温胆汤通过调控肠道菌群-胆汁酸轴改善代谢综合征痰证大鼠的代谢表型

doi:10.12122/j.issn.1673-4254.2025.06.07

摘要/Abstract

摘要：

目的基于肠道菌群-胆汁酸轴探讨温胆汤对代谢综合征（MS）痰证大鼠的影响。方法将40只Wistar大鼠随机分为正常组（n=8）和造模组（n=32），采用高脂高糖高盐饮食联合低剂量腹腔注射链脲佐菌素诱导MS痰证大鼠模型。根据模型评价标准筛选成模大鼠，将成模大鼠随机分为模型组、温胆汤组（3.6 g·kg^-1·d^-1）、二甲双胍组（0.1 g·kg^-1·d^-1），分别给予相应药物干预4周。动态记录大鼠一般情况、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、空腹血糖（FBG）、血清胰岛素（FINS）等指标，计算Lee's指数和HOMA-IR。ELSIA检测血清脂多糖水平，HE染色观察肝脏组织病理学改变，Western blotting检测肝脏中FXR、CYP7A1、FGFR4及回肠中FXR、FGF15蛋白表达。16S rDNA测序技术分析盲肠内容物肠道菌群结构，超高液相色谱串联质谱法（UHPLC-MS/MS）测定血清胆汁酸含量。结果与正常组相比，模型组大鼠肝细胞出现严重脂肪变性、坏死；体质量、腹围、Lee's指数、FBG、FINS、HOMA-IR、TG、TC、LDL、脂多糖等含量升高（P<0.05），HDL降低（P<0.05）；拟杆菌门、巨单胞菌属、拟杆菌属相对丰度升高（P<0.05）；厚壁菌门丰度、Lachnospiraceae_NK4A136_group、异猪去氧胆酸、甘氨猪脱氧胆酸等降低（P<0.05）；肝组织FXR、FGFR4及回肠组织FXR、FGF15蛋白表达降低（P<0.05），肝脏CYP7A1蛋白表达升高（P<0.05）。与模型组相比，温胆汤治疗后肝组织病理改变明显减轻；体质量、腹围、Lee's指数、FBG、FINS、HOMA-IR、TG、TC、LDL、脂多糖等含量降低（P<0.05），HDL含量升高（P<0.05）；拟杆菌门、拟杆菌属相对丰度降低（P<0.05）；Lachnospiraceae_NK4A136_group、厚壁菌门相对丰度及异猪去氧胆酸、甘氨猪脱氧胆酸等含量升高（P<0.05）；肝组织FXR、FGFR4及回肠组织FXR、FGF15蛋白表达升高（P<0.05），肝脏CYP7A1蛋白表达降低（P<0.05）；相关性分析显示厚壁菌门、Lachnospiraceae_NK4A136_group与异猪去氧胆酸、猪脱氧胆酸含量呈正相关（P<0.01），拟杆菌门、巨单胞菌属、拟杆菌属与异猪去氧胆酸、猪脱氧胆酸含量呈负相关（P<0.05）。结论温胆汤能显著改善MS痰证大鼠的代谢表征，其作用机制或与调节肠道菌群-胆汁酸轴功能密切相关，可能通过介导FXR信号通路，调整MS痰证大鼠肠道菌群结构，维持胆汁酸稳态，从而改善MS痰证。

关键词: 代谢综合征, 肠道菌群, 胆汁酸, 痰证, 温胆汤, 代谢表型

Abstract:

Objective To investigate the therapeutic mechanism of Wendan Decoction for phlegm syndrome in rats with metabolic syndrome (MS). Methods Forty Wistar rats were randomly divided into normal control group (n=8) and 3 phlegm syndrome model groups (induced by high-fat, high-sugar, and high-salt feeding and a single-dose intraperitoneal STZ injection; n=24) treated with daily gavage of saline, Wendan Decoction (3.6 g/kg), or metformin (0.1 g/kg) for 4 weeks. General conditions and glucose and lipid metabolism parameters of the rats were monitored, and serum LPS, liver histopathology, hepatic expressions of FXR, CYP7A1 and FGFR4 and ileal expressions of FXR and FGF15 were examined. Gut microbiota structure was analyzed using 16S rDNA sequencing, and serum bile acids were quantified with UHPLC-MS/MS. Results The rat models of phlegm syndrome exhibited severe hepatic steatosis and necrosis, increased body weight, abdominal circumference, Lee's index, FBG, FINS, HOMA-IR, TG, TC, LDL and LPS, and decreased HDL level. The abundance of Bacteroidetes, Megamonas, and Bacteroides in gut microbiota increased while Firmicutes, Lachnospiraceae_NK4A136_group, isohyodeoxycholic acid, and glycohyodeoxycholic acid decreased significantly; hepatic FXR and FGFR4 expressions and ileal FXR and FGF15 expressions decreased while hepatic CYP7A1 expression increased significantly in the rat models. Treatment with Wendan Decoction effectively alleviated hepatic pathology, reduced body weight and abdominal circumference, improved glucose and lipid metabolic profiles and gut microbiota structure, and reversed the changes in hepatic and ileal protein expressions. Correlation analysis revealed that Firmicutes and Lachnospiraceae_NK4A136_group were positively correlated while Bacteroidetes, Megamonas and Bacteroides were negative correlated with the levels of isohyodeoxycholic acid and hyodeoxycholic acid. Conclusion Wendan Decoction can significantly improve metabolic profiles in rats with phlegm syndrome of MS possibly by regulating the intestinal flora-bile acid axis to modulate the intestinal flora structure and maintain bile acid homeostasis via the FXR signaling pathway.

