Abstract：
In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.
摘要：
近年来，一些实验观察表明，肠道微生物组在调节正或负代谢稳态中起作用。吲哚-3-丙酸(IPA),色氨酸分解代谢产物主要由C.孢子菌产生，最近已显示在代谢和心血管疾病的背景下发挥有利或不利的作用。我们进行了一项研究，以描绘以低和高IPA水平为特征的人类受试者的临床和多组学特征。低IPA血液水平的受试者表现出胰岛素抵抗，超重,与高IPA患者相比，低度炎症和代谢综合征的特征。代谢组学分析显示IPA与亮氨酸呈负相关,异亮氨酸,和缬氨酸代谢。结肠组织的转录组学分析揭示了几种信号的富集，调节和代谢过程。宏基因组学揭示了反刍动物的几个OTU，alistipes,Blautia,丁酸弧菌和akkermansia在高IPA组中显著富集，而在低IPA组大肠杆菌-志贺氏菌中显著富集，巨球菌和脱硫弧菌属更丰富。接下来,我们测试了在小鼠模型中用IPA治疗可以概括人类受试者的观察结果的假设，至少部分。我们发现，用IPA短期治疗（4天，20/mg/kg）改善葡萄糖耐量和Akt磷酸化在骨骼肌水平，同时调节血液中的BCAA水平和结肠组织中的基因表达，所有与在对IPA水平进行分层的人类受试者中观察到的结果一致。我们的结果表明，IPA治疗可能被认为是改善菌群失调患者胰岛素抵抗的潜在策略。
