanding and modulating the Testis-Gut microbiota Axis may yield novel therapeutic strategies to enhance male fertility and combat the global decline in sperm quality.

Edible plant oils modulate gut microbiota during their health-promoting effects: a review.

Edible plant oils are widely used in cooking, cosmetics, health supplement capsules, and other industries, due to their various health-promoting effects. There is increasing evidence that edible plant oils can modulate gut microbiota during their health-promoting effects in animal experiments and cohort or clinical studies. However, the information concerning the gut microbiota modulation of edible plant oils during their health-promoting effects is scattered. In this article, the research progress on gut microbiota modulation of edible plant oils (especially camellia oil, olive oil, and flaxseed oil) is summarized. Meanwhile, a summary on correlations between modulated gut microbiota and changed biochemical indexes is provided. The alterations of edible plant oils on gut microbiota-derived metabolites and the correlations between altered metabolites and modulated gut microbiota as well as changed biochemical indexes are reviewed. Furthermore, the prospects for gut microbiota modulation of edible plant oils during their health-promoting effects are put forward. Existing literature has shown that edible plant oils could modulate gut microbiota during their health-promoting effects, and some differential gut microbiota biomarkers were gained. Some similarities and differences existed while the oils exhibited health-promoting actions. Dosage and treatment time have influences on gut microbiota modulation of edible plant oils. Different edible plant oils exhibited different behaviors in modulating gut microbiota, and edible plant oils were mostly different in modulating gut microbiota compared to edible animal oils. Moreover, the modulated gut microbiota was significantly correlated with the changed biochemical indexes. Furthermore, edible plant oils altered SCFAs and other gut microbiota-derived metabolites. The altered metabolites were obviously correlated with the modulated gut microbiota and changed biochemical indexes. This review is helpful to the future research and application of edible plant oils in health-promoting effects from the perspective of gut microbiota.

Explore the mechanism of mulberry leaf combined with gut microbiota to improve hyperlipidemia based on network pharmacology

PurposeTo elucidate the underlying mechanisms by which mulberry leaves, in conjunction with gut microbiota, ameliorate hyperlipidemia and identify key gut microbial taxa involved, a mulberry leaf/gut microbiota-active components-metabolites-target-pathway network was constructed.MethodologyInformation on active constituents of mulberry leaves, metabolites generated by gut microbiota, and target proteins associated with hyperlipidemia were retrieved from multiple databases. Employing bioinformatics tools, relevant pathways and targets involved in the synergistic effect of mulberry leaves and gut microbiota on hyperlipidemia improvement were systematically analyzed. Through multi-level data analysis and integration of existing knowledge on the interplay between mulberry leaves, gut microbiota, and hyperlipidemia, the atherosclerosis signaling pathway was identified as the central pathway, with AKT1 as the core target protein. Based on metabolites produced by gut microbiota that act on AKT1, 29 specific gut microbial strains were found to exhibit synergistic action within the context of mulberry leaf-mediated hyperlipidemia alleviation. This culminated in the establishment of a comprehensive mulberry leaf/gut microbiota-active components-metabolites-target-pathway network. Moreover, molecular docking and visualization analyses demonstrated stable interactions between the selected gut microbiota-derived metabolites and the central target AKT1.ConclusionThese findings provide a robust scientific basis for the application of mulberry leaf-based formulations combined with probiotics in the development of specialized medical foods targeting hyperlipidemia, grounded in the elucidated molecular mechanisms and identified key gut microbial players.

Dietary curcumin supplementation enhances growth performance and anti-inflammatory functions by modulating gut microbiota, microbiota-derived metabolites, and expression of inflammation-related genes in broilers.

Curcumin (CUR) is a natural polyphenolic substance that has been widely used since ancient times for its multiple beneficial functions. However, whether CUR affects growth performance of broilers by altering gut microbiota and metabolite and the underlying mechanism are largely unknown. This study was conducted to evaluate the effect of dietary CUR supplementation on growth performance, anti-inflammatory function, intestinal morphology and barrier, cecum microbiota and metabolite profile of broilers. Sixty 1-day-old male broilers were randomly divided into control group (CON, fed a control diet) and CUR group (fed a control diet supplemented with 200mg/kg CUR) after 2 days of adaptation. Results showed that after feeding to 52-day-old, compared with CON broilers, the CUR broilers showed improved feed utilization efficiency and growth performance. Furthermore, the CUR broilers showed an improved intestinal morphology, which was demonstrated by a lower crypt depth in the jejunum. The 16S rRNA gene sequencing and non-targeted metabonomics (LC-MS/MS) analysis results showed that the cecum microbiota ecology and function were significantly improved, and the abundance of beneficial flora and metabolites were increased, while the harmful bacteria and metabolites were significantly decreased. In addition, RT-qPCR results showed that CUR significantly reduced inflammatory responses, promoted the formation of the mucosal barrier and enhanced digestion, absorption and transport of lipids and glucose related genes expression in the intestine. These above findings demonstrated that dietary CUR supplementation improved growth performance, intestinal morphology and anti-inflammatory functions, mainly by manipulating cecum microbiota and microbiota-derived metabolites, which provides a credible explanation for the growth-promoting effect and anti-inflammatory functions of CUR and aids our understanding of the mechanisms underlying.

The gut microbiota in thrombosis.

