Nature Communications
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2025
·Vol. 16
·期 1
·11294
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IF 15.7
Chen Zhezhe,Zhu Qiongjun,Xu Hong,Hu Yiqing,Wang Yanan,Chen Zhebin,Wang Yao,Huang Xingru,Fu Guosheng,Ma Boxuan,Zhang Wenbin
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE −/− mice demonstrate that PDMF@LGG reduces TMAO levels, alleviates atherosclerotic plaque formation, and regulates gut microbial composition and various metabolites. Together, PDMF@LGG represents a potential candidate for atherosclerotic therapy caused by TMAO and broadens the range of treatable atherosclerosis.
研究领域:
微生物组学
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心血管病学
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分子代谢
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纳米医学
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转化医学
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药理学
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肠道微生物与宿主互作
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PINEAL RESEARCH
·
2024
·Vol. 76
·期 3
·e12954
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IF 8.3
Yueqi Chen,Chuan Yang,Zihan Deng,Tingwen Xiang,Qingrong Ni,Jianzhong Xu,Dong Sun,Fei Luo
Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella , and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the “gut-bone” axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
研究领域:
药理学
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微生物学
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骨生物学
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代谢组学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Hong Zhang,Kai Ren,Xiaoting Ni,Liwang Lin,Longyu Li,Wenlei Zhang,Zengliang Gao,Shiao Ren,Lili Fan,Xin Hai
Arsenic (As), a widely recognized environmental pollutant, has been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety and depression. Trimethylamine N-oxide (TMAO), a microbiota-host co-metabolite derived from dietary quaternary amines (e.g., choline), has been associated with the progression of multiple neurological disorders. This study demonstrates that the gut microbiota-derived metabolite TMAO potentiates As-induced neurotoxicity. Using network toxicology, we identified genes targeted by As and TMAO in depression, revealing significant enrichment in pathways related to apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress. In C57BL/6 mice, a high-choline diet exacerbated As-induced depressive behaviors, hippocampal damage, and astrocyte depletion, which were mediated by elevated TMAO levels. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) analysis confirmed that TMAO enhanced arsenic accumulation in plasma and brain tissues. In vitro experiments further demonstrated that TMAO exacerbated As-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis, and ferroptosis. Mechanistically, TMAO upregulated the ER stress PERK/eIF2α/ATF4 signaling pathway in response to As exposure. Knockdown of PERK attenuated As- and TMAO-mediated apoptosis and ferroptosis in cultured cells. Collectively, these findings indicate that dietary choline exacerbates arsenic-induced depressive-like phenotypes by increasing TMAO levels and activating the PERK/eIF2α/ATF4 signaling pathway.
研究领域:
神经毒理学
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环境卫生
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分子生物学
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神经科学
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毒理学
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营养科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Dongsheng Yu,Benli Jia,Fuqiang Zu,Wen Zhang,Danfeng Guo
Background Cholestatic liver injury (CLI) is mainly driven by intrahepatic cholestasis, a pathological condition characterized by systemic and intrahepatic accumulation of bile acids. Ciwujianoside B (CWB), the active constituent of Eleutherococcus senticosus , has demonstrated protective effects in various hepatic pathologies, but its functional role in CLI has not yet been investigated. Purpose This study aims to evaluate the therapeutic potential of CWB against CLI and investigate its mechanism. Methods CLI was induced via bile duct ligation, and the protective effects of CWB were assessed through H&E, Sirius red, and immunohistochemical staining. Inflammatory cytokines in serum were measured by ELISA. Integrated analysis of 16S rDNA sequencing, serum metabolomics, and fecal microbiota transplantation was performed to investigate the interactions between gut microbiota and host metabolism. Trimethylamine oxide (TMAO) was supplemented to evaluate its impact on the hepatoprotective effects of CWB. In AML-12 cells, flavin-containing monooxygenase 3 (FMO3) was knockdown or overexpressed to assess TMAO levels, apoptosis, reactive oxygen species (ROS) content, and endoplasmic reticulum (ER) stress. The interaction between CWB and FMO3 was evaluated with molecular docking and molecular dynamics simulations. Results CWB alleviated hepatocellular damage and apoptosis, which was accompanied by reduced serum levels of ALT, AST, ALP, and inflammatory cytokines. Mechanistic analyses revealed that CWB remodeled the gut microbiota, suppressed Cut C and Cut D levels in feces, thereby reducing systemic TMAO accumulation. Exogenous TMAO supplementation reversed the protective effect of CWB. Antibiotic treatment partially abrogated the hepatic protective effects of CWB. CWB significantly suppressed FMO3 expression. Knockdown of FMO3 in AML-12 cells led to a reduction in intracellular TMAO levels, apoptosis rate, ROS content and ER stress activation. Molecular docking revealed a stable binding interaction between CWB and FMO3. Conclusions Our results suggest that CWB alleviates CLI by suppressing TMAO biosynthesis, primarily through reducing trimethylamine-producing bacteria and directly inhibiting hepatic FMO3 expression.
