Search Results (476)

Drought stress represents a major constraint on global apple production, with the widely used semi-dwarfing rootstock ‘M.26’ being particularly vulnerable to water deficit. Although the osmolyte trimethylamine N-oxide (TMAO) has been shown to improve abiotic stress tolerance in the model plant Arabidopsis, its potential role in enhancing drought resilience in woody fruit trees remains largely unexplored. Under prolonged moderate drought stress, exogenous TMAO application significantly promoted plant growth, mitigating the drought-induced suppression of plant height by 5.3–12.2% compared to untreated drought-stressed controls and alleviating the decline in above-ground biomass. This improvement was underpinned by a substantial alleviation of root growth inhibition, with TMAO restoring total root length and biomass from 37% in the control to only 6.1–9.5%. TMAO also fine-tuned the root-to-shoot ratio to favor resource allocation to roots. Consequently, TMAO-treated plants maintained superior leaf water status, exhibiting higher relative water content (drought-induced reduction limited to ~17.5% with TMAO versus 26.3% in the control). Physiologically, TMAO alleviated the drought-induced stomatal limitation of photosynthesis, sustaining higher net photosynthetic rate, stomatal conductance, and transpiration rate. Crucially, under severe drought stress, TMAO pretreatment markedly enhanced ‘M.26’ survival rates from approximately 39% in the untreated control to 60–68%, representing a relative increase of approximately 74%. Collectively, this study demonstrates that exogenous application TMAO significantly enhances drought tolerance in apple rootstock ‘M.26’, highlighting its potential as an effective and environmentally safe plant growth regulator for more sustainable cultivation of fruit trees under irregular/erratic irrigation conditions. Full article

Background: Chronic kidney disease (CKD) represents a state of persistent, sterile low-grade inflammation in which sustained innate immune activation accelerates renal decline and cardiovascular complications. Diet-induced gut dysbiosis and intestinal barrier dysfunction lower mucosal immune tolerance, promote metabolic endotoxemia, and position the gut as an upstream modulator of systemic inflammatory signaling along the gut–kidney axis. Scope: Most studies address microbiota-derived metabolites, food-derived bioactive peptides, or omega-3 fatty acids separately. This review integrates evidence across these domains and examines their convergent actions on epithelial barrier integrity, immune polarization, oxidative-inflammatory stress, and inflammasome-dependent pathways relevant to CKD progression. Key mechanisms: CKD-associated dysbiosis is characterized by reduced short-chain fatty acid (SCFA) production and increased generation and accumulation of uremic toxins and co-metabolites, including indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, and altered bile acids. Reduced SCFA availability weakens tight junction-dependent barrier function and regulatory immune programs, favoring Th17-skewed inflammation and endotoxin translocation. Bioactive peptides modulate inflammatory mediator networks and barrier-related pathways through effects on NF-κB/MAPK signaling and redox balance, while omega-3 fatty acids and specialized pro-resolving mediators support resolution-phase immune responses. Across these modalities, shared control points include barrier integrity, metabolic endotoxemia, oxidative stress, and NLRP3 inflammasome activation. Conclusions: Although evidence remains heterogeneous and largely preclinical, combined nutritional modulation targeting these convergent pathways may offer greater immunomodulatory benefit than isolated interventions. Future multi-omics-guided, factorial trials are required to define responder phenotypes and translate precision immunonutrition strategies into clinical CKD care. Full article

The gut microbiota has emerged as a central regulator of the gut–brain axis, profoundly influencing neural, immune, and metabolic homeostasis. Increasing evidence indicates that disturbances in microbial composition and function contribute to the onset and progression of neurodegenerative diseases (NDs) through mechanisms involving neuroinflammation, oxidative stress, and impaired neurotransmission. Gut dysbiosis is characterized by a loss of microbial diversity, a reduction in beneficial commensals, and an enrichment of pro-inflammatory taxa. These shifts alter intestinal permeability and systemic immune tone, allowing microbial metabolites and immune mediators to affect central nervous system (CNS) integrity. Metabolites such as short-chain fatty acids (SCFAs), tryptophan derivatives, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO) modulate blood–brain barrier (BBB) function, microglial activation, and neurotransmitter synthesis, linking intestinal imbalance to neuronal dysfunction and cognitive decline. Disruption of this gut–brain communication network promotes chronic inflammation and metabolic dysregulation, key features of neurodegenerative pathology. SCFA-producing and tryptophan-metabolizing bacteria appear to exert neuroprotective effects by modulating immune responses, epigenetic regulation, and neuronal resilience. The aim of this work was to comprehensively explore the current evidence on the bidirectional communication between the gut microbiota and the CNS, with a focus on identifying the principal molecular, immune, and metabolic mechanisms supported by the strongest and most consistent data. By integrating findings from recent human studies, this review sought to clarify how microbial composition and function influence neurochemical balance, immune activation, and BBB integrity, ultimately contributing to the onset and progression of neurodegenerative processes. Collectively, these findings position the gut microbiota as a dynamic interface between the enteric and CNS, capable of influencing neurodegenerative processes through immune and metabolic signaling. Full article

