Search Results (206)

Growth differentiation factor-15 (GDF-15) is an established marker of oxidative stress and a general stress-response mitokines. In this study, we aim to investigate the association of GDF-15 with the metabolic signature of gut and mitochondrial activity in HF and ageing population. A total of 25 HF (67.9 ± 10.0 years) and 29 age-matched healthy participants (HPs) (67.8 ± 11.1 years) were recruited and underwent detailed body composition assessment via dual X-ray absorptiometry; total fat mass and appendicular lean soft tissue index (ALSTI/body mass index (BMI)) were calculated. Utilizing semi-targeted Gas Chromatography–Mass Spectrometry on fasting plasma, a panel of gut microbial-derived (e.g., hippuric acid, indole derivatives, and sarcosine) and tricarboxylic acid cycle metabolites was identified. Results showed higher GDF-15 tertiles were associated with greater HF prevalence, fat mass, NT-proBNP, and TNF-α (p < 0.05). Gut-derived metabolites exhibited phenotype-specific patterns; 3-hydroxyindole predicted higher fat mass in HP; hippuric acid was inversely related in HF; and sarcosine correlated with GDF-15 only in HP. In HF, GDF-15 was strongly driven by pyruvic and fumaric acid, indicating disease-specific mitochondrial stress. In conclusion, these observed associations could be evaluated in future mechanistic studies as sensitive biomarkers of systemic oxidative stress markers, informing potential microbiome-targeted therapeutic avenues. Full article

Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies. Full article

Background: The heart depends on a continuous and flexible energy supply from fatty acids, glucose, and other substrates. Emerging evidence shows that gut microbiota-derived metabolites—such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), secondary bile acids, indoles, phenylacetylglutamine (PAGln), and branched-chain amino acids—modulate cardiac metabolism and function. Although clinical evidence linking these metabolites to cardiovascular outcomes is expanding, most data remain associative, with limited causal or interventional proof. Methods: A comprehensive narrative review was conducted (PubMed 2010–2025) to integrate preclinical, clinical, and Mendelian randomization studies on microbiota-derived metabolites and cardiovascular disease, complemented by evidence from dietary and interventional trials. Results: Gut-derived metabolites regulate mitochondrial energetics, inflammatory, immune system, and oxidative pathways, and endothelial and platelet activation. Elevated plasma TMAO and PAGln levels are often associated with adverse cardiovascular outcomes, while SCFAs and indole derivatives may related to protective effects. However, findings across cohorts remain heterogeneous, largely due to differences in diet, renal function, and analytical methods. Dietary patterns rich in fiber and plant-based nutrients favor beneficial metabolite profiles, underscoring the nutritional modulation of the gut–heart axis. Conclusions: The diet–microbiota–metabolite axis represents an emerging pathway connecting nutrition to cardiovascular health. Translating this knowledge into prevention and therapy will require large-scale randomized studies and integrated multi-omics approaches. Dietary modulation of microbial metabolism may ultimately become a novel strategy for cardiometabolic protection. Full article

Chronic Kidney Disease (CKD) and Colorectal Cancer (CRC) share a profound epidemiological link, supported by Mendelian randomization studies suggesting causality. This review articulates a refined Gut–Kidney Axis, focusing on the pathophysiology of indole-derived uremic toxins. CKD-induced dysbiosis drives hepatic synthesis and systemic accumulation of indoxyl sulfate, which is proposed to promote carcinogenesis via Aryl Hydrocarbon Receptor (AhR) and Akt signaling, ultimately upregulating c-Myc and EGFR. We propose a two-compartment model: while systemic indoxyl sulfate reflects the total gut indole pool (mainly from planktonic bacteria), adherent bacteria like Fusobacterium nucleatum may create high-concentration indole hotspots within the tumor microenvironment. Clinically, we advocate for protein-independent DNA methylation biomarkers (SEPT9, SDC2) to avoid renal confounding. Furthermore, we propose a novel diagnostic panel integrating serum indoxyl sulfate (systemic load) and urinary indoxyl sulfate (gut production) to guide therapy. Therapeutically, targeting upstream drivers (AhR/Akt) may bypass resistance to anti-EGFR therapies in KRAS-mutated tumors. We also discuss the repurposing of the oral adsorbent AST-120 and emerging bacteriophage therapies as strategies to disrupt this oncogenic axis. This review offers a comprehensive framework for stratified management of CKD-associated CRC. Full article

