Integrated 'omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome

doi:10.19852/j.cnki.jtcm.20231018.004

Journal of Traditional Chinese Medicine ›› 2023, Vol. 43 ›› Issue (6): 1176-1189.DOI: 10.19852/j.cnki.jtcm.20231018.004

• Research Articles • Previous Articles Next Articles

Integrated 'omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome

LI Chaoran¹, YANG Yan², FENG Chuwen³, LI Heng⁷, QU Yuanyuan⁵, WANG Yulin⁶, WANG Delong⁶, WANG Qingyong⁵, GUO Jing⁵, SHI Tianyu⁵, SUN Xiaowei⁴, WANG Xue⁸, HOU Yunlong⁹, SUN Zhongren⁶(), YANG Tiansong¹⁰()

1 Department of Acupuncture, Zhejiang Chinese Medical University, Hangzhou 310000, China
2 Department of Chinese Medical Literature, College of Basic Medicine, Heilongjiang University of Chinese medicine, Harbin 150040, China
3 Department of Rehabilitation, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China
4 Department of Acupuncture, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China
5 Graduate School, the Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China
6 Department of Acupuncture, the Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China
7 Shanghai Applied Protein Technology Co., Ltd., Shanghai 200233, China
8 Department of Acupuncture, Chongqing Changshou District People's Hospital, Chongqing 401220, China
9 College of integrated Chinese and Western Medicine, Hebei University of Chinese Medicine, and National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Hebei 050000, China
10 Department of Rehabilitation, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, and Traditional Chinese Medicine Informatics Key Laboratory of Heilongjiang Province, Harbin 150040, China

Received:2023-05-22 Accepted:2023-08-08 Online:2023-10-25 Published:2023-10-18
Contact: Prof. SUN Zhongren, Department of Acupuncture, Heilongjiang, University of Chinese Medicine, Harbin 150040, China. sunzhong_ren@163.com; Prof. YANG Tiansong, Department of Rehabilitation, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, and Traditional Chinese Medicine Informatics Key Laboratory of Heilongjiang Province, Harbin 150040, China. yangtiansong2006@163.com. Telephone: +86-15557137527
Supported by:
Based on TGF-β/Smad Signaling Pathway to Studying the Role and Mechanism of NF-κB in the Treatment of Chronic Fatigue Syndrome with Electroacupuncture(81704170);Mechanism Study on Electroacupuncture Regulating MDM2 Ubiquitination PSD-95 Level and Remodeling Synaptic Structure of Hippocampal Neurons to Improve Cognitive Dysfunction in CFS(81873378);Study on the Mechanism of Electroacupuncture Adjusting Gut Microbiota to Improve Oxidative Inflammatory Response in the Treatment of Chronic Fatigue Syndrome(LH2020H092);Experimental Study on Electroacupuncture Improving Protein Expression Differences and Target Effects in Hippocampus and Hypothalamus of Rats with Chronic Fatigue Syndrome(LBH-Q18117);Study on the Effect and Mechanism of Moxibustion on Gut Microbiota in Rats with Chronic Fatigue Syndrome(ZHY2020-79);The Mechanism of TGF-β/ Smad Mediated NF- κB Inflammatory Pathway in the Treatment of Chronic Fatigue Syndrome by Electroacupuncture(ZHY16-003);The Mechanism of Electroacupuncture Improving Hippocampal Synaptic Plasticity in CFS Cognitive Dysfunction Rats(ZHY2022-136);Study on the Mechanism of Moxibustion Regulating the Gut Microbiota of Chronic Fatigue Syndrome Targeting the 5-HT Signal System(2021RCZXZK02);Study on the Mechanism of Moxibustion Repairing the Barrier Function-Inflammatory Response of Chronic Fatigue Syndrome by the Gut-Brain Axis(ZS21ZA08);Based on Gut Microbiota and Metabolism to Study the Mechanism in the Treatment of Chronic Fatigue Syndrome by Moxibustion(2019BS03)

1. .pdf(582KB)

Abstract

Abstract:

OBJECTIVE: To observe the efficacy of moxibustion in the treatment of chronic fatigue syndrome (CFS) and explore the effects on gut microbiota and metabolic profiles.
METHODS: Forty-eight male Sprague-Dawley rats were randomly assigned to control group (Con), CFS model group (Mod, established by multiple chronic stress for 35 d), MoxA group (CFS model with moxibustion Shenque (CV8) and Guanyuan (CV4), 10 min/d, 28 d) and MoxB group (CFS model with moxibustion Zusanli (ST36), 10 min/d, 28 d). Open-field test (OFT) and Morris-water-maze test (MWMT) were determined for assessment the CFS model and the therapeutic effects of moxibustion.16S rRNA gene sequencing analysis based gut microbiota integrated untargeted liquid chromatograph-mass spectrometer (LC-MS) based fecal metabolomics were executed, as well as Spearman correlation analysis, was utilized to uncover the functional relevance between the potential metabolites and gut microbiota.
RESULTS: The results of our behavioral tests showed that moxibustion improved the performance of CFS rats in the OFT and the MWMT. Microbiome profiling analysis revealed that the gut microbiomes of CFS rats were less diverse with altered composition, including increases in pro-inflammatory species (such as Proteobacteria) and decreases in anti-inflammatory species (such as Bacteroides, Lactobacillus, Ruminococcus, and Prevotella). Moxibustion partially normalized these changes in the gut microbiota. Furthermore, CFS was associated with metabolic disorders, which were effectively ameliorated by moxibustion. This was demonstrated by the normalization of 33 microbiota-related metabolites, including mannose (P = 0.001), aspartic acid (P = 0.009), alanine (P = 0.007), serine (P = 0.000), threonine (P = 0.027), methionine (P = 0.023), 5-hydroxytryptamine (P = 0.008), alpha-linolenic acid (P = 0.003), eicosapentaenoic acid (P = 0.006), hypoxanthine (P = 0.000), vitamin B6 (P = 0.000), cholic acid (P = 0.013), and taurocholate (P = 0.002). Correlation analysis showed a significant association between the perturbed fecal microbiota and metabolite levels, with a notable negative relationship between LCA and Bacteroides.
CONCLUSIONS: In this study, we demonstrated that moxibustion has an antifatigue-like effect. The results from the 16S rRNA gene sequencing and metabolomics analysis suggest that the therapeutic effects of moxibustion on CFS are related to the regulation of gut microorganisms and their metabolites. The increase in Bacteroides and decrease in LCA may be key targets for the moxibustion treatment of CFS.

Key words: moxibustion, fatigue syndrome, chronic, gastrointestinal microbiome, 16S rRNA gene sequencing, metabolomics

LI Chaoran, YANG Yan, FENG Chuwen, LI Heng, QU Yuanyuan, WANG Yulin, WANG Delong, WANG Qingyong, GUO Jing, SHI Tianyu, SUN Xiaowei, WANG Xue, HOU Yunlong, SUN Zhongren, YANG Tiansong. Integrated 'omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome[J]. Journal of Traditional Chinese Medicine, 2023, 43(6): 1176-1189.

Figures/Tables 6

Figure 1 Experimental design A: flow chart of the experiment; B: modeling method: MCS; C: illustration of moxibustion. C1: Guanyuan (CV4) and Shenque (CV8) for the MoxA group; C2: Zusanli (ST36) for the MoxB group. RR: routine rearing; MCS: multivariate compound stress; MAT: moxibustion A treatment; MBT: moxibustion B treatment.

Table 1 Semiquantitative score of the rats’ biological characteristics

Score	Spiritual statue	Skin and hair	Color of ear and tail	Feces
0	Active	Skin and fat were closely connected, pliable, and elastic; hair bright and smooth	Rosy with brightness	Dry feces, with shape
1	Slightly slow reaction, independent movement decreased	A bit flaccid skin, soft, pulling force decreased; yellow hair without brightness	Slight red, lacking of brightness	Sticky, soft feces, with shape
2	Listlessness, limb crunched with slow movement	Flaccid skin, little fat, easy to catch; hair dry or tangled, without brightness	Slight white, lacking of brightness	Shapeless, but not watery
3	Spiritual languor, disappearance of aggressive and adversarial behavior	Flaccid skin, no fat under the skin, and bony; dry and sparse hair of the whole body	Pale of green	Watery, green, sticky, malodorous

Figure 2 Behavioral indicators of rats in different groups A: numbers of crossing; B: numbers of entering the central region. A and B for OFT; C: latency time; D: numbers of platform crossing. C and D for MWMT. Data are presented as mean ± standard deviation, then analyzed using one-way analysis of variance followed by the Least-Significant Difference post hoc test for A, C, and Kruskal-Wallis sum-rank test for B, D. n = 12 per group. Compared with the Con group, aP < 0.01; compared with the Mod group, bP < 0.01; cP < 0.05. OFT: open-field test; MWMT: Morris-water-maze test. Con: Control group; Mod: Model group (multiple chronic stress for 35 d); MoxA: MoxibustionA group [moxibustion Shenque (CV8) and Guanyuan (CV4), 10 min/d, 28 d]; MoxB: MoxibustionB group [CFS model with moxibustion Zusanli (ST36), 10 min/d, 28 d].