Background: Metabolic syndrome (MetS) is a multifactorial condition characterized by insulin resistance, dyslipidemia, hypertension, and central obesity, and is strongly influenced by lifestyle factors. Growing evidence highlights the gut microbiota as a key mediator linking diet and physical exercise to cardiometabolic health. Objective: This narrative review aims to qualitatively synthesize current evidence on the effects of physical exercise and major dietary patterns including the Mediterranean diet (MedDiet), Dietary Approaches to Stop Hypertension (DASH), and ketogenic/very-low-calorie ketogenic diets (KD/VLCKD) on gut microbiota composition and function, and their implications for metabolic health in MetS. Methods: A qualitative narrative synthesis of experimental, observational, and interventional human and animal studies was performed. The reviewed literature examined associations between structured physical exercise or dietary interventions and changes in gut microbiota diversity, key bacterial taxa, microbial metabolites, and cardiometabolic outcomes. Considerable heterogeneity across studies was noted, including differences in populations, intervention duration and intensity, dietary composition, and microbiota assessment methodologies. Results: Across human interventional studies, moderate-intensity physical exercise was most consistently associated with increased gut microbial diversity and enrichment of short-chain fatty acid (SCFA)-producing taxa, contributing to improved insulin sensitivity and reduced inflammation. MedDiet and DASH were generally linked to favorable microbiota profiles, including increased abundance of Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bifidobacterium, alongside reductions in pro-inflammatory metabolites such as lipopolysaccharides and trimethylamine N-oxide. In contrast, KD and VLCKD were associated with rapid weight loss and glycemic improvements but frequently accompanied by reductions in SCFA-producing bacteria, depletion of Bifidobacterium, and markers of impaired gut barrier integrity, raising concerns regarding long-term microbiota resilience. Conclusions: Lifestyle-based interventions exert diet- and exercise-specific effects on the gut microbiota–metabolism axis. While MedDiet, DASH, and regular moderate physical activity appear to promote sustainable microbiota-mediated cardiometabolic benefits, ketogenic approaches require careful personalization, limited duration, and medical supervision. These findings support the integration of dietary quality, exercise prescription, and individual microbiota responsiveness into translational lifestyle strategies for MetS prevention and management. Full article

Gut-derived metabolites, particularly trimethylamine N-oxide (TMAO), have been implicated in the pathophysiology of heart failure (HF). This study investigated the associations between TMAO, cardiac function, and clinical parameters to evaluate TMAO’s potential as a biomarker for heart failure with reduced ejection fraction (HFrEF). Forty HFrEF patients and forty-one matched healthy controls were recruited for serum TMAO quantification using enzyme-linked immunosorbent assay (ELISA). Associations were examined using Spearman correlation and regression models. TMAO levels were significantly elevated in HFrEF patients (3.64 µM [IQR 3.00–4.31]) compared with controls (1.22 µM [IQR 0.92–2.36]) (p < 0.05). Elevated TMAO correlated with impaired cardiac structural and functional parameters, as well as lower serum albumin. Multinomial regression revealed that both TMAO (OR 1.83, 95% CI 1.04–3.23, p = 0.036; OR 2.05, 95% CI 1.18–3.57, p = 0.010, respectively) and albumin (OR 0.56, 95% CI 0.36–0.89, p = 0.015; OR 0.61, 95% CI 0.39–0.93, p = 0.022, respectively) were independently associated with HFrEF severity, showing significant correlations in both mildly (EF 30–40%) and moderately (20–30%) reduced EF groups. Receiver operating characteristic (ROC) analyses showed that TMAO had good discriminative ability for HFrEF (AUC = 0.853), and it improved when combined with clinical covariates (AUC = 0.967), supporting its role as a potential biomarker. These findings support integrating this gut-derived metabolite and nutritional marker into HFrEF risk stratification frameworks. 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: Diabetes can increase cardiovascular risk (CVR) through hyperglycemia and intestinal damage. The purpose of this study is to evaluate several intestinal permeability biomarkers in predicting CVR in patients with type 2 diabetes mellitus (T2DM). Methods: This study was conducted in 2024 with a total of 70 patients with T2DM, aged 19–64 years (32.9% men, 67.1% women). Socio-demographic data and health status were collected; Framingham Risk Score (FRS), anthropometric measures, and serum parameters (glucose, HbA1c, lipids, CRP, TNF-α, IL-6, trimetilamine-N-oxide (TMAO), zonulin, intestinal fatty acid binding protein (I-FABP)) were evaluated, and visceral adiposity index (VAI) and plasma atherogenic index (PAI) were calculated. Results: The mean age of patients (n = 70) was 55.0 ± 7.55 years. According to FRS, 18.5% of individuals were determined to be at medium–high CVR; a positive correlation was found between BMI, waist–height ratio, body fat ratio, VAI value, and FRS total score (p < 0.05). Serum TMAO, zonulin, and I-FABP levels did not differ between low-risk and medium–high-risk patients (p > 0.05). Serum TMAO, zonulin, and I-FABP levels were positively correlated with TNF-α and IL-6 levels, and serum TMAO and I-FABP levels were positively correlated with triglyceride levels (p < 0.05). Moreover, serum zonulin and I-FABP levels were positively correlated with PAI (p < 0.05). Conclusions: Abdominal obesity and intestinal permeability may affect inflammatory processes and blood lipids in patients with T2DM. Further studies with large samples are needed to examine dietary factors related to the relationship between intestinal permeability and cardiometabolic risk. Full article