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
·
IF 5.895
Xiaofei Zhou,Bowei Zhang,Xiuli Zhao,Yongxi Lin,Yuan Zhuang,Jingting Guo,Shuo Wang
Hyperuricemia is an independent hazard factor of renal injury and can induce renal fibrosis, promoting the development of chronic kidney disease (CKD). This study aimed to explore the probability of chlorogenic acid (CGA) as a potential substance for preventing hyperuricemia nephropathy (HN). Pretreatment with CGA downregulated SUA, BUN, and CR levels, relieved oxidative stress and inflammatory response, alleviated kidney fibrosis, and contributed to the prevention of HN. In the gut microbiota, Blautia, Enterococcus, and Faecalibaculum related to trimethylamine N-oxide (TMAO) synthesis were significantly increased in HN rats. In addition, it showed a significant increase in serum TMAO content in HN rats. However, CGA regulated the cascade response of the microbiota-TMAO signaling to reverse the increase of serum TMAO. CGA also decreased the protein expression of protein kinase B (AKT) phosphorylation, phosphatidylinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) by reducing the production of TMAO. CGA delayed kidney fibrosis in HN rats as evidenced by regulating the cascade response of the microbiota-TMAO-PI3K/AKT/mTOR signaling pathway. In summary, CGA can be an excellent candidate for HN prevention.
研究领域:
药理学
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肾病学
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微生物学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
Food & Function
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2024
·
IF 5.1
wenwen Li,Zeyuan Deng,Shuang Xiao,qian Du,Mengru Zhang,Hailing Song,Caidong Zhao,Liufeng Zheng
The high-fat diet (HFD) is a major risk factor for cardiovascular disease. However, the specific effects of HFD on vascular inflammation and the protective role of vitexin, a bioactive small-molecule compound derived from food, require further research. This study investigated the protective effects of vitexin intervention against HFD-induced vascular inflammation and its underlying mechanism. The results demonstrated that vitexin intervention significantly reduced body weight, serum total cholesterol, and low-density lipoprotein cholesterol levels in HFD-fed mice. Vitexin also improved vascular pathological changes and inflammatory status in the mice. Furthermore, vitexin intervention reduced serum TMAO levels in HFD-fed mice and achieved this effect by altering gut microbiota composition. HFD significantly increased N6-methyladenosine (m6A) levels in aorta tissues, while vitexin intervention reversed this abnormal m6A level. Vitexin could directly bind to fat mass and obesity-associated protein (FTO), potentially promoting m6A demethylation. The dose-response relationship between TMAO and inflammation/m6A was further validated in HUVEC cell and in vivo mouse experiments. Specifically, TMAO increased m6A levels and inflammation, while vitexin inhibited TMAO-mediated m6A modification, exhibiting anti-inflammatory effects. In conclusion, this study demonstrates the protective role of vitexin against HFD-induced vascular inflammation by inhibiting TMAO-mediated RNA m6A modification and laying the foundation for the development of functional foods.
研究领域:
药理学
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心脏病学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2021
·
IF 11.799
Shan Jiang,Yongjie Shui,Yu Cui,Chun Tang,Xiaohua Wang,Xingyu Qiu,Weipeng Hu,Lingyan Fei,Yun Li,Suping Zhang,Liang Zhao,Nan Xu,Fang Dong,Xiaoqiu Ren,Ruisheng Liu,Pontus B. Persson,Andreas Patzak,En Yin Lai,Qichun Wei,Zhihua Zheng
Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l -carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg −1 min −1 ) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca 2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001 ) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001 ) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca 2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.