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) share key molecular features, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss. Increasing evidence indicates that gut dysbiosis and alterations in microbiota-derived metabolites are involved in these processes through multiple pathways along the gut–brain axis. However, while broad compositional changes are well-documented, a critical knowledge gap remains regarding the specific biochemical signal transduction pathways translating dysbiosis into pathology. This narrative review addresses this gap by synthesizing current human and experimental studies addressing gut microbiota alterations in AD, PD, and ALS, with particular emphasis on the biochemical and molecular mechanisms mediated by gut-derived metabolites. Dysbiosis in neurodegenerative diseases is frequently associated with reduced abundance of short-chain fatty acid (SCFA)-producing bacteria and altered metabolism of SCFAs, bile acids, tryptophan-derived indoles, trimethylamine-N-oxide (TMAO), and lipopolysaccharides (LPS). These microbial metabolites have been shown to modulate intestinal and blood–brain barrier integrity, influence Toll-like receptor- and G protein-coupled receptor-dependent signaling, regulate microglial activation, and affect molecular pathways related to protein aggregation in experimental models. In addition, emerging evidence highlights the involvement of oxidative and nitrosative stress, immune–metabolic crosstalk, and altered xenobiotic metabolism in microbiota–host interactions during neurodegeneration. By integrating microbiological, metabolic, and molecular perspectives, this review underscores the important and emerging role of microbiota-derived molecules in neurodegenerative disorders and outlines key chemical and metabolic pathways that may represent targets for future mechanistic studies and therapeutic strategies. Full article

Melatonin, an indolic neuromodulator with putative oncostatic and proposed anti-inflammatory properties, primarily demonstrated in preclinical models, is produced at extrapineal sites—most notably in the gut. Its canonical actions are mediated by high-affinity GPCRs (MT1/MT2) and by NQO2, a cytosolic enzyme with a melatonin-binding site (historically termed “MT3”). A growing body of work highlights a bidirectional interaction between the gut microbiota and host melatonin. We integrated two lines of work: (i) three clinical cohorts—cardiac arrhythmias (n = 111; 46–75 y), epilepsy (n = 77; 20–59 y), and stage III–IV solid cancers (25–79 y)—profiled with stool 16S rRNA sequencing, SCFA measurements, and circulating melatonin/urinary 6-sulfatoxymelatonin and (ii) an age-spanning cognitive cohort with melatonin phenotyping, microbiome analyses, and exploratory immune/metabolite readouts, including a novel observation of melatonin binding on bacterial membranes. Across all three disease cohorts, we observed moderate-to-severe dysbiosis, with reduced alpha-diversity and shifted beta-structure. The core dysbiosis implicated tryptophan-active taxa (Bacteroides/Clostridiales proteolysis and indolic conversions) and depletion of SCFA-forward commensals (e.g., Faecalibacterium, Blautia, Akkermansia, and several Lactobacillus/Bifidobacterium spp.). Synthesised literature indicates that typical human gut commensals rarely secrete measurable melatonin in vitro; rather, their metabolites (SCFAs, lactate, and tryptophan derivatives) regulate host enterochromaffin serotonin/melatonin production. In arrhythmia models, dysbiosis, bile-acid remodelling, and autonomic/inflammatory tone align with melatonin-sensitive antiarrhythmic effects. Epilepsy exhibits circadian seizure patterns and tryptophan–metabolite signatures, with modest and heterogeneous responses to add-on melatonin. Cancer cohorts show broader dysbiosis consistent with melatonin’s oncostatic actions. In the cognitive cohort, the absence of dysbiosis tracked with preserved learning across ages, and exploratory immunohistochemistry suggested melatonin-binding sites on bacterial membranes in ~15–17% of samples. A unifying microbiota–tryptophan–melatonin axis plausibly integrates circadian, electrophysiologic, and immune–oncologic phenotypes. Practical levers include fiber-rich diets (to drive SCFAs), light hygiene, and time-aware therapy, with indication-specific use of melatonin. Our conclusions regarding microbiota–melatonin crosstalk rely primarily on local paracrine effects within the gut mucosa (where melatonin concentrations are 10–400× plasma levels), whereas systemic chronotherapy conclusions depend on circulating melatonin amplitude and phase. This original research article presents primary data from four prospectively enrolled clinical cohorts (total n = 577). Full article