Background/Objectives: Numerous studies have documented cardioprotective effects of adiponectin in animal models of cardiometabolic disease (CMD). Adiponectin receptor agonist ALY688 has demonstrated functional significance against pressure overload-induced cardiac remodeling events in a mouse model of heart failure with reduced ejection fraction (HFrEF), potentially through modulation of the systemic metabolome. However, the specific metabolites and their pathophysiological contribution to cardioprotection in cardiac hypertrophy or heart failure remain unclear. This study aimed to characterize systemic metabolic alterations across five tissues in HFrEF and determine how ALY688 modifies these pathways to mediate cardioprotection in the transverse aortic constriction (TAC) model. Methods: Targeted metabolic profiling was performed on heart, liver, muscle, epididymal white adipose tissue (eWAT), and serum collected five weeks post-surgery from wild-type male C57BL/6 mice. Mice underwent either Sham or TAC-induced left ventricular pressure overload, with or without daily subcutaneous ALY688 administration. Metabolites were quantified using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and statistically analyzed at the tissue level. Results: Consistent with pathological cardiac remodeling, the comprehensive metabolomic analysis revealed that TAC induced widespread disruption of systemic metabolic homeostasis. ALY688 treatment significantly modified several key metabolite classes, including triglycerides (TGs) and glycosylceramides (HexCer). Notably, ALY688 also altered multiple gut-derived metabolites, including trimethylamine N-oxide (TMAO), 5-aminovaleric acid (5-AVA), and glycodeoxycholic acid (GDCA), highlighting a potential gut–liver–heart axis mediating its cardioprotective effects. Conclusions: These findings demonstrate that ALY688 mitigates TAC-induced metabolic dysregulation across multiple tissues. The identified metabolic signatures suggest that ALY688 exerts cardioprotective effects, at least in part, through restoration of systemic metabolic homeostasis and engagement of a gut–liver–heart metabolic axis. These results provide mechanistic insight into adiponectin receptor agonism and support further exploration of ALY688 as a potential therapeutic strategy for HFrEF. 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