Key words: metabolic syndrome, intestinal flora, bile acid, phlegm syndrome, Wendan Decoction, metabolic phenotype

黄凯悦, 齐景馨, 罗文谦, 林怡萱, 陈梅妹, 甘慧娟. 温胆汤通过调控肠道菌群-胆汁酸轴改善代谢综合征痰证大鼠的代谢表型[J]. 南方医科大学学报, 2025, 45(6): 1174-1184.

Kaiyue HUANG, Jingxin QI, Wenqian LUO, Yixuan LIN, Meimei CHEN, Huijuan GAN. Wendan Decoction ameliorates metabolic phenotypes in rats with metabolic syndrome and phlegm syndrome by modulating the gut microbiota-bile acid axis[J]. Journal of Southern Medical University, 2025, 45(6): 1174-1184.

图/表 19

表1 两组大鼠造模后比较

Tab.1 Comparison of general conditions and glucose and lipid metabolism parameters between normal and model groups (Mean±SD)

Indicator	NC group (n=8)	MG group (n=24)
Weight (g)	363.74±14.85	387.68±26.37*
Body length (cm)	22.66±0.40	22.57±0.41
Abdominal girth (cm)	18.94±0.32	20.60±0.67**
Lee's index	314.96±2.72	322.88±2.08**
TG [mmol/L, M (P25, P75)]	1.13(1.01, 1.20)	1.48(1.15,1.78)**
TC (mmol/L)	2.49±0.07	3.56±0.57**
HDL (mmol/L)	1.32±0.10	0.63±0.14**
LDL (mmol/L)	0.30±0.11	1.78±0.59**
FBG (mmol/L)	4.35±0.26	12.27±2.59**
FINS (μU/mL)	40.21±5.37	75.83±17.89**
HOMA-IR	7.82±1.45	41.68±14.63**

表2 各组大鼠干预后比较

Tab.2 Comparison of general conditions and glucose and lipid metabolism parameters of the rats after interventions (n=8, Mean±SD)

Indicators	NC group	MOD group	WDT group	MET group
Weight (g)	373.76±13.28	392.61±25.51	353.84±27.74^△△	359.29±29.29^△
Body length (cm)	23.68±0.25	23.44±0.27	23.63±0.23	23.54±0.29
Abdominal girth (cm)	20.28±0.30	21.93±0.30**	19.71±0.48^△△	19.99±0.59^△△
Lee's index	304.22±1.45	312.27±3.52**	299.17±5.08^△△	301.81±5.57^△△
TG (mmol/L)	0.70±0.10	1.07±0.11**	0.78±0.15^△△	0.93±0.14^△
TC (mmol/L)	2.43±0.09	3.63±0.39**	2.73±0.40^△△	2.83±0.33^△△
HDL (mmol/L)	0.97±0.20	0.59±0.14**	1.06±0.13^△△	0.99±0.17^△△
LDL (mmol/L)	0.26±0.02	1.08±0.18**	0.40±0.09^△△	0.49±0.13^△△
FBG (mmol/L)	4.84±0.17	14.23±1.66**	8.45±3.07^△△	9.66±2.66^△△
FINS [μU/mL, M(P25, P75)]	67.12(61.33, 69.65)	81.30(80.17, 84.82)**	67.75(64.43, 71.07)^△△	72.92(70.53, 79.02)
HOMA-IR	14.15±0.84	52.72±6.74**	25.24±9.67^△△	32.00±10.06^△△
LPS (ng/mL)	0.99±0.24	3.68±0.41**	1.94±0.18^△△	2.48±0.27^△△

图1 各组大鼠肝脏组织病理观察

Fig.1 Pathological observation of liver tissues of the rats in each group (HE, original magnification:×200). A: Normal group. B: Model group. C:Wendan Decoction group. D: Metformin group.

