Gut-derived Metabolites Research Articles

Importance of Gut Microbiota Dysbiosis and Circadian Disruption-Associated Biomarkers in Emergence of Alzheimer's Disease.

Alzheimer's disease (AD) is a major devastating neurodegenerative disorder afflicting majorly the geriatric population. Emerging studies augur the connection of gut dysbiosis and circadian disruption with the early onset of AD. Gut dysbiosis is characterized by dysregulated gut microbiota signature and compromised intestinal integrity, which provokes the translocation of bacterial metabolites into the systemic circulation. Noteworthy, gut-derived metabolites like calprotectin, trimethylamine-N-oxide, kynurenine, isoamylamine, and short-chain fatty acids play a key role in AD pathogenesis. Circadian dysregulation also corresponds with the exacerbated AD pathogenesis by accumulating Aβ and tau proteins. Moreover, circadian dysregulation is one of the causative factors for gut dysbiosis. This review discusses the complex interplay between the microbiota-gut-brain axis, circadian rhythmicity, and the emergence of AD. We reviewed preclinical and clinical studies on AD describing potential biomarkers of gut dysbiosis and circadian dysregulation. The identification of new biomarkers associated with the microbiota-gut-brain axis and circadian rhythmicity may help in early diagnosis and development of targeted therapies for mitigating neurodegenerative AD.

Gut-brain axis and brain health: modulating neuroinflammation, cognitive decline, and neurodegeneration.

The microbiota-gut-brain axis is a pivotal medium of crosstalk between the central nervous system (CNS) and the gastrointestinal tract. It is an intricate network of synergistic molecular pathways that exert their effects far beyond their local vicinity and even affect the systemic functioning of the body. The current review explores the involvement of the gut-brain axis (GBA) in the functioning of the nervous system, with a special emphasis on the neurodegeneration, cognitive decline, and neuroinflammation that occur in Alzheimer's disease (AD) and Parkinson's disease (PD). Gut-derived microbial metabolites play an important role in facilitating this interaction. We also highlighted the complex interaction between gut-derived metabolites and CNS processes, demonstrating how microbial dysbiosis might result in clinical disorders. Short-chain fatty acids have neuroprotective properties, whereas branched-chain amino acids, trimethylamine-N-oxide (TMAO), and tryptophan derivatives such as indole have negative effects at high concentrations. Furthermore, we cover pharmaceutical and nonpharmacological approaches for restoring the gut microbial balance and promoting neurological health. We further expanded on nutritional therapies and lifestyle changes, such as the Mediterranean diet and exercise. Next, we focused on food-controlling habits such as caloric restriction and intermittent fasting. Moreover, interventional techniques such as prebiotics, probiotics, and pharmacological medications have also been utilized to modify the GBA. Historical microbiome research from early discoveries to recent studies linking gut health to cognitive and emotional well-being has increased our understanding of the GBA.

The Gut-Kidney Axis in Chronic Kidney Diseases.

The gut-kidney axis represents the complex interactions between the gut microbiota and kidney, which significantly impact the progression of chronic kidney disease (CKD) and overall patient health. In CKD patients, imbalances in the gut microbiota promote the production of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which impair renal function and contribute to systemic inflammation. Mechanisms like endotoxemia, immune activation and oxidative stress worsen renal damage by activating pro-inflammatory and oxidative pathways. Insights into these mechanisms highlight the impact of gut-derived metabolites, bacterial translocation, and immune response changes on kidney health, suggesting new potential approaches for CKD treatment. Clinical applications, such as dietary interventions, prebiotics, probiotics and fecal microbiota transplantation, are promising in adjusting the gut microbiota to alleviate CKD symptoms and slow disease progression. Current research highlights the clinical relevance of the gut-kidney axis, but further study is essential to clarify these mechanisms' diagnostic biomarkers and optimize therapeutic interventions. This review emphasizes the importance of an integrated approach to CKD management, focusing on the gut microbiota as a therapeutic target to limit kidney injury.

