Landscape of gut microbiota and metabolites and their interaction in comorbid heart failure and depressive symptoms: a random forest analysis study

ABSTRACT: Depression is an individual risk factor for poor prognosis in patients with heart failure (HF). Recent studies show that gut microbiota and metabolites have critical role in comorbid HF and depressive symptoms. We recruited 95 subjects including 35 HF patients with depressive symptoms (HF-DS), 36 HF patients without depressive symptoms (HF-NDS), and 24 healthy controls (HC). The 16S rRNA, metagenome sequencing, and untargeted metabolomic analysis were employed to test fecal samples. Our analysis found there was a significant difference composition of gut microbiota in HF-DS, HF-NDS, and HC populations. At the genus level, Mediterranea, Tolumona, and Parabacteroides were significantly increased in HF-DS patients compared with HF-NDS patients, while Pedobacter, Azospirillum, and Ruminiclostridium were significantly decreased. Furthermore, anti-inflammatory mediators (abietic acid, quinic acid, linoleic acid, etc.) and neurotransmitters (catechin, serotonin, tryptamine, phenylethylamine, etc.) were reduced in HF-DS. The enrichment analysis revealed that the gut microbiota highly conformed with the functional pathways of metabolites, and amino acid-related metabolism, fatty acid-related metabolism, and cAMP signaling pathways may be crucial biological mechanisms involved in the development of comorbid depression and HF. Finally, Cloacibacillus and alpha-tocopherol were determined as diagnostic markers for HF-DS patients.

摘要：抑郁是心力衰竭（heart failure, HF）患者预后不良的独立危险因素。近期研究表明，肠道菌群及其代谢产物在心力衰竭与抑郁症状共病的发生发展中发挥关键作用。本研究共纳入95名受试者，包括35例伴抑郁症状的心力衰竭患者（HF-DS组）、36例不伴抑郁症状的心力衰竭患者（HF-NDS组）以及24名健康对照者（HC组）。本研究采用16S rRNA测序、宏基因组测序以及非靶向代谢组学分析对粪便样本进行检测。分析结果显示，HF-DS组、HF-NDS组与HC组人群的肠道菌群组成存在显著差异。在属水平上，与HF-NDS组患者相比，HF-DS组患者的Mediterranea、Tolumona以及Parabacteroides属的相对丰度显著升高，而Pedobacter、Azospirillum以及Ruminiclostridium属的相对丰度显著降低。此外，HF-DS组患者体内的抗炎介质（如松香酸、奎宁酸、亚油酸等）与神经递质（如儿茶素、5-羟色胺、色胺、苯乙胺等）水平均显著降低。富集分析结果显示，肠道菌群的功能通路与代谢产物的功能通路高度契合；氨基酸代谢、脂肪酸代谢以及环磷酸腺苷（cAMP）信号通路可能是介导心力衰竭与抑郁共病发生发展的关键生物学机制。最终，本研究确定Cloacibacillus与α-生育酚（alpha-tocopherol）可作为HF-DS患者的诊断标志物。