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.