Gut microbe-derived metabolite trimethylamine N-oxide accelerates fibroblast-myofibroblast differentiation and induces cardiac fibrosis

Yang, Wenlong; Zhang, Shuning; Zhu, Jianbing; Jiang, Hao; Jia, Daile; Ou, Tiantong; Zhou, Qi; Zou, Yunzeng; Qian, Juying; Sun, Aijun; Ge, Junbo

doi:10.1016/j.yjmcc.2019.07.004

Cited by 71 publications

(54 citation statements)

References 35 publications

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“…However, in most of these studies, experimental animals were severely affected by disease, old age, and/or other factors. For instance, animals with partially ligated carotid artery/coronary ligation [184,191,193] are ill, in pain, and stressed from the operation; this procedure may severely perturb the system and induce dysbiosis. Interestingly, severe cardiovascular stress caused by coronary ligation increased TMAO levels up to 30 µM in rats; however, sham operations also caused slightly higher than baseline TMAO levels (10 µM), likely due to postoperative dysbiosis [193].…”

Section: Unfavorable Effects Of Tmao In Animalsmentioning

confidence: 99%

“…In most animal experiments, high TMAO (0.12-0.3% of chow/drinking water) or L-carnitine or choline supplementation (≥1%) resulted in plasma levels between 30 and 100 µM [94,115,165,182,191,193], in some cases up to 400 µM TMAO [94,192], and many of these studies were conducted in female mice, which express high FMO3 and give rise to high TMAO concentrations in plasma. It should be noted that 1.3% L-carnitine in the diet of a mouse approximately corresponds to 2080 mg L-carnitine/kg (see calculation in the footnote of Table 2), which is an excessive dose, corresponding to a human equivalent dose of 11,818 mg L-carnitine/day [185].…”

Section: Unfavorable Effects Of Tmao In Animalsmentioning

confidence: 99%

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Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?

2020

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Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases. Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health. In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.

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Section: Unfavorable Effects Of Tmao In Animalsmentioning

confidence: 99%

Section: Unfavorable Effects Of Tmao In Animalsmentioning

confidence: 99%

Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?

2020

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“…A study reported by Organ et al demonstrated that the inbred mice fed with choline has significantly enhanced cardiac fibrosis in a transverse aortic constriction (TAC) model (Organ et al, 2016). Another study conducted in a model of myocardial infarction reported that choline promotes cardiac fibrosis (Yang et al, 2019). All these studies suggest that M 3 R participates in the proliferation of fibroblasts and collagen production.…”

Section: Introductionmentioning

confidence: 99%

Choline Attenuates Cardiac Fibrosis by Inhibiting p38MAPK Signaling Possibly by Acting on M3 Muscarinic Acetylcholine Receptor

et al. 2019

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Choline has been reported to produce a variety of cellular functions including cardioprotection via activating M 3 muscarinic acetylcholine receptor (M 3 R) under various insults. However, whether choline offers similar beneficial effects via the same mechanism in cardiac fibrosis remained unexplored. The present study aimed to investigate the effects of choline on cardiac fibrosis and the underlying signaling mechanisms, particularly the possible involvement of M 3 R. Transverse aortic constriction (TAC) mouse model was established to simulate the cardiac fibrosis. Transforming growth factor (TGF)-β1 treatment was employed to induce proliferation of cardiac fibroblasts in vitro. Choline chloride and M 3 R antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) were used to unravel the potential role of M 3 R. Cardiac function was assessed by echocardiography and interstitial fibrosis was quantified by Masson staining. Protein levels of collagens I and III were determined by Western blot analysis. The role of M 3 R in the proliferation cardiac fibroblasts was validated by silencing M 3 R with specific small interference RNA (siRNA). Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway including p38MAPK and ERK1/2 as well as the TGF-β1/Smad pathway were analyzed. M 3 R protein was found abundantly in cardiac fibroblasts. M 3 R protein level, as identified by Western blotting, was higher in mice with excessive cardiac fibrosis and in TGF-β1-induced cardiac fibrosis as well. Choline significantly inhibited interstitial fibrosis, and this beneficial action was reversed by 4-DAMP. Production of collagens I and III was reduced after choline treatment but restored by 4-DAMP. Expression silence of endogenous M 3 R using siRNA increased the level of collagen I. Furthermore, the TGF-β1/Smad2/3 and the p38MAPK pathways were both suppressed by choline. In summary, choline produced an antifibrotic effect both in vivo and in vitro by regulating the TGF-β1/Smad2/3 and p38MAPK pathways. These findings unraveled a novel pharmacological property of choline linked to M 3 R, suggesting that choline regulates cardiac fibrosis and the associated heart diseases possibly by acting on M 3 R.

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“…The origin of myofibroblasts, which cause excessive and uncontrolled generation of ECM proteins in the epiretinal membrane in PDR, remains unknown. Studies on several fibrotic diseases have shown that activated myofibroblasts or fibroblasts have different origins depending on the pathologic process 28,29 . hMCs have been reported to function as fibroblasts in the retina 7 .…”

Section: Discussionmentioning

confidence: 99%