探討腸道菌代謝物苯乙酰基谷氨酸與苯乙酰基甘胺酸在心血管疾病發展過程中所扮演的角色

Abstract

心血管疾病（Cardiovascular disease, CVD）是全球主要死亡原因之一。日益增多的證據表明，腸道菌叢在調節心血管疾病相關風險因子（包括高血壓、高血糖、高血脂、慢性發炎及動脈粥狀硬化）中扮演著至關重要的角色。由腸道微生物衍生的代謝物，如短鏈脂肪酸（Short-chain fatty acids, SCFA）和氧化三甲胺（Trimethylamine N-oxide, TMAO），與調控CVD的進程及嚴重程度有關。近期研究發現，源自苯丙胺酸（Phenylalanine, PHE）微生物代謝的苯乙酰谷氨酰胺（Phenylacetylglutamine, PAGln）及其小鼠類似物苯乙酰甘胺酸（Phenylacetylglycine, PAGly），與心血管疾病的死亡率增加有關。這些影響被認為是透過增強腎上腺素受體的訊息傳遞，進而促進血栓形成和導致心臟衰竭。然而，先前的研究僅採用腹腔注射給藥，以誘導體內PAGln/PAGly短暫升高，此方式可能無法準確反映生理條件下，這些代謝物經由未消化完的苯丙胺酸緩慢發酵生成的真實情況。為了能更貼近生物體的變化以模擬慢性暴露的影響，本研究透過飲用水給予小鼠PAGln/PAGly，並結合AAV-mPCSK9誘導的動脈粥狀硬化模型，探討其對肥胖、高膽固醇血症及動脈粥狀硬化的作用。實驗將小鼠分為四組，分別餵食添加控制組（水）、PAGln、PAGly或PHE的西方飲食（Western diet, WD），持續12週。實驗過程中發現，長期攝取PAGln/PAGly可顯著降低小鼠的體重、肥胖程度、胰島素阻抗及肝臟發炎。此效果可能是透過活化棕色脂肪組織中的β3-腎上腺素受體，以及其所依賴的解偶聯蛋白-1（Uncoupling protein 1, Ucp-1）介導的粒線體產熱作用所達成。另一方面，PAGln/PAGly的暴露亦會導致心率和血壓升高，這可能歸因於其具有類似腎上腺素的活性。值得注意的是，儘管給予PAGln的小鼠膽固醇水平受到控制，其動脈粥狀硬化斑塊的形成卻更為顯著。本研究首次揭示了PAGln/PAGly在心臟代謝疾病中所扮演的多面向角色，突顯其同時作為保護因子與致病因子的雙重特性，而這可能源於複雜的腎上腺素受體訊息傳遞。鑑於其在心血管疾病中作為「雙面刃」微生物代謝物的潛力，未來有必要進行更深入的機制探討，特別是針對腎上腺素受體所介導的各種表型，例如心臟衰竭、免疫調節及粒線體功能。

Cardiovascular disease (CVD) remains one of the leading causes of death globally. Increasing evidence suggests that the gut microbiota plays a crucial role in modulating CVD-related risk factors, including hypertension, hyperglycemia, hyperlipidemia, chronic inflammation, and atherosclerosis. Gut microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO) have been implicated in modulating the progression and severity of CVD. Recently, phenylacetylglutamine (PAGln) and its murine analog, phenylacetylglycine (PAGly)—both derived from the microbial metabolism of phenylalanine (PHE)—have been linked to increased cardiovascular mortality. These effects are thought to be mediated by enhanced thrombosis and heart failure via adrenergic receptor signaling. However, previous studies utilized only intraperitoneal (i.p.) administration to induce transiently high systemic levels of PAGln/PAGly. This approach may not accurately reflect physiological conditions, where these metabolites are produced slowly through the microbial fermentation of undigested phenylalanine. To better simulate chronic exposure, we administered PAGln/PAGly to mice via their drinking water and applied an AAV-mPCSK9-induced atherosclerosis model to investigate their impact on obesity, hypercholesterolemia, and atherosclerosis. Mice were assigned to four groups and fed a Western diet (WD) supplemented with either water, PAGln, PAGly, or PHE for 12 weeks. Interestingly, chronic exposure to PAGln/PAGly significantly reduced body weight, adiposity, insulin resistance, and liver inflammation, likely through the activation of β3-adrenergic receptors and subsequent Ucp-1-dependent mitochondrial thermogenesis in brown adipose tissue. Conversely, PAGln/PAGly exposure also increased heart rate and blood pressure, presumably due to their norepinephrine-like adrenergic activity. Notably, while their cholesterol levels were controlled, PAGln-treated mice developed more pronounced atherosclerotic plaque formation. This study is the first to reveal the multifaceted roles of PAGln/PAGly in cardiometabolic diseases, underscoring their dual function as both protective and pathogenic agents, a duality likely arising from complex adrenergic receptor signaling. Given their potential as double-edged microbial metabolites in CVD, further mechanistic studies are warranted, particularly those focusing on adrenergic receptor-mediated phenotypes such as heart failure, immune modulation, and mitochondrial function.