The gut microbiome has emerged as a key regulator of human health, influencing not only metabolism and immunity but also the development and treatment of cancer. Mounting evidence suggests that microbial dysbiosis contributes to oncogenesis by driving chronic inflammation, producing genotoxic metabolites, altering bile acid metabolism, and disrupting epithelial barrier integrity. At the same time, the gut microbiome significantly modulates the host response to oncotherapies including chemotherapy, radiotherapy, and especially immunotherapy, where microbial diversity and specific taxa determine treatment efficacy and toxicity. This review synthesizes current evidence on the role of the gut microbiome in both oncogenesis and oncotherapies, focusing on thirteen cancers with the strongest and most clinically relevant microbiome associations, colorectal cancer, gastric cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, pancreatic cancer, oral squamous cell carcinoma, cervical cancer, prostate cancer, breast cancer, lung cancer, brain cancer, and melanoma. These cancers were selected based on robust mechanistic data linking microbial alterations to tumor initiation, progression, and therapy modulation, as well as their global health burden and translational potential. In addition, we have provided mechanistic insights or clinical correlations between the microbiome and cancer outcomes. Across cancers, common microbial mechanisms included pro-inflammatory signaling (e.g., NF-κB and STAT3 pathways), DNA damage from bacterial toxins (e.g., colibactin, nitrosating species), and metabolite-driven tumor promotion (e.g., secondary bile acids, trimethylamine N-oxide). Conversely, beneficial commensals such as Faecalibacterium prausnitzii and Akkermansia muciniphila supported antitumor immunity and improved responses to immune checkpoint inhibitors. In conclusion, the gut microbiome functions as both a driver of malignancy and a modifiable determinant of therapeutic success. Integrating microbiome profiling and modulation strategies such as dietary interventions, probiotics, and fecal microbiota transplantation into oncology practice may pave the way for personalized and more effective cancer care. Full article

Background/Objective: Neuroimmune and metabolic dysregulation have been increasingly implicated in the cognitive heterogeneity of autism spectrum disorder (ASD). However, it remains unclear whether anti-inflammatory diets engage distinct biological and cognitive pathways in autistic and neurotypical children. This study examined whether a 12-week anti-inflammatory dietary protocol produces group-specific neuroimmune–metabolic signatures and cognitive responses in autistic children, neurotypical children receiving the same diet, and untreated neurotypical controls. Methods: Twenty-two children (11 with ASD, six a on neurotypical diet [NT-diet], and five neurotypical controls [NT-control]) completed pre–post assessments of plasma IFN-γ, CXCL1, RANTES (CCL5), trimethylamine-N-oxide (TMAO), and an extensive ENI-2/WISC-IV neuropsychological battery. Linear mixed-effects models were used to test the Time × Group effects on biomarkers and cognitive domains, adjusting for age, sex, and baseline TMAO. Bayesian estimation quantified individual changes (posterior means, 95% credible intervals, and posterior probabilities). Immune–cognitive coupling was explored using Δ–Δ correlation matrices, network metrics (node strength, degree centrality), exploratory mediation models, and responder (≥0.5 SD domain improvement) versus non-responder analyses. Results: In ASD, the diet induced robust reductions in IFN-γ, RANTES, CXCL1, and TMAO, with decisive Bayesian evidence for IFN-γ and RANTES suppression (posterior P(δ < 0) > 0.99). These shifts were selectively associated with gains in verbal learning, semantic fluency, verbal reasoning, attention, and visuoconstructive abilities, whereas working memory and executive flexibility changes were heterogeneous, revealing executive vulnerability in individuals with smaller TMAO reductions. NT-diet children showed modest but consistent improvements in visuospatial processing, attention, and processing speed, with minimal biomarker changes; NT controls remained biologically and cognitively stable. Network analyses in ASD revealed a dense chemokine-anchored architecture with CXCL1 and RANTES as central hubs linking biomarker reductions to improvements in fluency, memory, attention, and executive flexibility. ΔTMAO predicted changes in executive flexibility only in ASD (explaining >50% of the variance), functioning as a metabolic node of executive susceptibility. Responders displayed larger coordinated decreases in all biomarkers and broader cognitive gains compared to non-responders. Conclusions: A structured anti-inflammatory diet elicits an ASD-specific, coordinated neuroimmune–metabolic response in which suppression of CXCL1 and RANTES and modulation of TMAO are tightly coupled with selective improvements in verbal, attentional, and executive domains. Neurotypical children exhibit modest metabolism-linked cognitive benefits and minimal immune modulation. These findings support a precision-nutrition framework in ASD, emphasizing baseline immunometabolic profiling and network-level biomarkers (CXCL1, RANTES, TMAO) to stratify responders and design combinatorial interventions targeting neuroimmune–metabolic pathways. Full article