表3 大鼠肝脏中FXR、CYP7A1、FGFR4蛋白表达的比较

Tab.3 Comparison of FXR, CYP7A1 and FGFR4 protein expressions in rat livers (Mean±SD, n=3)

Group	FXR/GAPDH	CYP7A1/GAPDH	FGFR4/GAPDH
NC	0.59±0.08	0.65±0.18	0.61±0.06
MOD	0.27±0.06**	3.00±0.15**	0.19±0.10**
WDT	0.45±0.04^△△	1.58±0.25^△△	0.33±0.02^△
MET	0.41±0.06^△	2.60±0.64	0.32±0.03^△

表4 大鼠回肠中FXR、FGF15蛋白表达的比较

Tab.4 Comparison of FXR and FGF15 protein expressions in rat ileum (Mean±SD, n=3)

Group	FXR/GAPDH	FGF15/GAPDH
NC	0.42±0.08	0.57±0.11
MOD	0.18±0.01**	0.13±0.03**
WDT	0.28±0.03^△	0.38±0.09^△△
MET	0.35±0.02^△△	0.33±0.08^△

图2 大鼠肝脏组织FXR、CYP7A1及FGFR4蛋白表达电泳

Fig.2 FXR, CYP7A1 and FGFR4 protein expression electrophoresis in rat liver tissue.A: Normal group.B:Model group.C:Wendan Decoction group. D: Metformin group.

图3 大鼠回肠组织FXR、FGF15蛋白表达电泳

Fig.3 FXR, FGF15 protein expression electrophoresis in rat ileum.A: Normal group.B:Model group.C:Wendan Decoction group.D:Metformin group.

表5 对肠道菌群α多样性的影响

Tab.5 Comparison on α diversity of intestinal flora among the 4 groups (n=8)

Group	Chao1	Observed species	Shannon	Simpson
NC	1181.78±158.13	1173.88±155.67	7.67(6.96, 8.50)	0.98(0.93, 0.99)
MOD	784.50±93.77**	781.38±93.18**	6.60(6.36, 7.40)*	0.97(0.95, 0.98)
WDT	643.27±159.29	640.13±156.90	6.49(5.96, 7.00)	0.96(0.94, 0.97)
MET	695.19±153.57	689.50±152.21	6.85(6.41, 7.25)	0.97(0.96, 0.98)

图4 β多样性分析

Fig.4 Analysis of β diversity in the 4 groups. A:PCoA analysis diagram. B:NMDS analysis diagram. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

图5 各组大鼠门、属水平物种组成柱状图

Fig.5 Histogram of phylum (A) and genus level (B) species in each group.

表6 门水平差异物种分析

Tab.6 Differential species analysis at the phylum level (Mean±SD, n=8)

Group	Firmicutes	Bacteroidota
NC	64.13±10.29	21.13±8.24
MOD	40.27±9.55^**	31.57±8.91^*
WDT	70.08±10.79^△△	13.91±4.61^△△
MET	47.85±12.64	21.98±10.34^△

表7 属水平差异物种分析

Tab.7 Analysis of intestinal microbiota species at the genus level ［M (P25, P75), n=8］

Group	Lachnospiraceae_NK4A136_group	Megamonas	Bacteroides
NC	5.99 (2.87, 8.66)	0.07 (0.06, 0.15)	0.92±0.49
MOD	0.19 (0.16, 0.20)**	4.25 (2.24, 12.89)**	11.47±4.97**
WDT	2.56 (0.47, 7.63)^△	2.45 (0.50, 5.30)	2.01±1.20^△△
MET	0.17 (0.09, 0.33)	6.41 (3.04, 14.32)	6.19±3.03

图6 各组大鼠肠道菌群LEfSe差异分析柱状图

Fig.6 Histogram of LEfSe difference analysis in intestinal flora in each group. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

图7 PCA分析图

Fig.7 PCA analysis diagram. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

图8 各组大鼠OPLS-DA得分散点图及200次置换检验图

Fig.8 Distribution of OPLS-DA and 200 displacement tests in each group. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

图9 各组间差异胆汁酸热图

Fig.9 Differential bile acid heat maps among the 4 groups. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

图10 差异胆汁酸箱线图

Fig.10 Differential bile acid tank diagram. A: Normal group. B: Model group. C: Wendan Decoction group. D: Metformin group.

表8 肠道菌群-胆汁酸相关性分析

Tab.8 Correlation analysis of intestinal flora and bile acid

Flora	Isohyodeoxycholic acid		Hyodeoxycholic acid
Flora	r	P	r	P
Firmicutes	0.638	<0.001	0.526	0.002
Bacteroidota	-0.478	0.006	-0.380	0.032
Lachnospiraceae_NK4A136_group	0.653	<0.001	0.663	<0.001
Megamonas	-0.663	<0.001	-0.667	<0.001
Bacteroides	-0.839	<0.001	-0.751	<0.001

图11 肠道菌群与胆汁酸相关性分析

Fig.11 Correlation analysis between intestinal flora and bile acids. *P<0.05, **P<0.01.

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