研究领域:
心脏病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYSIOLOGICAL RESEARCH
·
2025
·
IF 2
D Shao,L Bai,Q Chen,Y Chen,Z Qiu,Y Liu,S Jin,Y Wu,J Dai
Trimethylamine N-oxide (TMAO) is involved in the development of kidney disease. However, the specific mechanism by which it leads to kidney injury is unclear. This study explored the role of regulated cell death in TMAO-induced kidney injury. We constructed a TMAO-induced chronic kidney injury model by intraperitoneal injection of TMAO (100 micromol/kg/day for three months). Plasma creatinine (Cre) and urea nitrogen (BUN) levels were measured to evaluate kidney function. Masson staining was used to evaluate kidney pathological changes. The expression levels of regulated cell death-related proteins were measured using western blotting. Plasma Cre and BUN, the area of kidney fibrosis in the TMAO group significantly increased. The western blotting results showed cleaved-Caspase-8, Caspase-8, Caspase-1, NOD-like receptor protein 3 (NLRP3), interleukin-1beta (IL-1beta), cleaved-gasdermin D (cleaved-GSDMD), Z-DNA binding protein 1 (ZBP1), phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL) significantly elevated in the TMAO group. The transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferroportin (FPN), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) protein expression in kidney tissue of the TMAO group significantly up-regulated. However, there was no change in iron and MDA levels. The results suggested that PANoptosis, including pyroptosis, apoptosis, and necroptosis components, might be involved in TMAO-induced chronic kidney injury.
研究领域:
肾脏病学
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细胞生物学
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分子生物学
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病理学
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药理学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
·
IF 5.1
Qian Chen,Huaxing Zhang,Yuhong Chen,Yangxuan Peng,Yuhan Yao,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xu Teng,Mingqi Zheng,Bing Xiao,Yuming Wu,Sheng Jin
Aims The present study aimed to investigate the direct link between trimethylamine N-oxide (TMAO) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Materials and methods Diastolic dysfunction is the main manifestation of HFpEF, so the “two-hit” mouse HFpEF model are used. After treated with high-fat diet (HFD) and N [w] -nitro-l-arginine methyl ester (L-NAME) for 8 weeks, the cardiac function, myocardial fibrosis, oxidative stress levels, and molecular alterations were assessed. Key findings The HFpEF mice displayed a declined diastolic function, characterized by an increase in the E/E' ratio, accompanied by a significant increase in plasma brain natriuretic peptide levels and cardiac fibrosis and down-regulation of SERCA2 expression, while, DMB treatment improved diastolic function. Subsequently, TMAO was injected intraperitoneally into the mice for 1 month and found that TMAO induced diastolic dysfunction. In addition, we found that either the HFD and L-NAME or TMAO treatment down-regulated Piezo1 expression, and the cardiomyocyte-specific Piezo1 knockout mice (Piezo1 ΔCM ) also had diastolic dysfunction. Moreover, the NOX4 expression was up-regulated and the reactive oxygen species levels were increased in the heart tissues of Piezo1 ΔCM or TMAO-treated mice, which was reversed by a Piezo1 activator (Yoda1) in the TMAO-treated mice. Yoda1 also reversed diastolic dysfunction in the HFpEF mice. Significance In conclusion, our data revealed that TMAO-induced oxidative stress injury by down-regulating Piezo1 to be involve in cardiac diastolic dysfunction of HFpEF. It should be noted that this preclinical study did not evaluate HFpEF-related symptoms such as exercise intolerance or pulmonary congestion, which warrant further validation.