Figure 3 Gut microbiota analysis A: alpha diversity; B: beta diversity (PCA plot); C: gut microbiota comparison at phylum levels; D: gut microbiota comparison at genus levels; E: cladogram of LEfSe analysis. N = 8 per group. PCA: principal component analysis; LSD: linear discriminant analysis effect size. Con: Control group; Mod: Model group (multiple chronic stress for 35 d); MoxA: MoxibustionA group [moxibustion Shenque (CV8) and Guanyuan (CV4), 10 min/d, 28 d]; MoxB: MoxibustionB group [CFS model with moxibustion Zusanli (ST36), 10 min/d, 28 d].

Figure 4 Metabolomics analysis A: PCA analysis in positive (A1) and negative (A2) ion modes in Con vs Mod vs MoxA group; B: PCA analysis in positive (B1) and negative (B2) ion modes in Con vs Mod vs MoxB group; C: OPLS-DA score plots among Con vs Mod group in positive (C1) and negative (C2) ion modes; D: OPLS-DA score plots among Mod vs MoxA group in positive (D1) and negative (D2) ion modes; E: OPLS-DA score plots among Mod vs MoxB group in positive (E1) and negative (E2) ion modes; F: Enriched KEGG pathways among Con vs Mod group (F1), Mod vs MoxA group (F2), and Mod vs MoxB group (F3). n = 8 per group. PCA: Principal Component Analysis; OPLS-DA: Orthogonal Partial Least Squares Discriminant Analysis; KEGG: Kyoto Encyclopedia of Genes and Genomes. Con: Control group; Mod: Model group (multiple chronic stress for 35 d); MoxA: MoxibustionA group [moxibustion Shenque (CV8) and Guanyuan (CV4), 10 min/d, 28 d]; MoxB: MoxibustionB group (CFS model with moxibustion Zusanli (ST36), 10 min/d, 28 d).

Table 2 Potential fecal biomarkers and their variation trends in CFS rats after moxibustion treatment

Metabolite	M/Z	RT (s)	P value	M/C	A/M	B/M
Alpha-D-Glucose	179.0573	581.66	≦0.01	↓	↑	↑
D-Lactose	341.1099	627.54	≦0.01	↓	↑	↑
D-galacturonic acid	193.0364	746.92	≦0.05	↓	↑	↑
N-Acetyl-D-glucosamine	202.0727	491.05	≦0.05	↓	↑	↑
L-Arabinose	149.0463	251.25	≦0.05	↓	↑	↑
D-Allose	239.0785	566.66	≦0.01	↓	↑	↑
D-Mannose	161.0467	781.22	≦0.01	↓	↑	↑
Maltotriose	487.1647	900.38	≦0.01	↓	↑	↑
D-Maltose	341.1098	748.53	≦0.01	↓	↑	↑
L-Fucose	163.0619	296.94	≦0.05	↓	↑	↑
N,N'-Diacetylchitobiose	425.1757	673.55	≦0.01	↓	↑	↑
D-Tagatose	161.0464	566.79	≦0.01	↓	↑	↑
N-Acetylmannosamine	280.1048	531.22	≦0.01	↓	↑	↑
alpha-Linolenic acid	279.2309	172.00	≦0.01	↓	↑	↓
Eicosapentaenoic acid	303.2309	92.16	≦0.01	↓	↑	↓
D-Aspartic acid	132.0310	775.96	≦0.01	↓	↑	↑
Pyridoxal (Vitamin B6)	166.0514	86.87	≦0.05	↓	↑	↑
L-Ascorbic acid	235.0471	628.60	≦0.01	↓	↑	↑
Taurocholate	533.3239	334.42	≦0.01	↓	↑	↑
Hypoxanthine	135.0320	348.16	≦0.01	↓	↑	↑
Xanthine	153.0397	329.69	≦0.01	↓	↑	↑
Uridine	303.0841	299.38	≦0.05	↓	↑	↑
Cytosine	112.0497	463.52	≦0.05	↓	↑	↑
L-Pyroglutamic acid	147.0755	717.28	≦0.05	↓	↑	↑
L-Malic acid	133.0152	790.60	≦0.05	↑	↑	↓
Cholic acid	426.3201	468.25	≦0.01	↓	↑	↓
L-Alanine	90.0542	663.82	≦0.01	↓	↑	↑
L-Methionine	148.0446	527.96	≦0.05	↓	↑	↑
D-Proline	116.0698	598.44	≦0.01	↓	↑	↑
L-Serine	104.0359	712.24	≦0.01	↓	↑	↑
L-Threonine	120.0646	679.34	≦0.05	↓	↑	↑
L-Asparagine	153.0312	456.38	≦0.05	↓	↑	↑
Serotonin	177.1013	260.55	≦0.01	↓	↑	↑

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Integrated 'omics analysis for the gut microbiota response to moxibustion in a rat model of chronic fatigue syndrome

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