onsdag den 17. april 2019

ME versus Sepsis

Research in myalgic encephalomyelitis (ME) has shown:

  1. ME patients have impaired pyruvate dehydrogenase (PDH) function (1).
  2. Dichloroacetate (DCA) increases PDH activity. A pilot study has shown, that DCA may be a treatment of ME (2, 3).
  3. Some ME patients may also have decreased fatty acid oxidation (4, 5, 6).
  4. ME patients have:
    * abnormalities in the conversion of citrate to isocitrate in the TCA-cycle (7)
    * a possible flow of metabolites to replenish succinate in the TCA-cycle (7)
    * decreased succinylcarnitine (5)
    * decreased FAD (4)
  5. ME is a hypometabolic syndrome, which resembles hibernation (4).
  6. ME patients have decreased oxygen extraction (8).
  7. A transcriptome of immune cells from ME patients showed the inflammatory response mey be involved in the pathomechanism (FDR, adjusted p-value = 0,00044) (9).
  8. The Standford ME symposium 2017 compaired ME with systemeic inflammatory response syndrome (SIRS) (10):


SIRS is an inflammatory state affecting the whole body. It is the body's response to an infectious or noninfectious insult. SIRS is closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection (11).

Reseach in sepsis has shown:
  1. PDH-complex activity is impaired in sepsis (12).
  2. DCA reactivates PDH-complex activity in a mice model of sepsis (using  Seahorse Technology). This rebalanced innate and adaptive immunity(12).
  3. There is a metabolic switch between carbohydrate-fuled hyperinflammation to lipid-fueled hypo-inflammation in sepsis (13).
  4. A sepsis-model with LPS-treated monocytes showed (14):
    * a block at isocitrate in the TCA cycle
    * a block at succinate dehydrogenase in the TCA-cycle (thereby limiting FAD)
    * decreased succinylcarnitine
    * increased itaconate
  5. Increased oxygen consumption for anabolism during hyper-inflammation in sepsis switch to decreased oxygen consumption during the hypo-inflammatory phase. The immunometabolic paralysis and the catabolic low-energy state is similar to hibernation (13, 14).
  6. There is a sepsis-associated dysfunction of the mitochondrial respiratory system. Mitochondria may be challenged by mediators of inflammation that impair oxygen utilization ( cytopathic hypoxia) (15).


Use the knowledge from research in sepsis to solve ME

ME is not sepsis, but we can be inspired by research in sepsis to create new studies in ME. Fx. we could measure itaconate. Is it involved in ME?
And we could incubate monocytes from ME patients with DCA in the Seahorse. Would the hibernation be resolved?

DCA is toxic, but there are other medications that may be repurposed to ME.

ME is not the only disease with flat batteries. Several scientists are looking into the metabolic shut-down, which follows a wide range of insults to the body (16).

Information from professor Systrom at the NIH ME/CFS Conference 2019: 40% of the ME patients have small fiber neuropathy (17). Interestingly, small nerve fibers are impaired in patients with sepsis (18).

Further reading about red blood cells, ME and sepsis:

Red blood cell deformability, metabolism and extracellular vesicles in ME/CFS


References:

  1. Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
  2. Comhaire:  2018 May;114:45-48. doi: 10.1016/j.mehy.2018.03.002. Epub 2018 Mar 5. Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial. https://www.ncbi.nlm.nih.gov/pubmed/29602463
  3. Comhaire:  Med Hypotheses. 2018 Nov;120:65-67. doi: 10.1016/j.mehy.2018.08.014. Epub 2018 Aug 25. Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? https://www.ncbi.nlm.nih.gov/pubmed/30220343
  4.  Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113
  5. Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract
  6. Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
    https://www.ncbi.nlm.nih.gov/pubmed/30563204
  7. Yamano et al: Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016 Oct 11;6:34990. doi: 10.1038/srep34990. https://www.ncbi.nlm.nih.gov/pubmed/27725700
  8. J Transl Med. 2014 Jan 23;12:20. doi: 10.1186/1479-5876-12-20.Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. Vermeulen RC1, Vermeulen van Eck IW https://www.ncbi.nlm.nih.gov/pubmed/24456560
  9. Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
    https://www.ncbi.nlm.nih.gov/pubmed/30791746
  10.  ME/CFS Standford Symposium 2017, Ron Davis slides: https://www.youtube.com/watch?v=s7bBMXQSmuM
  11.  Wikipedia SIRS https://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndrome
  12. McCall et al: Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival. JCI Insight. 2018 Aug 9;3(15). pii: 99292. doi: 10.1172/jci.insight.99292. eCollection 2018 Aug 9. https://www.ncbi.nlm.nih.gov/pubmed/30089711
  13. Wang et al: Sirtuins and Immuno-Metabolism of Sepsis. Int J Mol Sci. 2018 Sep 13;19(9). pii: E2738. doi: 10.3390/ijms19092738. https://www.ncbi.nlm.nih.gov/pubmed/30216989
  14. Zhu et al. Frontline Science: Monocytes sequentially rewire metabolism and bioenergetics during an acute inflammatory response J Leukoc Biol. 2019 Feb;105(2):215-228. doi: 10.1002/JLB.3HI0918-373R. Epub 2019 Jan 11  https://www.ncbi.nlm.nih.gov/pubmed/30633362
  15. Kohoutova et al: Variability of mitochondrial respiration in relation to sepsis-induced multiple organ dysfunction Physiol Res. 2018 Dec 31;67(Supplementum 4):S577-S592. https://www.ncbi.nlm.nih.gov/pubmed/30607965 
  16. Singer: Critical illness and flat batteries Crit Care. 2017 Dec 28;21(Suppl 3):309. doi: 10.1186/s13054-017-1913-9. https://www.ncbi.nlm.nih.gov/pubmed/29297363
  17. National Institute of Health ME/CFS konference april 2019, del 1 med Systrom:
    https://videocast.nih.gov/summary.asp?live=31636&bhcp=1
  18. Axer et al: The impairment of small nerve fibers in severe sepsis and septic shock. Crit Care. 2016 Mar 15;20:64. doi: 10.1186/s13054-016-1241-5. https://www.ncbi.nlm.nih.gov/pubmed/26984636
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