Myokines and Microbiota: New Perspectives in the Endocrine Muscle-Gut Axis.

This review explores the dual role of skeletal muscle as both a mechanical and endocrine organ, highlighting its contributions to overall health and its adaptability to various inputs such as nutrition, hormones, exercise, and injuries. In addition to its role in metabolism and energy conversion, skeletal muscle secretes signalling molecules called myokines (at rest) and exerkines (during/after physical exercise), which communicate with other organs like the brain, the cardiovascular system, and the immune system. Key molecules such as interleukins, irisin, and myostatin are discussed for their roles in mediating muscle health and inter-organ communication. This work also focuses on the muscle-gut axis, emphasising the bidirectional interaction between skeletal muscle and the gut microbiota, a complex ecosystem influencing immune defence, digestion, and metabolism. Muscle activity, particularly exercise, alters the gut microbial composition, promoting beneficial species, while gut-derived metabolites like short-chain fatty acids (SCFAs) impact muscle metabolism, mitochondrial function, and insulin sensitivity. Dysbiosis, or an imbalanced microbiota, can lead to muscle atrophy, inflammation, and metabolic dysfunction. This evidence highlights emerging research into myokines and exerkines as potential therapeutic targets for managing conditions like muscle decline, ageing, and metabolic diseases through muscle-gut interactions.

Kinetics of imidazole propionate from orally delivered histidine in mice and humans

Imidazole Propionate (ImP), a gut-derived metabolite from histidine, affects insulin signaling in mice and is elevated in type 2 diabetes (T2D). However, the source of histidine and the role of the gut microbiota remain unclear. We conducted an intervention study in mice and humans, comparing ImP kinetics in mice on a high-fat diet with varying histidine levels and antibiotics, and assessed ImP levels in healthy and T2D subjects with histidine supplementation. Results show that dietary histidine is metabolized to ImP, with antibiotic-induced gut microbiota suppression reducing ImP levels in mice. In contrast, oral histidine supplementation resulted in increases in circulating ImP levels in humans, whereas antibiotic treatment increased ImP levels, which was associated with a bloom of several bacterial genera that have been associated with ImP production, such as Lactobacilli. Our findings highlight the gut microbiota’s crucial role in regulating ImP and the complexity of translating mouse models to humans.

Bacillus amyloliquefaciens SS1-fermented soybean meal influenced the flesh texture of Nile tilapia: Involvement of microbial metabolite propionate

Microbial fermentation is recognized to improve feed utilization and health of farmed animals. However, its effect on flesh quality and the underlying mechanisms remain understudied. Herein, Bacillus amyloliquefaciens SS1, a probiotic strain isolated from the intestinal tract of Nile tilapia (Oreochromis niloticus) was used to ferment soybean meal (FSM). Two tilapia experimental diets containing FSM and raw soybean meal were formulated for an eight-week feeding trial. Results showed that dietary FSM significantly increased the carcass ratio of fish, while there was no significant difference in weight gain or feed utilization between the two dietary treatments. Texture profile analysis showed that muscle springiness was improved by the FSM diet. There was no discernible difference in myofiber morphology between the two treatments. However, the FSM-fed fish had significantly lower muscle lipid contents than the control, accompanied by suppressed lipogenesis, while lipolysis was promoted both in muscle and liver tissues. Interestingly, the FSM diet modified gut microbial community, resulting in increased propionate concentrations. By establishing a high-fat model using primary hepatocytes of tilapia, we demonstrated the role of propionate in reducing lipid accumulation. Our finding highlights the emerging roles of gut-derived metabolites in affecting flesh quality by modifying host metabolism, providing a foundation for improving the flesh quality of aquaculture fish starting from the feed.

Metagenomics Analysis Reveals Unique Gut Microbiota Signature of Slow-Transit Constipation.