研究领域:
心脏病学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Microorganisms
·
2026
·Vol. 14
·期 2
·
IF 4.2
Weijun Tang,Yan Lei,Linyuan Jiang,Huijuan Ren,Shambel Boki,Xinyue Du,Kexin Xiong,Shihao Liu,Yaoqiang Yue,Qingchao Wang
This study aimed to evaluate the effects of trimethylamine oxide (TMAO) supplementation (0.5% and 1%) to a high-carbohydrate diet on the growth performance, liver health, hepatic metabolome, intestinal microbiota and disease resistance of largemouth bass (Micropterus salmoides). After an eight-week feeding trial with three replicates, fish fed with TMAO-supplemented diets showed growth-promoting potential with increased difference with a prolonged rearing period. Importantly, TMAO supplementation significantly improved liver structure and function, with reduced intrahepatic glycogen accumulation due to reprogrammed glycogen metabolism, including down-regulatedgys2andugp2bbut up-regulatedpyglexpression levels. Targeted liver metabolomics analysis indicated the enhanced synthesis of long-chain fatty acid and amino acid in the 1% TMAO group, accompanied by decreased cortisol, indicating the attenuation of the stress response. Furthermore, TMAO supplementation changed the structure of the intestinal microbiota and particularly the intestinal content ofRomboutsia, an important probiotic that can effectively utilize different kinds of dietary carbohydrate, showed an increasing trend with the increased TMAO supplementation levels. Finally, after sampling, all remaining fish were challenged withNocardia seriolae. TMAO supplementation significantly enhanced the immune clearance function of largemouth bass against invadingN. seriolae, with alleviated granulomatous nodules within liver but enhanced hepatic expression levels ofnlrp3,caspase1,il-1βandil-18. These results collectively underscore the finding that TMAO may promote intestinalRomboutsiagrowth and reprogram hepatic metabolism to improve liver health, giving TMAO potential as a feed additive for growth and health promotion in largemouth bass.
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Yu Zhang,Songyuan Luo,Kai Huang,Jie Liu,Sen Li,Hongdong Song,Hongwei Cao,Xiao Guan
This study systematically evaluated the gastrointestinal fate of pea 7S, 11S globulin, and pea protein isolate (PPI) and their impact on gut using INFOGEST digestion, fecal fermentation, and multiomics approaches. During the gastrointestinal stage, pea proteins were largely digested, while pea 7S globulins and PPI exhibited partial resistance to gastric digestion. Intestinal digestion significantly enhanced Lys bioavailability, although Met remained as the first limiting amino acid across all pea proteins. During in vitro fermentation inoculated with microbiota from hyperuricemic individuals, pea proteins significantly reduced the production of trimethylamine N-oxide (TMAO) and guanosine relative to beef protein. Concurrently, pea protein supplementation promoted the generation of short-chain fatty acids and selectively enriched beneficial populations of gut microbiota such as Phascolarctobacterium and Akkermansia. Spearman correlation revealed that amino acid composition of pea proteins significantly affected microbial composition and gut-produced metabolites. Our results elucidate the structural-digestive-microbial interactions of pea proteins.
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PubMed
高影响因子
AQUACULTURE
·
2026
·
IF 4.4
Yu-Yang Liang,Ying-Man Yu,Chen-Chen Wu,Samwel M. Limbu,Meng-Ting Liu,Fang Qiao,Mei-Ling Zhang,Zhen-Yu Du,Yuan Luo
The expansion of intensive aquaculture and shifts in feed ingredient supply and demand have driven the adoption of high-energy feeds, resulting in metabolic disorders and diminished flesh quality in farmed fish. The natural compound trimethylamine oxide (TMAO) shows great promise as a functional feed additive, such as dietary TMAO supplementation significantly reduces the abdominal fat ratio in bluntnose black bream ( Megalobrama terminalis ), and decreases crude lipid content in the liver of Nile tilapia ( Oreochromis nilotica ), yet its effects and mechanisms in carnivorous fish such as the largemouth bass ( Micropterus nigricans ) remain unclear. This study investigated the effects of TMAO at different supplementation levels on the growth performance, lipid metabolism, fish flesh quality, and targeted metabolomics of largemouth bass. A 56-day feeding trial was designed with three TMAO supplementation levels (0.1%, 0.2%, and 0.4%). A total of 360 largemouth bass (8.78 ± 2.9 g) were randomly assigned to four treatment groups, each with three replicates. TMAO supplementation at all levels had no effect on growth performance. TMAO reduced hepatic lipid deposition in largemouth bass with a concentration-dependent effect, upregulating fatty acid β-oxidation gene expression. Targeted metabolomics analysis further revealed that TMAO increased carnitine content and elevated methylation levels by increasing SAM content in the liver. Furthermore, TMAO increased fish flesh hardness, promoted muscle fiber growth and development, enhanced muscle fiber density, and upregulated gene expression in the mTOR pathway. This study elucidates that dietary TMAO supplementation promotes lipid metabolism by increasing carnitine levels in the liver, and enhances muscle hardness by promoting muscle fiber growth and development.
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高影响因子
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