Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis

Wu, Qing; Sun, Lulu; Hu, Xiaomin; Wang, Xuemei; Xu, Feng; Chen, Bo; Liang, Xianyi; Xia, Jialin; Wang, Pengcheng; Aibara, Daisuke; Zhang, Shaofei; Zeng, Guangyi; Yun, Chuyu; Yan, Yu; Zhu, Yicheng; Bustin, Michael; Zhang, Shuyang; Gonzalez, Frank J.; Jiang, Changtao

doi:10.1172/jci142865

Cited by 88 publications

(60 citation statements)

References 53 publications

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“…This theory may also help to explain the discovered gut microbiota change and elevated ceramide level that may be related to different CAD prognoses. A prior study of our group has convincingly shown that intestinal farnesoid X receptor (FXR) may modulate atherosclerosis by elevating ceramide metabolism (60). FXR was identified as an orphan nuclear receptor that plays multiple roles in regulating bile acid homeostasis, lipid, and glucose metabolism (61).…”

Section: Discussionmentioning

confidence: 99%

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study

Fan

et al. 2021

Front. Cardiovasc. Med.

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Background: Cigarette smoking has been considered a modifiable risk factor for coronary artery disease (CAD). Changes in gut microbiota and microbe-derived metabolites have been shown to influence atherosclerotic pathogenesis. However, the effect of cigarette smoking on the gut microbiome and serum metabolites in CAD remains unclear.Method: We profiled the gut microbiota and serum metabolites of 113 male participants with diagnosed CAD including 46 current smokers, 34 former smokers, and 33 never smokers by 16S ribosomal RNA (rRNA) gene sequencing and untargeted metabolomics study. A follow-up study was conducted. PICRUSt2 was used for metagenomic functional prediction of important bacterial taxa.Results: In the analysis of the microbial composition, the current smokers were characterized with depleted Bifidobacterium catenulatum, Akkermansia muciniphila, and enriched Enterococcus faecium, Haemophilus parainfluenzae compared with the former and never smokers. In the untargeted serum metabolomic study, we observed and annotated 304 discriminant metabolites, uniquely including ceramides, acyl carnitines, and glycerophospholipids. Pathway analysis revealed a significantly changed sphingolipids metabolism related to cigarette smoking. However, the change of the majority of the discriminant metabolites is possibly reversible after smoking cessation. While performing PICRUSt2 metagenomic prediction, several key enzymes (wbpA, nadM) were identified to possibly explain the cross talk between gut microbiota and metabolomic changes associated with smoking. Moreover, the multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes by mediating metabolites such as glycerophospholipids.Conclusions: Our results indicated that both the gut microbiota composition and metabolomic profile of current smokers are different from that of never smokers. The present study may provide new insights into understanding the heterogenic influences of cigarette smoking on atherosclerotic pathogenesis by modulating gut microbiota as well as circulating metabolites.

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Section: Discussionmentioning

confidence: 99%

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study

Fan

et al. 2021

Front. Cardiovasc. Med.

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“…However, this avenue is controversial. Studies performed in Fxr −/− /ApoE −/− or Fxr −/− /Ldr −/− mice showed both protective and deleterious effects of FXR loss on atherogenesis and cholesterolemia [90][91][92][93]. The best pharmacological strategy to target hypercholesterolemia via FXR signaling is still questionable since the use of FXR agonists and antagonists generates interesting, albeit contentious results.…”

Section: Discussionmentioning

confidence: 99%

Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Gaillard

Masson

Garo

et al. 2021

IJMS

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Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.

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“…The gut microbiome provides extra nutrition for the host, including the degradation of protein and glycosaminoglycans and the production of short-chain fatty acids (SCFAs), bile acids, amino acids, and vitamins. In addition, the gut microbiome generates various enzymes, primary and secondary metabolites, and together affecting host metabolism processes ( Canfora et al, 2015 ; Chen S et al, 2019 ; Zhang et al, 2019a ; Wu J et al, 2021 ; Wu et al, 2021a ). Among these microbiome-derived metabolites, SCFAs, bile acids, and trimethylamine (TMA) are considered to have the most impact on metabolic diseases ( Figure 1 ).…”

Section: Microbiome and Metabolic Diseasesmentioning

confidence: 99%

Human Microbiome and Its Medical Applications

Zhang

Zhou

Xia

et al. 2022

Front. Mol. Biosci.

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The commensal microbiome is essential for human health and is involved in many processes in the human body, such as the metabolism process and immune system activation. Emerging evidence implies that specific changes in the microbiome participate in the development of various diseases, including diabetes, liver diseases, tumors, and pathogen infections. Thus, intervention on the microbiome is becoming a novel and effective method to treat such diseases. Synthetic biology empowers researchers to create strains with unique and complex functions, making the use of engineered microbes for clinical applications attainable. The aim of this review is to summarize recent advances about the roles of the microbiome in certain diseases and the underlying mechanisms, as well as the use of engineered microbes in the prevention, detection, and treatment of various diseases.

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Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis

Cited by 88 publications

References 53 publications

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study

Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Human Microbiome and Its Medical Applications

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