Altered gut microbiota may play a role in slow-transit constipation (STC). We conducted a study of gut microbiota composition and functionality in STC using metagenomic analyses. We assembled a clinical cohort of 24 patients with STC physiology age- and sex-matched to 24 controls. We performed shotgun metagenomic sequencing followed by prediction of metabolite composition from functional profiles. In a middle-aged (mean 55.3 years), predominantly female cohort, there were no significant differences in α-diversity indices, but permutational multivariate analysis of variance analysis showed significant between-group differences (R 2 = 0.050, P < 0.001) between STC patients and controls. Gordonibacter pamelaeae , Bifidobacterium longum , Firmicutes bacterium co-abundance gene group 94, and Anaerotruncus colihominis were more abundant in STC, whereas Coprococcus comes and Roseburia intestinalis were more abundant in controls. Gut-derived metabolites varying in STC relative to controls were related to bile acid and cholesterol metabolism. We found a unique metagenomic and metabolomic signature of STC.

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.

Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia–reperfusion in mice

The kidney is vulnerable to ischemia and reperfusion (I/R) injury that can be fatal after major surgery. Currently, there are no effective treatments for I/R-induced kidney injury. Trimethylamine N-oxide (TMAO) is a gut-derived metabolite linked to many diseases, but its role in I/R-induced kidney injury remains unclear. Here, our clinical data reveals an association between preoperative systemic TMAO levels and postoperative kidney injury in patients after post-cardiopulmonary bypass surgery. By genetic deletion of TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) and dietary supplementation of choline to modulate TMAO levels, we found that TMAO aggravated acute kidney injury through the triggering of endoplasmic reticulum (ER) stress and worsened subsequent renal fibrosis through TGFβ/Smad signaling activation. Together, our study underscores the negative role of TMAO in I/R-induced kidney injury and highlights the therapeutic potential through the modulation of TMAO levels by targeting FMO3, thereby mitigating acute kidney injury and preventing subsequent renal fibrosis.

Gut Microbiome and Microglial Interactions in Neurodegenerative Diseases

The gut microbiome is a diverse ecosystem of trillions of microbes in the gastrointestinal tract. The microbiome has been an area of growing interest as new methods, such as sequencing and culturing techniques, have developed, shedding light on the extensive effects the gut microbiome has on various other body systems. This review focuses on the neurological system and the communication pathways between the gut and brain via the gut-brain axis. Because of the gut-brain axis, a healthy gut environment fosters increased healthiness of the brain, but when the microbiome is imbalanced - a condition called dysbiosis - brain health suffers. When dysbiosis occurs, several negative ramifications occur in various parts of the body. In the brain, microglia cells (innate immune response cells) can express a different phenotype and may be overactivated, resulting in the initiation of proinflammatory pathways. Inflammation in the brain, or neuroinflammation, is a characteristic of many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Complex interactions between the gut microbiome and microglia exist, including how gut-derived metabolites such as trimethylamine oxide and short-chain fatty acids increase microglial activation and neuroinflammation. However, therapeutic approaches targeting microglia and the gut-brain axis through tryptophan metabolites and bile salts mitigate neuroinflammation. Understanding these mechanisms opens potential avenues for reducing neuroinflammation and treating neurodegenerative diseases through the gut microbiome and microglia relationship.

Gut Microbiota Dysbiosis, Oxidative Stress, Inflammation, and Epigenetic Alterations in Metabolic Diseases.

