Research for ME/CFS (myalgic encephalomyelitis or chronic fatigue syndrome)
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Main symptoms: Chronic fatigue. Ataxia. Post-exertional malaise (PEM). Inflammation (autoimmune disorder). Digestive issues/disorders (e.g., IBD). Brain fog. Muscle weakness/pain.
Dysbiosis and ME/CFS
Gut-derived D-lactic acid overproduction: Overgrowth of Gram-positive bacteria increases D-lactic acid production, lowering intestinal pH and increasing gut permeability. D-lactic acid production could contribute to mitochondrial dysfunction. Limited capacity to metabolize D-lactic acid exacerbated by digestive issues/disorders (IBD, etc).
Decreased short-chain fatty acids (SCFA): A reduction in SCFA-producing bacteria weakens the intestinal barrier by decreasing butyrate production. Butyrate deficiency is emerging as a key finding across multiple independent studies.
Increased Lipopolysaccharides (LPS) Theory: Endotoxins, or LPS, from Gram-negative bacteria can enter mesenteric lymph nodes and the bloodstream by disrupting tight-junction proteins, leading to an immune response and systemic inflammation.
Kynurenine production insufficiency theory. Kynurenine is a metabolite in the tryptophan pathway. Kynurenine production insufficiency can have a significant impact on NAD⁺ production. The kynurenine pathway is one of the major routes for de novo NAD⁺ synthesis in mammalian cells. This pathway starts with the conversion of the essential amino acid tryptophan (Trp) into kynurenine (KYN) through the action of enzymes such as indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO). Both enzymes responsible for converting tryptophan into kynurenine (IDO and TDO) are heme-dependent enzymes. Iron deficiency (anemia or low ferritin) can directly reduce the activity of these enzymes. Kynurenine is then metabolized through a series of reactions to ultimately produce NAD⁺. Vitamin B6 (Pyridoxal 5'-Phosphate) is critical for enzymes like kynureninase and kynurenine aminotransferase. Deficiencies reduce KP efficiency. Vitamin B2 (Riboflavin) supports kynurenine 3-monooxygenase activity. Magnesium regulates quinolinate phosphoribosyl transferase, zinc, manganese, copper, and cobalt all influence kynureninase and other KP enzymes. Vitamin D modulates tryptophan metabolism. N-Acetylcysteine (NAC), a glutathione precursor, lowers KYNA levels by 50% in animal models. Many multi-flower honeys contain kynurenic acid (a metabolite of kynurenine), and chestnut honey is particularly known for its high content. Balancing KP metabolites may restore NAD⁺ production (essential for cellular energy) and provide neuroprotective/anti-inflammatory effects. NAD⁺ precursors (e.g., nicotinic acid, nicotinamide riboside) can help support NAD⁺ synthesis. Caloric restriction (intermittent) has been shown to increase NAD⁺ levels, possibly through enhanced mitochondrial function and metabolic activity.
Past antibiotic intake hypothesis: Using antibiotics can disrupt the microbiome, impair anti-inflammatory metabolite production, and increase D-lactate-producing bacteria, potentially leading to conditions like D-lactic acidosis and intestinal barrier dysfunction.
The stress crash theory: Physiological stress may alter the gut microbiota by decreasing beneficial bacteria, potentially contributing to ME/CFS.
RNase L antiviral pathway dysregulation
The RNase L antiviral pathway is a key aspect of the immunological abnormalities observed in ME/CFS.
Normal Function of the RNase L Pathway: The RNase L pathway is a critical component of the cellular antiviral defense mechanism. It is activated by type I interferons (IFNs) and plays a role in degrading viral and cellular RNA, thereby inhibiting viral replication and promoting apoptosis (programmed cell death) in infected cells.
Activation by Interferons: When a cell detects viral RNA, it produces type I interferons (IFN-α and IFN-β). These interferons bind to receptors on the cell surface, initiating a signaling cascade that leads to the activation of the RNase L pathway.
2-5A Synthetase: The interferon signaling activates 2-5A synthetase, an enzyme that synthesizes 2-5A (2-5-anhydrosugar), a unique RNA molecule.
