Our findings paint a picture of ME as a truly multifaceted disorder involving inflammation with a possible origin at the immune-microbe interface in the gut. Chronic immune stimulation is likely given the symptomatology, but also elevated cytokine levels are found that correlate with symptom severity (5) and immune cell deficiencies (6). The deficiencies in cellular metabolism are not typically seen in other inflammatory diseases, although transient metabolic adaptations are common during immune responses (44).
It is important to note that ME is a heterogeneous disease and the likelihood of finding one pathogenic mechanism shared by all patients is low.
We believe that one unifying concept could be the failure in upregulating disease tolerance mechanisms in the event of an infection or virus reactivation and this is what we propose herein. Such disease tolerance mechanisms are important in limiting the reduction in host fitness as a consequence of the infection directly or as a consequence of the elicited immune defenses (41). Our data of upregulated disease tolerance pathways upon INMEST treatment support the hypothesis that ME is a result of a failure to upregulate disease tolerance mechanism when faced with infection and thereby leading to a deterioration of physiological functions (Fig. 6D), although the precise mechanisms of this remains to be unraveled. The reasons why ME patients differ so much in their symptomatology could be explained by differences in the underlying infectious disease or immune activation, and the relevant disease tolerance pathway failing to be induced.
The reasons for why ME patients would fail to upregulate disease tolerance pathways remains to be determined, although one interesting lead comes from an observation made of mutations in the enzyme IDO2 seen in 20/20 patients with severe ME (https://www.omf.ngo/2018/10/19/heal...on-the-molecular-basis-of-me-cfs-at-stanford/) and has led to the formulation of the metabolic trap hypothesis of ME (45). However, the IDO-enzymes are also involved in disease tolerance, specifically upon exposure to Endotoxin, a component of Gram-negative bacteria in the gut (46, 47).
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