Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance, by Lucie ST Rodriguez, Christian Pou, Lakshmikanth Tadepally, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie-Qiang Li, Per Julin, Petter Brodin in bioRxiv 2020.02.20.958249; [doi:org/10.1101/2020.02.20.958249]
Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.
The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation.
Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ~30% reduction in overall symptom scores after eight weeks of treatment.
By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation.
The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.
Discussion – excerpt:
The symptom relief induced by INMEST targeting the vagus nerve is significant and distinct from placebo, but must still be confirmed in larger trials with sufficient statistical power. We believe that this should be done using a self-treatment system available for use at home since the repeated visits to the clinic are so demanding for patients with ME. The main purpose of the current study was instead to use the INMEST treatment as a perturbation to the immune system and autonomic inflammatory reflex, as a means of uncovering the pathogenesis of the disorder. To this end the current study was successful and the biomolecular correlates found corroborate several previously suggested aspects of ME pathogenesis.
The mechanism of action of the INMEST-treatment in ME is not known, although some things are clear. We know that the vagus nerve nucleus in the brainstem is activated by INMEST, but also higher level centers such as the limbic system are activated (24). The effect of INMEST on heart rate variability differs from that of traditional vagus nerve stimulating methods (23). One possibility is that INMEST influences incoming (afferent) signals from the gut, conveying signals of dysbiosis or chronic immune activation and inflammation. This hypothesis is in line with previous proposals of ME as a disease caused by microbial dysbiosis in the gut (48). One possible mechanism of symptom relief upon INMEST-treatment could be through limiting such signals of enteric dysbiosis via the afferent vagus nerve.