Tuina for chronic fatigue syndrome: study protocol for a randomized controlled trial integrating tryptophan metabolism, gut microbiota, and brain network alterations

BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling multisystem disorder characterized by persistent fatigue, post‐exertional malaise, unrefreshing sleep, and neurocognitive and gastrointestinal symptoms. Effective non‐pharmacological treatments remain limited. Increasing evidence suggests that CFS involves not only peripheral metabolic and gastrointestinal abnormalities but also central nervous system dysfunction. Altered tryptophan metabolism and gut‐brain axis dysfunction may contribute to its pathophysiology. Tuina, a manual therapy used in traditional Chinese medicine, has been hypothesized to influence somatosensory, autonomic, stress‐related, and gastrointestinal pathways. However, randomized controlled trials evaluating its clinical effects and exploratory gut‐brain correlates in CFS remain scarce. METHODS: This multicenter, parallel‐group, randomized controlled trial will enroll 166 participants with CFS, who will be allocated in a 1:1 ratio to a Tuina group or a standardized usual care group. The Tuina group will receive treatment twice weekly for 8 weeks, whereas the control group will receive standardized usual care consisting of health education and symptom‐oriented management. The primary objective is to evaluate the effectiveness of Tuina on fatigue severity, assessed by the change in Fatigue Scale‐14 (FS‐14) score from baseline to week 8. Secondary outcomes include quality of life, sleep, pain, anxiety, depression, gastrointestinal symptoms, bowel function, and handgrip strength. Exploratory mechanistic outcomes include plasma tryptophan‐pathway metabolites, gut microbiota profiling, resting‐state functional magnetic resonance imaging, and magnetic resonance spectroscopy. Assessments will be conducted at baseline, weeks 4 and 8, and at 12 and 24 weeks after completion of treatment. DISCUSSION: This study is designed to evaluate the clinical effects of Tuina in CFS while exploring a biologically informed gut‐brain framework involving tryptophan metabolism, gut microbiota, and brain network alterations. To our knowledge, few randomized trials in CFS have prospectively integrated clinical, metabolomic, microbiome, and multimodal neuroimaging measures within a single protocol. The findings may help clarify whether a non‐pharmacological intervention can modulate interconnected peripheral and central pathways relevant to fatigue and related symptoms. CLINICAL TRIAL REGISTRATION: https://itmctr.ccebtcm.org.cn/mgt/project/view/1990257056896122880, Identifier ITMCTR2025002204.