Reproductive performance in livestock and poultry is a core determinant of economic efficiency in the animal industry. While traditional research has primarily focused on genetics, endocrinology, and immune regulation, emerging microbiome studies reveal that commensal microbiota within the gut and reproductive tracts play an underestimated yet pivotal role in host reproductive health. This review systematically synthesizes recent advances regarding the relationship between the microbiome and reproductive functions in major livestock species (cattle, pigs, sheep, and chickens). We first delineate the theoretical basis and mechanisms of the “gut-reproductive axis,” highlighting cross-system communication mediated by microbial metabolites, including short-chain fatty acids (SCFAs), indoles, and bile acids. Subsequently, we provide an in-depth comparative analysis of the microecological features of both female (vagina/uterus) and male (semen/epididymis) reproductive systems, examining their impacts on fertility, sperm quality, and pregnancy outcomes. Furthermore, we explore the molecular and systemic mechanisms governing microbial regulation of reproduction, encompassing the modulation of the hypothalamic-pituitary-gonadal (HPG) axis, the balance of local mucosal immunity and inflammation, and epigenetic regulation. Finally, we address current challenges—such as causal validation and the scarcity of multi-species databases—and propose future directions, including spatial multi-omics, AI-integrated analysis, and microbial intervention strategies. Ultimately, this review aims to offer a theoretical foundation and translational insights for elucidating reproductive regulatory networks and developing microbiome-driven precision strategies to enhance reproductive performance. Full article

P-cresol, indole and indole-3-acetic acid (IAA) are catabolites of amino acids, formed by the gut microbiome. Most of these aromatic hydrocarbon derivatives are excreted by the colon before reentering the body to form “exogenous” protein-bound uremic toxins (PBUTs), which aggravate chronic kidney disease (CKD). Removal efficiencies of these PBUT precursors from model phosphate-buffered saline solutions by three different surface-modified nanoporous carbon adsorbents (PCs) were studied. PCs were produced by physicochemical and/or acid base activation of carbonized rice husk waste. Removal rates achieved values of 32–96% within a 3 h contact time. High micro/mesoporosity and surface chemistry of the N- and P-doped biochars were established by N₂ adsorption studies, SEM/EDS analysis, XPS and FT-IR-spectroscopy. The ammoxidized PC-N1 had the highest adsorption capacity (1.97 mmol/g for IAA, 2.43 mmol/g for p-cresol and 2.42 mmol/g for indole), followed by “urea-nitrified” PC-N2, whilst the phosphorylated PC-P demonstrated the lowest adsorption capacity for these solutes. These results do not correlate with the total pore volume values for PC-N2 (0.91 cm³/g) < PC-P (1.56 cm³/g) < PC-N1 (1.84 cm³/g), suggesting that other parameters such as the micropore volume (PC-N1 > PC-N2 > PC-P) and the interaction of surface chemical functional groups with the solutes play key roles in the adsorption mechanism. N-doped PC-N1 and PC-N2 have basic functional groups with higher affinity with acidic IAA and p-cresol. The ion-exchange mechanism of phenolic and indolic compound chemisorption by nanoporous carbon adsorbents, modified with surface N- and P-containing functional groups, has been proposed. Full article

Background: Gut barrier dysfunction and altered gut microbial metabolism are emerging signatures of chronic gut disorders. Considering growing interest in combining structurally and mechanistically distinct bioactives, we investigated the individual and combined effects of serum-derived bovine immunoglobulin (SBI) and N-acetylglucosamine (NAG) on the gut microbiome and barrier integrity. Methods: The validated ex vivo SIFR^® (Systemic Intestinal Fermentation Research) technology, using microbiota from healthy adults (n = 6), was combined with a co-culture of epithelial/immune (Caco-2/THP-1) cells. Results: While SBI and NAG already significantly improved gut barrier integrity (TEER, transepithelial electrical resistance, +21% and +29%, respectively), the strongest effect was observed for SBI_NAG (+36%). This potent combined effect related to the observation that SBI and NAG each induced distinct, complementary shifts in microbial composition and metabolite output. SBI most selectively increased propionate (~Bacteroidota families) and health-associated indole derivatives (e.g., indole-3-propionic acid), while NAG most specifically boosted acetate and butyrate (~Bifidobacteriaceae, Ruminococcaceae, and Lachnospiraceae). The combination of SBI_NAG displayed effects of the individual ingredients, thus, for instance, enhancing all three short-chain fatty acids (SCFA) and elevating microbial diversity (CMS, community modulation score). Conclusions: Overall, SBI and NAG exert complementary, metabolically balanced effects on the gut microbiota, supporting combined use, particularly in individuals with gut barrier impairment or dysbiosis linked to lifestyle or early-stage gastrointestinal disorders. Full article

