Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain-gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)-based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain-gut axis-modulating interventions in ME/CFS or Long COVID was conducted.

The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome-modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Brain-gut axis-based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.