Gut dysbiosis, resulting from an imbalance in the gut microbiome, can induce excessive production of reactive oxygen species (ROS), leading to inflammation, DNA damage, activation of the immune system, and epigenetic alterations of critical genes involved in the metabolic pathways. Gut dysbiosis-induced inflammation can also disrupt the gut barrier integrity and increase intestinal permeability, which allows gut-derived toxic products to enter the liver and systemic circulation, further triggering oxidative stress, inflammation, and epigenetic alterations associated with metabolic diseases. However, specific gut-derived metabolites, such as short-chain fatty acids (SCFAs), lactate, and vitamins, can modulate oxidative stress and the immune system through epigenetic mechanisms, thereby improving metabolic function. Gut microbiota and diet-induced metabolic diseases, such as obesity, insulin resistance, dyslipidemia, and hypertension, can transfer to the next generation, involving epigenetic mechanisms. In this review, we will introduce the key epigenetic alterations that, along with gut dysbiosis and ROS, are engaged in developing metabolic diseases. Finally, we will discuss potential therapeutic interventions such as dietary modifications, prebiotics, probiotics, postbiotics, and fecal microbiota transplantation, which may reduce oxidative stress and inflammation associated with metabolic syndrome by altering gut microbiota and epigenetic alterations. In summary, this review highlights the crucial role of gut microbiota dysbiosis, oxidative stress, and inflammation in the pathogenesis of metabolic diseases, with a particular focus on epigenetic alterations (including histone modifications, DNA methylomics, and RNA interference) and potential interventions that may prevent or improve metabolic diseases.

Abstract Tu022: Gut-derived bacterial metabolites promote cardiac inflammation, leading to heart failure in murine model of DSS-induced colitis

Background: Inflammatory Bowel Disease (IBD) affects millions of people all over the world. This has been known to contribute to several other comorbidities. Recently, impaired gut-barrier permeability has been known to contribute to cardiovascular diseases in IBD patients. However, the precise mechanisms remain unclear. In this study, we propose that bacterial metabolites, like peptidoglycan, may play a role in promoting cardiac inflammation and ultimately leading to heart failure in mice following colitis. Methods: We induced colitis in C57 black mice with DSS (dextran sodium sulfate) treatment. Further, we collected fecal sample for 16s rRNA analysis to evaluate microbial flora. Additionally, heart and intestine tissues were collected to determine inflammatory genes expression (qPCR), immune cell infiltration (FACS), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify the circulating peptidoglycan (PGN) level. The effect of PGN on NFkB inflammatory pathways was evaluated in macrophages. Results: Echo-data showed cardiac dysfunction in DSS mice. Masson’s trichrome staining showed deteriorated intestinal villi, while western blot data indicated decreased Occludin and increased PV-1 level, suggesting a leaky gut in DSS treated mice. Comparative analysis of 16s rRNA sequencing data showed significantly altered Firmicutes/Bacteroidetes ratio in DSS treated mice as compared to control mice. Moreover, plasma PGN level was significantly increased 3 weeks following DSS treatment. Real-time gene expression data of pro-inflammatory cytokines (TNFα) and fibrosis associated genes (col1α1, fibronectin) were increased in DSS mice heart. Increased CD68 expression in the immunostaining data of DSS mice heart suggests the recruitment of inflammatory macrophages. At the molecular level, CDK9 expression was significantly increased in macrophage following PGN treatment, which ultimately leads to an increase in NFkB signaling. Finally, CDK9 inhibition attenuated PGN-induced NFkB signaling. Conclusion: Together, our study suggests that colitis-induced gut leakage leads to CDK9-mediated NFκB upregulation, contributing to cardiac inflammation. Ongoing research will shed light on the underlying molecular mechanisms of cardiovascular dysfunction.

Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1

IntroductionGut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. ObjectivesThis study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. MethodsMetagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. ResultsAlterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin–proteasome degradation, restoring SIRT1′s role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. ConclusionOur findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.

Sex Differences in Cardiovascular Diseases: Exploring the Role of Microbiota and Immunity.

