Fig. 4: Potential mechanisms for inflammation, fatigue, and PEM.

Mechanistic model of Inflammation (A) before and (B) after exercise. A Before exercise, plasma levels of TAGs, DAGs, and HTRA1 were elevated in ME/CFS; levels of SELL, CDH5, CD93, ADGRD1, CLEC3B, and COMP were lower. Elevated levels of TAGs and DAGs reflect inflammation. Reduced levels of SELL, CD93, ADGRD1, CSF1, KDR and CDH5 result in impaired recruitment of immune cells to tissues. Reduced levels of CLEC3B and COMP, as well as elevated levels of HTRA1, may disrupt ECM homeostasis. B After exercise, plasma levels of TAGs, DAGs, HTRA1, and CDH1 were elevated in ME/CFS; levels of SELL, ADGRD1, CLEC3B, and COMP were reduced. Levels of IL-6, BMP1, and WNT5A were elevated in long duration ( > 3 years) ME/CFS. Elevated levels of CDH1 and BMP1 reflect impairments in leukocyte adhesion and ECM homeostasis. Elevated levels of BATF3 and proC reflect altered immune cells recruitment and activation. Elevated levels of WNT5A reflect activation of non-canonical WNT signaling, leading to adipogenesis and inflammation. ADGRD1, G-protein coupled receptor D1; BATF3, basic leucine zipper transcriptional factor ATF-like 3; BMP1, bone morphogenetic protein 1; CDH1, cadherin-1; CDH5, Cadherin-5/VE-cadherin; CLEC3B, tetranectin; COMP, cartilage oligomeric matrix protein; CSF1, colony stimulating factor 1; DAG, diglyceride; ERVV1, endogenous retrovirus group V member 1; HTRA1, high-temperature requirement serine protease A1; KDR, kinase insert domain receptor; LRP8, low-density lipoprotein receptor-related protein 8; proC, Protein C; SELL, L-selectin; TAG, triglyceride; WNT5A, wingless-type MMTV integration site family, member 5A. Abnormalities in energy and lipid metabolism (C) before and (D) after exercise. C Before exercise, plasma levels of TAGs and DAGs were elevated in ME/CFS; ratios of ORN:CIT, and ARG: CIT, were elevated; levels of 12,13-diHOME were reduced. Levels of CIT were reduced in long duration ME/CFS. Reduced level of CIT, together with elevated ORN:CIT ratios, reflect impairments in urea cycle, leading to improper detoxification and inflammation. D After exercise, plasma levels of citric acid increased in ME/CFS but decreased in HC; levels of CAR were reduced; ratios of ORN:CIT and ARG:CIT were decreased. Plasma levels of ASP increased in long duration ME/CFS. Increased levels of citrate reflect TCA cycle impairment, increased fatty acid synthesis, and inflammation. Decreased ratios of ORN:CIT and ARG:CIT, together with increased levels of ASP reflect impairments in urea cycle possibly due to reduced activity of CIT transporters or of enzymes for urea cycle intermediates. Increased levels of 12,13-diHOME and reduced levels of CAR reflect decreased flux of β-oxidation, further accumulating TAGs and DAGs. ARG, arginine; ASP, aspartic acid; CIT, citrulline; CAR, carnitine; DAG, diglyceride; diHOME, dihydroxyoctadecenoic acid; ORN, ornithine; TAG, triglyceride. Abnormalities in gut microbiome and TRP metabolism (E) before and (F) after exercise. E Before exercise, plasma levels of TFF1 and ILA were reduced in ME/CFS; levels of GA were elevated; ratios of KYN:TRP were reduced, ratios of KYNA:KYN were elevated. Plasma levels of CIT were reduced in long duration ME/CFS. Reduced levels of ILA and leucate reflect dysbiosis and enhanced inflammation in the gut. Elevated levels of GA reflect deconjugation of xenobiotic metabolites, leading to inflammation. F After exercise, plasma levels of PPA and GA were elevated in ME/CFS; ratios of KYN:TRP were increased while ratios of KYNA:KYN were decreased. Plasma levels of REG4 were elevated in long duration ME/CFS. Increased ratios of KYN:TRP and increased plasma levels of 3-MA reflect activation of KYN pathway, diverting the TRP metabolism from serotonin pathway, leading to reduced serotonin production and cognitive dysfunction. Elevated levels of PPA reflect dysbiosis, leading to mitochondrial dysfunction and, potentially, neuroinflammation. Elevated levels of REG4 reflect compromised regeneration of gut lining, leading to impaired gut barrier function. CIT, citrulline; GA, glucuronic acid; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; IAA, Indole-3-acetic acid; ILA, indole-3-lactate/indole lactic acid; IPPA, indole-3-propionic acid; IPYA, indole-3-pyruvic acid; KYN, kynurenine; KYNA, kynurenic acid; PPA, propionic acid; QA, quinolinic acid; REG4, regenerating islet-derived 4; TRP, tryptophan; TFF1, Trefoil Factor 1; 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 3MA- 3-methoxy anthranilate; 5-HT, 5-hydroxytryptamine; ME/CFS^LD, ME/CFS with >3 Years of illness.