摘要:
目的 探究肠道真菌在慢性肾脏病（chronic kidney disease，CKD）相关心力衰竭（heart failure，HF）进展中的作用。方法 本研究分为两部分，第一部分为临床研究。通过对CKD患者（CKD组）、CKD合并HF患者（CKD+HF组）和健康人群（健康对照组）的粪便样本进行18S rRNA测序，观察3组肠道真菌菌群差异。第二部分为动物实验。将雄性C57BL/6J小鼠随机分为对照组（喂正常饲料）、CKD组（喂0.2%腺嘌呤饲料）、CKD+两性霉素B组（喂0.2%腺嘌呤饲料+两性霉素B 0.5 mg/L直饮） ，每组10只。造模成功后，通过检测3组小鼠运动耐量、左心室射血分数（left ventricular ejectionfraction,LVEF）、左心室短轴缩短率（left ventricular shortening fraction,LVFS）、N-末端脑利钠肽前体（N-terminal pro-brain natriuretic peptide，NT-proBNP）、心脏组织切片HE染色和Masson染色，比较3组之间心脏功能和组织形态学差异。结果 临床研究发现，与健康对照组（n=18）和CKD组（n=17）相比，CKD+HF组（n=18）患者肠道中Ascomycota菌门相对丰度显著增加（P=0.007，P=0.009） ，Desmodorida菌属、Candiada-Lodderomyces-clade菌属相对丰度显著增加（P=0.005，P=0.003）。动物实验发现，与对照组相比，CKD组小鼠运动耐量、LVEF和LVFS均显著降低（P均<0.001） ，血清NT-proBNP水平显著升高（P<0.001） ；心肌HE和Masson染色显示，心肌细胞排列紊乱且纤维化水平增加（P<0.001）。而与CKD组相比，CKD+两性霉素B组小鼠运动耐量、LVEF和LVFS均显著改善（P均<0.001） ，NT-proBNP水平显著降低（P<0.001） ；心肌HE和Masson染色显示，心肌细胞排列整齐且心肌纤维化水平显著降低（P<0.001）。结论 肠道真菌与CKD患者HF进展存在一定相关性，耗竭肠道真菌或可一定程度上改善心脏重构，延缓HF的发生发展。肠道真菌有望成为CKD患者HF治疗的新靶点。
Abstract:
Objective To investigate the role of intestinal fungi in the progression of heart failure (HF) associated with chronic kidney disease (CKD). Methods This study consisted of two parts. The first part was a clinical study. Fecal samples from CKD patients (CKD group), CKD patients with HF (CKD+HF group), and healthy individuals (healthy control group) were subjected to 18S rRNA sequencing to compare differences in intestinal fungal microbiota among the three groups. The second part was an animal experiment. Male C57BL/6J mice were randomly divided into a control group (fed a standard diet), a CKD group (fed a 0.2% adenine diet), and a CKD+amphotericin B group (fed a 0.2% adenine diet + 0.5 mg/L amphotericin B in drinking water), with 10 mice in each group. After successful modeling, cardiac function and histomorphological differences among the three groups were compared by assessing exercise tolerance, left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and histological examinations (HE staining and Masson staining) of cardiac tissue. Results The clinical study revealed that compared with the healthy control group (n=18) and the CKD group (n=17), the relative abundance of Ascomycota phylum in the intestines of the CKD+HF group (n=18) was significantly increased (P=0.007, P=0.009), along with significant increases in the relative abundances of Desmodorida and Candida-Lodderomyces clade (P=0.005, P=0.003). In the animal experiment, compared with the control group, the CKD group exhibited significantly reduced exercise tolerance, LVEF, and LVFS (all P<0.001), elevated serum NT-proBNP levels (P<0.001), and disordered cardiomyocyte arrangement with increased fibrosis (P<0.001) as shown by HE and Masson staining. In contrast, compared with the CKD group, the CKD+amphotericin B group demonstrated significant improvements in exercise tolerance, LVEF, and LVFS (all P<0.001), reduced NT-proBNP levels (P<0.001), and well-arranged cardiomyocytes with markedly decreased myocardial fibrosis (P<0.001). Conclusions Intestinal fungi may be associated with the progression of HF in CKD patients. Depletion of intestinal fungi could potentially ameliorate cardiac remodeling and delay the onset and progression of HF. Intestinal fungi may serve as a novel therapeutic target for HF in CKD patients.
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