Cardiovascular diseases (CVDs) are the most common cause of mortality and morbidity in Western countries, thus representing a global health concern. CVDs show different patterns in terms of the prevalence and presentation in men and women. The role of sex hormones has been extensively implicated in these sex-specific differences, due to the presence of the menstrual cycle and menopause in women. Moreover, the gut microbiota (GM) has been implicated in cardiovascular health, considering the growing evidence that it is involved in determining the development of specific diseases. In particular, gut-derived metabolites have been linked to CVDs and kidney disorders, which can in turn promote the progression of CVDs. Considering the differences in the composition of GM between men and women, it is possible that gut microbiota act as a mediator in regard to the sex disparities in CVDs. This narrative review aims to comprehensively review the interplay between sex, GM, and CVDs, discussing potential mechanisms and therapeutic options.

Gut-derived metabolite 3-methylxanthine enhances cisplatin-induced apoptosis via dopamine receptor D1 in a mouse model of ovarian cancer.

Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

Involvement of the gut microbiome-brain axis in alcohol use disorder.

The human intestine is colonized by a variety of microorganisms that influence the immune system, the metabolic response, and the nervous system, with consequences for brain function and behavior. Unbalance in this microbial ecosystem has been shown to be associated with psychiatric disorders, and altered gut microbiome composition related to bacteria, viruses, and fungi has been well established in patients with alcohol use disorder. This review describes the gut microbiome-brain communication pathways, including the ones related to the vagus nerve, the inflammatory cytokines, and the gut-derived metabolites. Finally, the potential benefits of microbiota-based therapies for the management of alcohol use disorder, such as probiotics, prebiotics, and fecal microbiota transplantation, are also discussed.

Urinary Equol and Equol-Predicting Microbial Genera Are Favorably Associated with Body Fat Measures among Chinese Adults

BackgroundMany studies have investigated the intake of dietary isoflavones in relation to obesity risk, whereas the association using objective biomarkers of isoflavones, particularly equol (a gut-derived metabolite of daidzein with greater bioavailability than other isoflavones) has been less studied. In addition, the associations between equol and gut microbiota profile at the population level remain to be fully characterized. ObjectivesWe aimed to identify equol-predicting microbial species and to investigate the associations of equol-predicting microbial species and urinary excretion of isoflavones including glycitein, genistein, daidzein, and equol with diverse obesity markers in free living-individuals. MethodsIn this 1-y longitudinal study of 754 community-dwelling adults, urinary isoflavones, fecal microbiota, height, weight, and circumferences of waist and hip were measured at baseline and again after 1 y. Liver fat [indicated by the controlled attenuation parameter (CAP)] and other body composition were also measured after 1 y. Linear models and linear mixed-effects models were used to analyze the associations for single measure and repeated measures, respectively. ResultsAmong 305 participants (median age: 50 y, IQR, 37–59 y) including 138 males and 167 females, higher urinary excretion of equol was associated with lower CAP (β = −0.013, P < 0.001) and body fat mass (β= −0.014, P = 0.046). No association was found between any other urinary isoflavones and obesity markers (all P > 0.05). We identified 21 bacterial genera whose relative abundance were positively associated with urinary equol concentrations (all Pfalsediscovery rate < 0.05), and constructed an equol-predicting microbial score to reflect the overall equol-producing potential of host gut microbiota. This score was inversely associated with CAP (β = −0.040, P = 0.011). ConclusionsHigh urinary equol concentrations and equol-predicting microbial species could be favorably associated with liver fat and other obesity markers.

Gut microbiota and metabolites of cirrhotic portal hypertension: a novel target on the therapeutic regulation.

