Trial Report Sijunzi decoction...improves fatigue symptoms with changes in gut microbiota in CFS: A randomized, double-blind, placebo-controlled etc., 2024, Dai

[Dolphin]

https://www.sciencedirect.com/science/article/abs/pii/S0944711324002952

Phytomedicine
Available online 13 April 2024, 155636


Original Article
Sijunzi decoction, a classical Chinese herbal formula, improves fatigue symptoms with changes in gut microbiota in chronic fatigue syndrome: A randomized, double-blind, placebo-controlled, multi-center clinical trial

Liang Dai et al.
1
Institute of Digestive Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
2
State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine
3
Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China
4
Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin, 214413, China
5
Clinical Research Academy, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518036, China
6
Shanghai Changning Tianshan Hospital of Traditional Chinese Medicine, Shanghai, 200051, China

https://doi.org/10.1016/j.phymed.2024.155636

ABSTRACT

Backgroud
Chronic fatigue syndrome (CFS) severely impact patients’ quality of life and lacks well-acknowledged drug therapy. Sijunzi decoction (SJZD), a classical Chinese herbal formula, has been widely used for spleen deficiency syndrome like fatigue in China. However, there is a lack of evidence on the effectiveness of SJZD in treating CFS.

Purpose
To evaluate the efficacy and safety of SJZD for CFS.

Study Design
A multicenter, double-blinded, randomized controlled trial.

Methods
Participants with definite diagnoses of CFS and spleen deficiency syndrome were randomly assigned in 1:1 ratio to receive SJZD or placebo granules for 2 months. The primary outcome was the change of Chalder fatigue questionnaire (CFQ) scoring after treatment. Other outcomes included changes in short form-36 physical function (SF36-PF) score, spleen deficiency scale score, Euroqol Questionnaire-Visual Analogue Scale (ED-VAS) score, and clinical global impression (CGI) evaluating by corresponding questionnaires. Fecal metagenome sequencing was conducted to explore the potential mechanism of SJZD effect.

Results
From June 2020 to July 2021, 105 of 127 participants completed the study at four hospitals in China. After a 2-month treatment, intention-to-treat (ITT) analysis found participants who received SJZD had larger reduction than placebo control (mean change 6.65 [standard deviation (SD) 6.11] points vs. 5.31 [SD 5.19] points; difference 1.34, 95% confidence interval [CI] -0.65 to 3.33). Per-protocol (PP) analysis reported confirmative results with a significant difference between SJZD and placebo group (2.24, 95% CI 0.10 to 4.39). SJZD also significantly improved overall health status compared with placebo in per-protocol population (p = 0.009). No significant difference was found between groups in changes of SF36-PF, spleen deficiency scale scoring, and CGI. Fecal metagenome sequencing and correlation analyses indicated that the beneficial effect of SJZD may be related to the abundance change of Pediococcus acidilactici. No serious adverse event or abnormal laboratory test was found during the whole study.

Conclusion
Our results indicated that SJZD can improve fatigue symptom and overall health status in patients with CFS under good medication adherence. Potential therapeutic effects may be related to the regulation of gut microbiota. Large-scale trials with longer intervention period are encouraged to further support SJZD's application.

Clinical trial registration
(ID, ISRCTN23930966, URL = https://www.isrctn.com/ISRCTN23930966).

Graphical Abstract

https://twitter.com/user/status/1779614357871006065

 

[SNT Gatchaman]

widely used for spleen deficiency syndrome like fatigue in China

I had to look this up to see if this meant a claim that eg anyone post splenectomy would have "chronic fatigue". From the introduction in Integrative metabolic and microbial profiling on patients with Spleen-yang-deficiency syndrome (2018, Nature Scientific Reports) —

In traditional Chinese medicine (TCM), “Spleen” is completely different with that of the spleen organ in western medicine. “Spleen” in TCM is associated with stomach that is responsible for food and fluid assimilation and transformation into usable nutrients for the body. Thus, “Spleen dysfunction” in TCM is a panel of comprehensive syndromes that are involved with various disorders in digestive and circulatory systems. The typical characters of “Spleen dysfunction” include poor appetite and digestion, fatigue, and bleeding disorders. Spleen-deficiency syndrome (SDS) is a typical syndrome of TCM, which is characterized by poor appetite, fullness and sleepiness after eating, fatigue, pale face and tongue, weight loss, and loose stools. Spleen-yang-deficiency syndrome (SYDS) is one of the most common types of SDS. Patients with SYDS are usually diagnosed with abnormalities in the gastroenterological system such as diarrhea, chronic gastroenteritis or hepatitis and candida infection in western medicine. However, to date the biological mechanisms underlying SYDS are largely unknown.

 

[Hutan]

The productivity issues of Long Covid are noted

Noticeably, persistent fatigue has become a frequent symptom of long COVID, which may further increase the prevalence of CFS (Cai et al., 2023, Huang et al., 2021). Although CFS does not contribute to overall mortality, it significantly affects the mental well-being and quality of life, leading to a considerable rise in healthcare expenditures and a noticeable decline in social productivity (Lin et al., 2011, Roberts et al., 2016, Similä et al., 2020).