Cyanobacterial blooms are a common water pollution phenomenon worldwide now. Among them, Microcystis blooms occur most frequently internationally, and most of them can produce hepatotoxins—microcystins (MCs). When the bloom occurs in water bodies, common carp, as the top consumers in the aquatic food chain, inevitably ingest a large amount of cyanobacteria. The effects on the intestinal digestion, immunity, and microbiota of the carp remain to be revealed. In the present study, 21-day gavage exposure to Microcystis paste (equivalent to 378.25 μg/kg of MC-LR) was conducted on juvenile carp mainly to investigate the adverse effects of MCs on the fish intestinal digestion, immunity, and microbiota. The results showed that Microcystis exposure caused intestinal barrier damage, intestinal structure destruction, and increased permeability. Analysis of the activities of three main intestinal digestive enzymes showed that Microcystis exposure affected the intestinal digestion of fish. Targeted metabolome analysis and 16S rRNA sequencing showed that the abundance of opportunistic pathogens such as Proteobacteria and Aeromonas increased in the exposed fish, and the contents of intestinal metabolites lipopolysaccharide (LPS) and trimethylamine oxide (TMAO) increased. However, the abundance of Firmicutes and Bacillus that produce short-chain fatty acids (SCFAs) was significantly reduced. These results indicated that Microcystis exposure could imbalance the intestinal flora and increase the abundance of Gram-negative bacteria, thereby activating the inflammatory response in the common carp. In summary, oral Microcystis exposure by the common carp can negatively affect fish digestion, immunity, and flora homeostasis of the fish intestinal tract. This study also provides a theoretical basis for a comprehensive evaluation of the beneficial effects of SCFAs on regulating metabolic disorders, activating lipid catabolism, and nutrient utilization of fish in aquaculture. Full article

The gut microbiota is crucial for metabolic homeostasis and cardiovascular health. Dysbiosis triggers a gut–brain–heart axis dysfunction: vagal signaling promotes neuroinflammation and cerebral damage, which in turn impairs cardiac function. This bidirectional cycle is further exacerbated by reduced cerebral perfusion. Trimethylamine-N-oxide (TMAO), a metabolite of dietary choline and L-carnitine, acts as a primary mediator in this network. Elevated TMAO levels—resulting from bacterial conversion and hepatic oxidation—are linked to atherosclerosis and heart failure. Mechanistically, TMAO activates the NLRP3 inflammasome, inhibits the SIRT3-SOD2 pathway, and promotes platelet hyperreactivity. Furthermore, it modulates the autonomic nervous system, enhancing sympathetic activity and cardiac arrhythmias. Clinical evidence suggests TMAO is a potent predictor of mortality in HF. While current HF therapies focus on end-organ response (beta-blockers) or humoral pathways (ACE inhibitors), directly targeting the microbiota and TMAO offers a novel therapeutic frontier. Integrating TMAO assessment into risk models and utilizing advanced in vitro gut–brain models will be essential for developing personalized, groundbreaking cardiovascular interventions. Within this framework, the main aim of the present review is to describe how cardiac autonomic control can be directly modulated by the microbiota and its byproducts like TMAO. This latter is a leading target candidate for novel HF prevention and therapy interventions. Full article

Background and Objectives: Peripheral arterial disease (PAD), frequently observed in individuals with type 2 diabetes mellitus (T2DM), is associated with diminished life quality, increased cardiovascular risk, and higher mortality rates. Similarly, trimethylamine N-oxide (TMAO), a uremic toxin produced by gut microbiota, has been linked to hypertension, cardiovascular disease, and increased overall mortality. In this study, we aimed to investigate whether serum TMAO levels are related to PAD in T2DM cases. Materials and Methods: In this cross-sectional investigation performed at one medical center, 120 patients with type 2 diabetes mellitus (T2DM) were included. High-performance liquid chromatography–mass spectrometry and an automated oscillometric device were used to measure serum TMAO levels and ankle–brachial index (ABI) values, respectively. Individuals exhibiting an ABI of less than 0.9 were classified as belonging to the low-ABI group. Results: Of the 120 participants, 23 (19.2%) had low ABI. Compared with the normal-ABI group, the low-ABI group was older (p = 0.017) and exhibited higher levels of urine albumin-to-creatinine ratio (UACR, p < 0.001), C-reactive protein (CRP, p < 0.001), and TMAO (p < 0.001). After adjusting for age, UACR, and CRP, multivariable logistic regression analysis identified serum TMAO concentration as an independent predictor of PAD in T2DM patients (odds ratio [OR]: 1.051; 95% confidence interval [CI]: 1.017–1.086; p = 0.003). In Spearman’s rank correlation analyses, log-transformed left ABI (log-left ABI, p = 0.017) and log-right ABI (p = 0.001) negatively correlated with log-TMAO. In patients with T2DM, the predictive performance of serum TMAO levels for PAD yielded an area under the receiver operating characteristic (ROC) curve of 0.812 (95% CI: 0.701–0.923; p < 0.001). Conclusions: Among individuals with T2DM, higher serum TMAO levels were associated with lower left and right ABI values and an increased likelihood of PAD. Full article