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

Feb 10, 2026Journal of translational medicine

Possible use of treatments targeting the brain-gut connection in Long COVID and chronic fatigue syndrome: a case-based review

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Abstract

A patient with post-COVID ME/CFS showed a significant reduction in total fatigue after treatment with electroacupuncture-based deep peroneal nerve stimulation.

Early improvements in motivation and mental fatigue were observed, with delayed improvements in physical fatigue following transient symptom flares.
Among eight randomized controlled trials involving 790 participants, synbiotic and herbal therapies showed benefits in reducing fatigue or post-exertional malaise.
Alterations in specific bacterial populations and central nervous system metabolism were noted alongside the therapeutic effects of gut microbiome-modulating interventions.
Transcranial direct current stimulation (tDCS) combined with exercise improved fatigue, while standalone tDCS and other nerve stimulation methods had limited efficacy.
Brain-gut axis interventions may alleviate fatigue by modulating neuroinflammation, restoring microbiome balance, and improving intestinal barrier function.

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BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

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

Abstract

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