RNase L Activation: The 2-5A molecules bind to and activate RNase L, converting it from an inactive to an active state.
RNA Degradation: Activated RNase L degrades both viral and cellular RNA, leading to the inhibition of viral replication and the induction of apoptosis in infected cells.
In ME/CFS, there is hyperactivation of the 2-5A synthetase/RNase L pathway, leading to the production of an abnormal low molecular weight (LMW) RNase L. This LMW RNase L contributes to uncontrolled RNA degradation, apoptosis, and subsequent proteolytic cleavage of vital proteins, potentially leading to a vicious cycle of cellular dysfunction and fatigue.
Abnormal Low Molecular Weight (LMW) RNase L: In a subset of CFS patients, the RNase L enzyme is cleaved into an abnormal low molecular weight form (LMW RNase L). This LMW RNase L is more active than the native enzyme, leading to uncontrolled RNA degradation.
Increased RNA Degradation: The hyperactive LMW RNase L results in the excessive degradation of both viral and cellular RNA. This can result in apoptosis and the subsequent release of proteolytic enzymes such as elastase and calpain.
Proteolytic Cleavage: These proteolytic enzymes further cleave vital cellular proteins, including the authentic RNase L enzyme, creating a vicious cycle of cellular dysfunction.
Ion Channel Dysfunction: The LMW RNase L may also bind to ion channels in cell membranes, disrupting proper ion flux and leading to inefficient ion transport. This can cause a variety of symptoms, including fatigue, muscle weakness, and cognitive dysfunction.
The uncontrolled RNA degradation and subsequent cellular dysfunction contribute to the severe fatigue and other symptoms experienced by ME/CFS patients. The LMW RNase L is considered a potential biological marker for ME/CFS, distinguishing it from other diseases.
Nuclear Factor Kappa Beta (NF-κB)
NF-κB is a transcriptional regulator that modulates cellular responses to environmental stimuli and cytokines. In CFS, NF-κB is hyperactivated, leading to increased production of nitric oxide (NO) and other inflammatory mediators. Excessive NO production is cytotoxic and can contribute to fatigue by disturbing iron metabolism and mitochondrial respiration.
Natural Killer Cell Functioning
Natural killer (NK) cells are part of the nonspecific immune system, and their malfunctioning is documented in CFS patients. Reduced NK cell cytotoxicity is observed in a subgroup of CFS patients, potentially contributing to fatigue. The exact cause of reduced NK activity is unclear but may involve genetic predisposition and impaired NO-mediated activation of NK cells.
Treatment Strategy for ME/CFS
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Address likely mineral/vitamin deficiencies: multivitamin/mineral.
COX-2/NF-κB inhibition: Celecoxib, Sikonin, Honokiol, Luteolin, Scutellaria baicalensis (baicalein/baicalin).
PDK inhibition: Shikonin.
FAS inhibition: EGCG, Orlistat, Silibinin, Andrographis.
Address likely D-Lactic acid overproduction: bicarbonate, thiamine, shikonin.
Address (brain) inflammation: Boswellia AKBA, Luteolin.
Address Kynurenine production insufficiency: NAC, Magnesium (Mg malate), Zinc, Vitamins B2, B6, Manganese, Copper, and D3 (check multivitamin).
Inhibit L-carnethine: Andrographis.
Support NAD⁺ synthesis: Caloric restriction (intermittent), NAD⁺ precursors (e.g., nicotinic acid/VitB3, nicotinamide riboside).
Address LPS: Activated Charcoal (Use cautiously).
Mast Cell Stabilizers: Luteolin, Quercetin.
Addressing the hyperactivation of the 2-5A synthetase/RNase L pathway: The LMW RNase L is created when the normal enzyme is "chopped" by two speci[1]fic proteolytic enzymes: Elastase and Calpain. Inhibiting these enzymes can prevent the fragmentation of RNase L. Boswellia Serrata, specifically extracts high in AKBA (Acetyl-11-keto-beta-boswellic acid). Boswellia is a potent natural inhibitor of elastase and 5-LOX (an inflammatory enzyme). Curcumin & Quercetin are both broad-spectrum anti-inflammatories and have been shown to inhibit calpain and protect against the oxidative stress that triggers these enzymes.