Chronic kidney disease (CKD), which affects over 850 million individuals globally, is increasingly regarded as a systemic condition in which the gut microbiota represents a key pathogenic node. This review provides an integrated overview of mechanistic, translational and clinical data implicating the gut–kidney axis in CKD. The CKD-associated microbiota displays a characteristic dysbiosis, marked by depletion of short-chain fatty acid–producing commensals, overgrowth of proteolytic and urease-expressing taxa and disruption of epithelial barrier integrity. These disturbances favor the generation and systemic accumulation of gut-derived uremic toxins, most notably indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid and trimethylamine-N-oxide, which promote endothelial dysfunction, vascular calcification, fibrosis and chronic inflammation, thereby hastening renal function loss and heightening cardiovascular risk. Microbiome-directed interventions, including dietary modification, prebiotics, probiotics, synbiotics, intestinal dialysis, fecal microbiota transplantation, gut-acting sorbents and nephroprotective phytochemicals, are summarized with emphasis on their effects on uremic toxin burden and clinical surrogates. System-level implications of the gut–kidney axis for cardiovascular disease, immunosenescence and sarcopenia are discussed, together with future priorities for integrating multi-omics profiling and precision microbiome-based strategies into nephrology practice. Full article

Background: Polysaccharides modulate host health by interacting with gut microbiota and reshaping the host–microbial metabolome, potentially facilitating immune regulation. Methods: This study evaluated the modulatory effect of Artocarpus heterophyllus Lam. (jackfruit) polysaccharide (JFP-Ps) against cyclophosphamide (Cy)-induced immunosuppression in mice, focusing on gut microbiota modulation and metabolite changes. Results: JFP-Ps effectively increased the beneficial bacteria ratio, such as Lactobacillus and Lachnospiraceae, while inhibiting some species like Akkermansia. Metabolomic analysis showed that JFP-Ps notably regulated gut microbe-associated metabolites, including short-chain fatty acids (SCFAs), amino acids, bile acids, indoles, and derivatives. These metabolites were involved in various metabolic pathways, including primary bile acid synthesis and biosynthesis of phenylalanine, tyrosine, and tryptophan, along with tryptophan catabolism, purine metabolic processes, and unsaturated fatty acid production. Additionally, significant correlations between microbial groups and functional metabolites were identified. Overall, JFP-Ps exerted an immuno-modulatory effect by reshaping gut microbiota and enhancing co-metabolism with the host. Conclusions: These results provided valuable insights into host–microbiota interactions and gut microbiota-targeted intervention strategies of tropical natural bioactive polysaccharides. Full article

Background: Asthma and atherosclerosis frequently coexist in clinical populations and share convergent immunometabolic pathways amplified by gut microbial dysbiosis. We propose the gut–lung–vascular axis as a unifying mechanistic framework connecting epithelial and endothelial inflammation providing a foundation for understanding shared inflammatory mechanisms beyond tissue-specific disease boundaries. Methods: A targeted narrative review systematically appraised clinical, experimental and multi-omics studies published over the last five years to delineate microbiota-driven pathways relevant to asthma and atherosclerosis. Particular emphasis was placed on specific microbial taxa, metabolite profiles and immunometabolic networks that connect gut dysbiosis with respiratory and cardiovascular dysfunction. Results: Across human and experimental cohorts, dysbiosis marked by depletion of short-chain fatty acids (SCFAs) producing taxa (Faecalibacterium, Roseburia, Bacteroides) and enrichment of pathobionts (Proteobacteria, Haemophilus, Moraxella, Streptococcus) promotes epithelial and endothelial barrier dysfunction, amplifying Th2/Th17-skewed inflammation and endothelial injury. Key metabolites, including SCFAs, trimethylamine N-oxide (TMAO), secondary bile acids (BA), indole/tryptophan derivatives and lipopolysaccharides (LPS), serve as molecular connectors linking gut, airway and vascular inflammation. Microbial signatures and metabolomic patterns hold emerging diagnostic and therapeutic potential, and several drug classes (e.g., statins, corticosteroids, proton-pump inhibitors (PPIs)) further modulate host–microbiota interactions. Conclusions: Shared microbial taxa and metabolite signatures in asthma and atherosclerosis support microbiota-mediated immune dysregulation along the gut–lung–vascular axis as a common pathogenic framework. Microbial and metabolite profiling may enable improved risk stratification and precise, microbiota-targeted therapies. Integrating microbiome-informed diagnostics and personalized interventions could help reduce systemic inflammation and the burden of these overlapping inflammatory diseases. Full article

