Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra-3/daf-11 signaling in Caenorhabditis elegans.
Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra-3/daf-11 signaling in Caenorhabditis elegans.
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DOI：
10.1111/acel.13351
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发表时间：
2021-05
期刊：
影响因子：
7.8
通讯作者：
Kapahi P
中科院分区：
文献类型：
--
作者：
Khanna A;Sellegounder D;Kumar J;Chamoli M;Vargas M;Chinta SJ;Rane A;Nelson C;Peiris TH;Brem R;Andersen J;Lithgow G;Kapahi P
在线虫中，来自食物中细菌的信号可以调节行为和健康寿命。食物是动物的主要营养来源。在这里，我们描述了三甲胺(TMA)的双重作用，三甲胺是一种人类肠道菌群代谢物，它充当营养信号和神经毒素。TMA及其相关代谢物是由人体肠道微生物群产生的，已被认为是糖尿病和心血管疾病的危险生物标志物。我们证明了酪胺受体Tyra-3是一种保守的G蛋白偶联受体(GPCR)，需要它来感知TMA并介导其反应。TMA通过Tyra-3激活双突神经元(ASK)和纤毛神经元(BAG)中的鸟苷酸环化酶DAF-11信号，从而介导食物感觉行为。缺乏TMA生产的细菌突变株可以促进Dauer的形成，延长寿命，并且不太受欢迎作为食物来源。在帕金森氏病模型中，TMA水平的增加会导致神经损伤，并缩短寿命。我们的结果揭示了TMA在线虫中调节的保守信号通路，这可能与其在哺乳动物系统中的作用有关。TMA改变线虫的发育、衰老和神经退化。观察结果表明，细菌代谢产物TMA通过DAF-11和DAF-16途径改变线虫的发育、衰老和神经变性。
In the nematode Caenorhabditis elegans, signals derived from bacteria in the diet, the animal's major nutrient source, can modulate both behavior and healthspan. Here we describe a dual role for trimethylamine (TMA), a human gut flora metabolite, which acts as a nutrient signal and a neurotoxin. TMA and its associated metabolites are produced by the human gut microbiome and have been suggested to serve as risk biomarkers for diabetes and cardiovascular diseases. We demonstrate that the tyramine receptor TYRA‐3, a conserved G protein‐coupled receptor (GPCR), is required to sense TMA and mediate its responses. TMA activates guanylyl cyclase DAF‐11 signaling through TYRA‐3 in amphid neurons (ASK) and ciliated neurons (BAG) to mediate food‐sensing behavior. Bacterial mutants deficient in TMA production enhance dauer formation, extend lifespan, and are less preferred as a food source. Increased levels of TMA lead to neural damage in models of Parkinson's disease and shorten lifespan. Our results reveal conserved signaling pathways modulated by TMA in C. elegans that are likely to be relevant for its effects in mammalian systems. TMA alters development, aging and neurodegeneration in C. elegans. Observed results suggests that the bacterial metabolite TMA alters development, aging and neurodegeneration in C. elegans through DAF‐11 and DAF‐16 pathways.
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影响因子：
64.5
作者：
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通讯作者：
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作者：
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