Lifestyle and dietary adjustments: pacing activity/exercise. A balanced diet with enough fiber for butyrate production. Chestnut or multi-flower 100% honey (moderate consumption). Grated carrot (reduce LPS). No fermented foods (kefir, etc).
Basic protocol:
Multivitamin (with Zinc, Vitamins B2, B6, Manganese, Copper, D3, and (iron))
Honokiol
Shikonin
EGCG
bicarbonate
thiamine (in addition to multi)
Boswellia AKBA
Luteolin
NAC
Mg malate
Andrographis
Activated Charcoal
Quercetin
Curcumin
Celecoxib
References
Meeus, Mira & Mistiaen, Wilhelm & Lambrecht, Luc & Nijs, Jo. (2009). Immunological Similarities between Cancer and Chronic Fatigue Syndrome: The Common Link to Fatigue?. Anticancer research. 29. 4717-26.
Comhaire F. How I treat my patients with Myalgic Encephalomyelitis, Chronic Fatigue Syndrome (ME/CVS), Fibromyalgia or “long COVID”. J Clin Images Med Case Rep. 2025; 6(3): 3508.
Frémont, Marc & Coomans, Danny & Sebastien, Massart & Meirleir, Kenny. (2013). High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 22. 10.1016/j.anaerobe.2013.06.002.
Roelens, S., Herst, C. V., D’Haese, A., Smet, K. D., Frémont, M., Meirleir, K. D., & Englebienne, P. (2001). G-Actin Cleavage Parallels 2-5A-Dependent RNase L Cleavage in Peripheral Blood Mononuclear Cells—Relevance to a Possible Serum-Based Screening Test for Dysregulations in the 2-5A Pathway. Journal Of Chronic Fatigue Syndrome, 8(3–4), 63–82. https://doi.org/10.1300/J092v08n03_07
Sheedy, John & Wettenhall, Richard & Scanlon, Denis & Gooley, Paul & Lewis, Donald & Mcgregor, Neil & Stapleton, David & Butt, Henry & Meirleir, Kenny. (2008). Increased D-Lactic Acid Intestinal Bacteria in Patients with Chronic Fatigue Syndrome. In vivo (Athens, Greece). 23. 621-8.
De Meirleir, K.L., Mijatovic, T., Subramanian, K. et al. Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. J Transl Med 16, 322 (2018). https://doi.org/10.1186/s12967-018-1696-z
Hsu, CY., Ahmad, I., Maya, R.W. et al. The potential therapeutic approaches targeting gut health in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a narrative review. J Transl Med 23, 530 (2025). https://doi.org/10.1186/s12967-025-06527-x
Guo, Cheng & Che, Xiaoyu & Briese, Thomas & Allicock, Orchid & Yates, Rachel & Cheng, Aaron & Ranjan, Amit & March, Dana & Hornig, Mady & Komaroff, Anthony & Levine, Susan & Bateman, Lucinda & Vernon, Suzanne & Klimas, Nancy & Montoya, Jose & Peterson, Daniel & Lipkin, W. & Williams, Brent. (2021). Deficient Butyrate-Producing Capacity in the Gut Microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients is Associated with Fatigue Symptoms. 10.21203/rs.3.rs-1017818/v1.
König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Front Immunol. 2022 Jan 3;12:628741. doi: 10.3389/fimmu.2021.628741. Erratum in: Front Immunol. 2022 Mar 30;13:878196. doi: 10.3389/fimmu.2022.878196. PMID: 35046929; PMCID: PMC8761622.
Gomaa AA, Mohamed HS, Abd-Ellatief RB, Gomaa MA. Boswellic acids/Boswellia serrata extract as a potential COVID-19 therapeutic agent in the elderly. Inflammopharmacology. 2021 Aug;29(4):1033-1048. doi: 10.1007/s10787-021-00841-8. Epub 2021 Jul 5. PMID: 34224069; PMCID: PMC8256410.
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