A perspective on CFS treatment approaches in China

Current symptomatic treatment options with relatively solid evidences contain immune modulator rintatolimod, counseling therapy and graded exercise therapy (Clark et al., 2017, Smith et al., 2015, Strayer et al., 2012). However, in Asia, rintatolimod has not been widely approved. And due to conservative attitude towards non-pharmaceutical interventions, cognitive behavior therapies are not generally accepted (Chen, 2018, Sun et al., 2018). Therefore, many patients often turn to traditional Chinese medicine (TCM) for consultation, with herbal medicine being the primary intervention.

Re the Chalder Fatigue Questionnaire and the suggestion that 11 is the lowest score:

Scoring schemes for the Chalder Fatigue Scale = 11 question Likert form

Less than usual 0
No more than usual 1
More than usual 2
Much more than usual 3

MEPedia has this commentary:

Separate problems have been noted with this scoring method. The introduction to this version of the CFQ, asks respondents to compare themselves to how they felt when they were last well.[15] A response of ‘no more than usual’ (score 1) would thus indicate full recovery. Persons without fatigue problems would score 11/33, indicating that they had fatigue ‘no more than usual’.[23] Indeed, the use of the CFQ in healthy community samples yielded scores of 12-14.[34][6][7]

The Likert score of the CFQ also offers the option “less than usual” (score 0). It’s not clear what such an answer means. It seems to indicate an abnormal absence of fatigue complaints. Evidence that this option confuses respondents, comes from a trial on cognitive behavioral therapy in patients with multiple sclerosis. Post-treatment MS patients recorded a score of less than 10, indicating they had less fatigue than healthy persons. Even the control which received relaxation therapy had lower fatigue scores than healthy persons.[26] This may indicate that they misinterpreted the "less than usual” (score 0) option, or that their "healthy" level involved some level of tiredness that disappeared with treatment, or simply that they felt abnormally alert. Results like these can question the reliability of the Likert scoring system of the CFQ.

As is suggested by MEPedia - for the participants in the MS trial who reported a score of less than 10, it seems likely that the participants in the SJZD trial baselines changed when they answered the CFQ the second time.

So, the first time, the participants might answer relative to their healthy baseline e.g. recording '2' - my fatigue level is more than is usual
The second time, the participants might answer relative to the baseline at the beginning of the trial - e.g. recording '1' - my fatigue is no more than usual/ no more than it was when the researchers last asked me, before the treatment
That is one of the major flaws* with the CFQ - no real change in fatigue can result in an apparent improvement after treatment.

*or joys - if you are trying to prove an ineffective treatment is effective. There are reasons why the CFQ is so favoured by researchers running trials of treatments.

Throw in a translation problem, and this variable baseline problem could easily result in scores of less than 11.

 

[Hutan]

I'm always interested in how other cultures have described and categorised post-infection syndromes.

Spleen-deficiency syndrome (SDS) is a typical syndrome of TCM, which is characterized by poor appetite, fullness and sleepiness after eating, fatigue, pale face and tongue, weight loss, and loose stools.

It's actually not that far away from ME/CFS definitions. I've seen descriptions of ME/CFS that sound less like my conception of the disease than that SDS description. I'd be interested to see more detailed descriptions of SDS.

And, I'm not ruling out the possibility that some cultures may have found a remedy that does help post-infection fatigue syndromes.

The Chinese medicine Si-Jun-Zi Decoction is a famous herbal formula composed of four Chinese herbs: Ginseng Root, Atractylodes macrocephala, licorice root, and Poria root. This formula is considered mild in nature. It balances qi and invigorates the spleen. Modern pharmacological studies show that this prescription affects several other physiological functions such as improving gastrointestinal function [5], strengthening the immune system [6, 7], improving bone marrow hematopoietic function, and speeding up the production of red blood cells.

Atractylodes is a type of daisy. Poria is a mushroom. All of those ingredients have pharmacoactive compounds.

But, I don't think we have seen a convincing TCM ME/CFS paper yet. The difference between the active and placebo groups here is small, if there is any difference at all. No difference on the SF-36 PF suggests that any actual benefit is so small that it's essentially irrelevant.

 

[MeSci]

You've missed out the 'S' at the beginning of the title.

 

[Trish]

You've missed out the 'S' at the beginning of the title.

Fixed.

 

[Mij]

The Chinese medicine Si-Jun-Zi Decoction is a famous herbal formula composed of four Chinese herbs: Ginseng Root, Atractylodes macrocephala, licorice root, and Poria root.

Ginseng made me feel very jittery and brought on insomnia years ago. It took me a while to figure out why my sleep changed when I sleeping well back then.

Also, pwME took licorice root (DGL) rec'd for GERD, but it shouldn't be taken in large amounts b/c it can raise blood levels of aldosterone.