Hepatocellular carcinoma (HCC) is a global health threat, and gut microbiota play a pivotal role in its pathogenesis through the gut–liver axis. However, the literature contains divergent or opposing findings: key microbial metabolites, such as secondary bile acids and indole derivatives, exhibit potent pro- and anti-tumorigenic activities across different studies, hindering a unified understanding of their veritable roles. To resolve this ambiguity, this review proposes a unifying “context dependency” framework. We posit that the functions of gut microbiota and their metabolites are not fixed but are dynamically determined by the host’s physiological and pathological “context,” defined here as the integrated dynamic background shaped by local metabolite concentrations, host immune status, specific receptor expression, and tumor microenvironment (TME) features. This framework is systematically substantiated through an analysis of the dichotomous effects of major microbial metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and indole derivatives. We further elucidate that the key “contextual factors” governing these functional outcomes include the TME, host immune status, metabolite concentration gradients, and the activation patterns of specific signaling pathways (e.g., farnesoid X receptor/takeda G protein-coupled receptor 5, aryl hydrocarbon receptor). This novel framework not only provides a theoretical foundation for integrating existing paradoxical findings but also paves the way for the future development of context-specific precision diagnostic biomarkers and targeted microbial intervention therapies for HCC. Full article

Biofilms are more than just structural microbial communities. They are dynamic chemical ecosystems that synthesize a range of extracellular compounds involved in functions that extend beyond biofilm architecture. From quorum-sensing molecules like acyl-homoserine lactones (AHLs) to short-chain fatty acids (SCFAs), phenazines, indoles, and reactive sulfur species (RSS), biofilm-derived metabolites can impact the physiology and behavior of microorganisms living in the same ecosystem, including other bacteria and protozoa. It has recently been demonstrated that such molecules may also modulate competition between microbes, promote cooperation, and impact motility, differentiation, or virulence of free-living and parasitic protozoa. This review aims to discuss biofilm compounds that mediate interspecies or interkingdom interactions and their involvement in regulating gut and environmental microbiomes functions, and host–pathogen relationships with special emphasis on protozoan activity and the infection outcome. This review will also address how this chemical dialog can be explored to identify new therapeutic interventions against microbial infections and parasitic diseases. Full article

Gut microbiota, through both its species composition and its metabolites, impacts expression and activity of intestinal drug transporters. This phenomenon directly affects absorption process of orally administered drugs and contributes to the observed inter-individual variability in pharmacotherapeutic responses. This review summarizes mechanistic evidence from in vitro and animal studies and integrates clinical observations in which alterations in gut microbiota are associated with changes in oral drug exposure, consistent with potential regulation of key intestinal drug transporters—such as P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2), MRP2/3 proteins (ABCC2/3), and selected Organic Anion-Transporting Polypeptides (OATPs, e.g., SLCO1A2, SLCO2B1)—by major bacterial metabolites including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived indoles. The molecular mechanisms involved include activation of nuclear and membrane receptors (PXR, FXR, AhR, TGR5), modulation of transcriptional and stress-response pathways (Nrf2, AP-1) with simultaneous suppression of pro-inflammatory pathways (NF-κB), and post-translational modifications (e.g., direct inhibition of P-gp ATPase activity by Eggerthella lenta metabolites). The review also highlights the pharmacokinetic implications of, e.g., tacrolimus, digoxin, and metformin. In conclusion, the significance of “drug–transporter–microbiome” interactions for personalized medicine is discussed. Potential therapeutic interventions are also covered (diet, pre-/probiotics, fecal microbiota transplantation, modulation of PXR/FXR/AhR pathways). Considering the microbiota as a “second genome” enables more accurate prediction of drug exposure, reduction in toxicity, and optimization of dosing for orally administered preparations. Full article