Dataset Information

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension.

ABSTRACT:

Aims

We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats.

Methods and results

In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained the amelioration of PAH.

Conclusion

Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat.

SUBMITTER: Yang Y

PROVIDER: S-EPMC9442843 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension.

Yang Yicheng Y Zeng Qixian Q Gao Jianing J Yang Beilan B Zhou Jingjing J Li Ke K Li Li L Wang Anxin A Li Xin X Liu Zhihong Z Luo Qin Q Zhao Zhihui Z Liu Bingyang B Xue Jing J Jiang Xue X Konerman Matthew C MC Zheng Lemin L Xiong Changming C

European heart journal open 20220329 5

<h4>Aims</h4>We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats.<h4>Methods and results</h4>In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values d ...[more]

PMID: 36071697

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Project description:BackgroundProstate cancer was the fourth most diagnosed cancer worldwide in 2022. Radical treatments and androgen deprivation therapy benefit newly diagnosed patients but impact quality of life, often leading to castration-resistant prostate cancer. Short-term dietary changes significantly affect the gut microbiota, which differs markedly between prostate cancer patients and healthy individuals, impacting both cancer progression and treatment response. A high-choline diet increases the risk of fatal prostate cancer, potentially mediated by the conversion of choline to the trimethylamine N-oxide (TMAO) by the gut microbiota.MethodsThe CCK8 assay was employed to investigate whether TMAO affects the proliferation ability of prostate cancer cells and to determine the appropriate drug concentration. Subsequently, CCK8 time gradients, colony formation assays, and EdU assays measured TMAO's influence on cell proliferation. Wound healing and transwell migration assays evaluated TMAO's effect on cell migration. RNA-seq analysis was performed to explore the mechanisms by which TMAO influences the proliferation and migration of prostate cancer cells. qPCR and Western blotting were utilized to validate the expression of related mRNA or proteins. Finally, we performed in vivo experiments to evaluate the effect of a high choline diet on the growth of subcutaneous tumors and lung metastases in mice.ResultsOur study found that TMAO enhances the proliferation and migration of prostate cancer cells by upregulating HMOX1 via activation of the MAPK signaling pathway, specifically p38 MAPK. In mouse subcutaneous tumor and lung metastatic tumor experiments, the high-choline diet increased prostate cancer cell proliferation and migration, resulting in significantly greater tumor volume and number of metastases than controls.ConclusionThis study is the first to demonstrate the role of the gut microbiota-derived metabolite TMAO in prostate cancer. TMAO promotes the proliferation and migration of prostate cancer cells by activating the p38 pathway and increasing HMOX1 expression. Reducing choline intake through dietary intervention may delay the onset and progression of prostate cancer, presenting significant clinical application value.

Project description:ObjectiveType 2 diabetes is related to obesity and altered bone health, and both are affected by gut microbiota. We examined associations of weight loss diet-induced changes in a gut microbiota-related metabolite trimethylamine N-oxide (TMAO), and its precursors (choline and l-carnitine), with changes in bone mineral density (BMD) considering diabetes-related factors.Research design and methodsIn the 2-year Preventing Overweight Using Novel Dietary Strategies trial (POUNDS Lost), 264 overweight and obese participants with measurement of BMD by DXA scan were included in the present analysis. The participants were randomly assigned to one of four diets varying in macronutrient intake. Association analysis was performed in pooled participants and different diet groups. Changes in blood levels of TMAO, choline, and l-carnitine from baseline to 6 months after the dietary intervention were calculated.ResultsWe found that a greater reduction in plasma levels of TMAO from baseline to 6 months was associated with a greater loss in whole-body BMD at 6 months and 2 years (P = 0.03 and P = 0.02). The greater reduction in TMAO was also associated with a greater loss in spine BMD (P = 0.005) at 2 years, independent of body weight changes. The associations were not modified by baseline diabetes status and glycemic levels. Changes in l-carnitine, a precursor of TMAO, showed interactions with dietary fat intake in regard to changes of spine BMD and hip BMD at 6 months (all P < 0.05). Participants with the smallest decrease in l-carnitine showed less bone loss in the low-fat diet group than the high-fat diet group (P spine = 0.03 and P hip = 0.02).ConclusionsTMAO might protect against BMD reduction during weight loss, independent of diet interventions varying in macronutrient content and baseline diabetes risk factors. Dietary fat may modify the relation between change in plasma l-carnitine level and changes in BMD. Our findings highlight the importance of investigating the relation between TMAO and bone health in patients with diabetes.

Dataset Information

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension.

Aims

Methods and results

Conclusion

Publications

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension.

Similar Datasets

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