The regulatory role of gut microbiota and gut-derived metabolites through the gut-liver axis in the development of cirrhotic portal hypertension (PH) has received increasing attention. The review summarized a series of investigations on effects of metabolites derived from microbiota and medicines targeting microbiome including rifaximin, VSL#3, statins, propranolol, FXR agonists as well as drugs derived from bile acids (BAs) on PH progression. Patients with PH exhibit alterations in gut microbial richness and differential overall microbiota community, and several results clearly displayed the correlation of PH with enrichment of Veillonella dispar or depletion of Clostridiales, Peptostreptococcaceae, Alistipes putredinis, Roseburia faecis and Clostridium cluster IV. The gut-derived metabolites including hydrogen sulfide, tryptophan metabolites, butyric acid, secondary BAs and phenylacetic acid (PAA) participate in a range of pathophysiology process of PH through modulating intrahepatic vascular resistance and portal blood flow associated with the formation and progression of PH. Established and emerging drugs targeting on bacterial translocation and intestinal eubiosis are gradually identified as potential strategies for treatments of liver cirrhosis and PH by modulating intestinal inflammation, splanchnic arterial vasodilation and endothelial dysfunction. Future explorations should further characterize the alteration of the fecal microbiome and metabolite profiles in PH and elucidate the regulatory mechanism of the intestinal microbiome, gut-derived metabolites and gut microbiota targeted pharmaceutical treatments involved in PH.

Obesity-associated inflammation countered by a Mediterranean diet: the role of gut-derived metabolites.

The prevalence of obesity has increased dramatically worldwide and has become a critical public health priority. Obesity is associated with many co-morbid conditions, including hypertension, diabetes, and cardiovascular disease. Although the physiology of obesity is complex, a healthy diet and sufficient exercise are two elements known to be critical to combating this condition. Years of research on the Mediterranean diet, which is high in fresh fruits and vegetables, nuts, fish, and olive oil, have demonstrated a reduction in numerous non-communicable chronic diseases associated with this diet. There is strong evidence to support an anti-inflammatory effect of the diet, and inflammation is a key driver of obesity. Changes in diet alter the gut microbiota which are intricately intertwined with human physiology, as gut microbiota-derived metabolites play a key role in biological pathways throughout the body. This review will summarize recent published studies that examine the potential role of gut metabolites, including short-chain fatty acids, bile acids, trimethylamine-N-oxide, and lipopolysaccharide, in modulating inflammation after consumption of a Mediterranean-like diet. These metabolites modulate pathways of inflammation through the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, toll-like receptor 4 signaling, and macrophage driven effects in adipocytes, among other mechanisms.

Effects of resveratrol on changes in trimethylamine-N-oxide and circulating cardiovascular factors following exercise training among older adults

PurposeTrimethylamine-N-oxide (TMAO) is a gut-derived metabolite associated with cardiovascular disease (CVD). In preclinical and observational studies, resveratrol and exercise training have been suggested as potential strategies to reduce the systemic levels of TMAO. However, evidence from experimental studies in humans remains unknown. This project examined the dose-dependent effects of a combined resveratrol intervention with exercise training on circulating TMAO and other related metabolite signatures in older adults with high CVD risk. MethodsForty-one older adults [mean (±SD) age of 72.1 (6.8) years] participated in a 12-week supervised center-based, multi-component exercise training intervention [2×/week; 80 min/session] and were randomized to one of two resveratrol dosages [Low: 500 vs. High:1000 mg/day] or a cellulose-based placebo. Serum/plasma were collected at baseline and post-intervention and evaluated for TMAO and associated analytes. ResultsAfter the 12-week intervention, TMAO concentration increased over time, regardless of treatment [mean (±SD) Placebo: 11262 (±3970); Low:13252 (±1193); High: 12661(±3359) AUC; p = 0.04]. Each resveratrol dose produced different changes in metabolite signatures. Low dose resveratrol upregulated metabolites associated with bile acids biosynthesis (i.e., glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycocholic acid). High dose resveratrol modulated metabolites enriched for glycolysis, and pyruvate, propanoate, β-alanine, and tryptophan metabolism. Different communities tightly correlated to TMAO and resveratrol metabolites were associated with the lipid and vascular inflammatory clinical markers [|r| > 0.4, p < 0.05]. ConclusionThese findings suggest a distinct dose-dependent adaptation response to resveratrol supplementation on circulating metabolite signatures but not on TMAO among high-risk CVD older adults when combined with an exercise training intervention.