The gut microbiota has emerged as an environmental risk factor that affects thrombotic phenotypes in several cardiovascular diseases. Evidence includes the identification of marker species by sequencing studies of the gut microbiomes of patients with thrombotic disease, the influence of antithrombotic therapies on gut microbial diversity, and preclinical studies in mouse models of thrombosis that have demonstrated the functional effects of the gut microbiota on vascular inflammatory phenotypes and thrombus formation. In addition to impaired gut barrier function promoting low-grade inflammation, gut microbiota-derived metabolites have been shown to act on vascular cell types and promote thrombus formation. Therefore, these meta-organismal pathways that link the metabolic capacities of gut microorganisms with host immune functions have emerged as potential diagnostic markers and novel drug targets. In this Review, we discuss the link between the gut microbiota, its metabolites and thromboembolic diseases.

Gut microbiota-derived Metabolite, Shikimic Acid, inhibits vascular smooth muscle cell proliferation and migration

Gut microbiota dysbiosis is linked to vascular wall disease, but the mechanisms by which gut microbiota cross-talk with the host vascular cells remain largely unknown. Shikimic acid (SA) is a biochemical intermediate synthesized in plants and microorganisms, but not mammals. Surprisingly, recent metabolomic profiling data demonstrate that SA is detectable in human and murine blood. In this study, analyzing data from germ-free rats, we provide evidence in support of SA as a bona fide gut microbiota-derived metabolite, emphasizing its biological relevance. Since vascular cells are the first cells exposed to circulating metabolites, in this study, we examined, for the first time, the effects and potential underlying molecular mechanisms of SA on vascular smooth muscle cell (VSMC) proliferation and migration, which play a key role in occlusive vascular diseases, such as post-angioplasty restenosis and atherosclerosis. We found that SA inhibits the proliferation and migration of human coronary artery SMCs. At the molecular level, unexpectedly, we found that SA activates, rather than inhibits, multiple pro-mitogenic signaling pathways in VSMCs, such as ERK1/2, AKT, and mTOR/p70S6K. Conversely, we found that SA activates the anti-proliferative AMP-activated protein kinase (AMPK) in VSMCs, a key cellular energy sensor and regulator. However, loss-of-function experiments demonstrate that AMPK does not mediate the inhibitory effects of SA on VSMC proliferation. In conclusion, these studies demonstrate that a microbiota-derived metabolite, SA, inhibits VSMC proliferation and migration in vitro and prompt further evaluation of the possible underlying molecular mechanisms and the potential protective role in VSMC-related vascular wall disease in vivo.

Analysis of gut microbiota-derived metabolites regulating pituitary neuroendocrine tumors through network pharmacology.

Pituitary neuroendocrine tumors (PitNETs) are a special class of tumors of the central nervous system that are closely related to metabolism, endocrine functions, and immunity. In this study, network pharmacology was used to explore the metabolites and pharmacological mechanisms of PitNET regulation by gut microbiota. The metabolites of the gut microbiota were obtained from the gutMGene database, and the targets related to the metabolites and PitNETs were determined using public databases. A total of 208 metabolites were mined from the gutMGene database; 1,192 metabolite targets were screened from the similarity ensemble approach database; and 2,303 PitNET-related targets were screened from the GeneCards database. From these, 392 overlapping targets were screened between the metabolite and PitNET-related targets, and the intersection between these overlapping and gutMGene database targets (223 targets) were obtained as the core targets (43 targets). Using the protein-protein interaction (PPI) network analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway and metabolic pathway analysis, CXCL8 was obtained as a hub target, tryptophan metabolism was found to be a key metabolic pathway, and IL-17 signaling was screened as the key KEGG signaling pathway. In addition, molecular docking analysis of the active metabolites and target were performed, and the results showed that baicalin, baicalein, and compound K had good binding activities with CXCL8. We also describe the potential mechanisms for treating PitNETs using the information on the microbiota (Bifidobacterium adolescentis), signaling pathway (IL-17), target (CXCL8), and metabolites (baicalin, baicalein, and compound K); we expect that these will provide a scientific basis for further study.

The Associations Among Gut Microbiota, Branched Chain Amino Acids, and Parkinson's Disease: Mendelian Randomization Study.

In experimental and observational studies, the characteristics of gut microbiota have been associated with Parkinson's disease (PD), among which metabolic pathways played an important role. However, the causality remained unclear. Herein, we aimed to determine the potential impact of gut microbiota and gut microbiota-derived metabolites on PD risk using a Mendelian randomization (MR) approach. We included as exposures gut microbial taxa abundance and gut-derived metabolites (branched chain amino acids [BCAAs]), with PD as the outcome. In addition, we explored whether BCAAs act as a mediating factor in the pathway from gut microbiota to PD. We found evidence of a causality of 15 microbial taxa and PD before and after sensitivity analyses, but not after multiple testing correction. There was significant association between BCAAs levels and the risk of PD, especially isoleucine (OR = 0.995, 95% CI 0.992-0.999, p = 0.004, pFDR = 0.012). In addition, the causality of gut microbiota and BCAAs was also explored that the increased g_Coprococcus abundance can result in the decrease in isoleucine level (OR = 1.046; 95% CI, 1.009-1.085; p = 0.016). Our findings indicated suggestive association between gut microbiota and its metabolites and PD. Furthermore, higher BCAAs levels were associated with the decreased PD risk. This study may provide new targets for PD treatment, such as dietary BCAAs supplementation.

Inhibition of the NF-κB/HIF-1α signaling pathway in colorectal cancer by tyrosol: a gut microbiota-derived metabolite

BackgroundThe development and progression of colorectal cancer (CRC) are influenced by the gut environment, much of which is modulated by microbial-derived metabolites. Although some research has been conducted on the...