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Scientists show how immune system can be modulated by manipulation of sugar metabolism

Discussion in 'Other Health News and Research' started by Galixie, Aug 22, 2017.

  1. Galixie

    Galixie

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    nandixon, aimossy, MastBCrazy and 6 others like this.
  2. lnester7

    lnester7 Seven

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    That is great I struggle with high IL10 but I wonder if it is a good thing to lower or counterproductive in our case (if it is a defense mechanism)
     
  3. Snowdrop

    Snowdrop Rebel without a biscuit

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  4. Hip

    Hip Senior Member

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    This post looks at how high IL-10 (that has been induced by viruses) may hamper viral clearance. Coxsackievirus B, EBV, HHV-6 and cytomegalovirus all are able to produce or induce IL-10, in order to thwart the immune response, and prevent viral clearance. Thus reducing IL-10 may have beneficial effects in such chronic viral infections.

    Interesting that 2-deoxy-D-glucose can inhibit the production of IL-10; although it does not seem to be available as a supplement or drug.
     
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  5. JES

    JES Senior Member

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    The news-medical article does not explicitly mention fasting, but PLOS one talks about "fasting metabolism". I have been interested to attempt fasting for a long time, as it has been linked to several immune system changes. Unfortunately the first time I tried water fasting a few years ago, I got so weak and dizzy and experienced increased palpitations, that I had to stop the experiment after around 36 hours. I will probably try it again in the near future and meanwhile increase electrolyte intake to see if it makes any difference.

    Anyway, I have a gut feeling that these type of treatments could have a huge potential in various diseases.
     
  6. ebethc

    ebethc Senior Member

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    are IL-10 and IL-12 particularly noted in CFS?
     
  7. Jesse2233

    Jesse2233 Senior Member

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    They're not, but that doesn't mean they aren't important
     
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  8. Murph

    Murph :)

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    abstract of the original paper

    Abstract
    A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines.

    Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10.

    Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

    --

    This section of the paper, on AMPK, is also interesting. @ChrisArmstrong's presentation at the symposium explained the way gut dysfunction could trigger AMPK activation and thereby trigger a low energy state.

    Apart from its crucial role as a master regulator of cellular metabolic homeostasis, the enzyme adenosine AMPK has been shown to exert an important role in regulation of immunity, [810]. Importantly, AMPK controls dendritic and T-cell metabolic adaption and plays a key role in effector responses in vivo [1113]. Furthermore, it has been demonstrated that AMPK regulates IL-10-mediated anti-inflammatory signaling pathways in murine macrophages [14].


    Various extrinsic signals that regulate glucose and amino acid metabolism as well as bacterial stimuli converge on signaling factors of the phosphatidylinositide 3-kinase (PI3K) pathway, including Akt, 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR). These kinases lie at the crossroad of a complex nutrient hormonal signaling network coordinating the regulation of cell metabolism and effector mechanisms of the immune response [12, 1517]. Recently, it has been shown that mTOR signaling is closely intertwined with the AMPK nutrient sensing pathway that is responsible for processing energy status, insulin, growth factors, and environmental cues, transmitting signals to downstream targets to effectuate both, cellular and the metabolic response [18].

    Upon activation, AMPK induces, among other signaling cascades, the formation of the tuberous sclerosis complex (TSC) via phosphorylation of TSC2 and regulatory-associated protein of mTOR (Raptor) [19], which in turn inhibits phosphorylation of mTOR and its downstream targets, ribosomal protein S6 kinase (rpS6k) and 4E-binding protein 1(4E-BP1) [12, 20]. It has previously been reported that inhibition of mTOR by rapamycin in human monocytes or murine macrophages stimulated with lipopolysaccharide (LPS) enhances the production of IL-12 and IL-23, whereas IL-10 is blocked [2123]. In order to further elucidate the impact of upstream regulation of mTOR signaling on its cytokine modulating effect the present study was aimed at investigating whether metabolic interference by mimicking fasting metabolism via AMPK activation could reproduce the effect of mTOR inhibition on cytokine induction in innate immune cells.


    The results show that in human and mouse monocytes, glucose-deprivation with 2-deoxy-D-glucose (2-DG) as well as specific AMPK activators bring about effects similar to mTOR inhibition leading to consistent inhibition of IL-10 production. Furthermore, 2-DG was also able to reproduce the effect of rapamycin in a Listeria infection model leading to profound reduction in bacterial burden.


    The paper talks about inhibiting mTor to inhibit IL10. Montoya's cytokine paper shows severe patients have higher IL10 ( not statistically significant after correcting for multiple comparisons but strikes the eye on the graph. It's also not one of the 17 with a linear associaton with severity but it has the general pattern and can't have missed inclusion in that group by much). Obviously in severe patients it's not so simple as being stuck in an AMPK activated, low mTOR, low IL10 state.
     
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  9. Murph

    Murph :)

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    At the symposium Ron was talking about how you can't be sure progress in this disease will be as slow as in solving previous diseases because technology is so much better now. The other speed multiplier is that the world has so many more scientists now, and they are all using that better technology.

    E.g. There are a dozen or so immunologists in Austria with a deep knowledge of biochemical pathways that are super relevant for us.

    This makes the life of our researchers easier. They're not working in a vacuum! Papers keep flooding in that illuminate aspects of the disease.

    Also, those researchers might be looking for a novel application of their findings. A lucky email from a German speaker that piques the interest of one of those Austrians and we could end up with a lab in Vienna trying to solve me/cfs too!
     
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  10. Jesse2233

    Jesse2233 Senior Member

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    @Murph you think there is anything we can do to encourage these Austrian researchers to get involved?
     
  11. Murph

    Murph :)

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    I reckon an email to them showing some of the Fluge Mella PDH findings couldn't hurt! What else ties in neatly?
     
  12. Keela Too

    Keela Too Sally Burch

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    I find this interesting on two accounts related to my own experience.

    1. I have been fasting (36 or 48hrs at a time, once or twice a week - also one 70 hr fast) and it has helped my functioning level positively. About 15- 20% extra as measured by steps.
    2. I also had an amazing week when I was put on antibiotics for a recent dog bite turned icky. I thought I would be slowed up by them, but quite the reverse.

    Both these observations seem to tie in with what this paper suggests.
     
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  13. anni66

    anni66 mum to ME daughter

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    I' ve started looking at AMPK as my daughter has low ATP, low intracellular magnesium and very poor ADP/ ATP conversion. I don' t have a scientific background so may have picked up somethings incorrectly but it certainly is a multi tasking molecule.

    it seems to potentially play a role in tumour suppression via interaction with LKB1, and can be phosphorylated on TH172 in response to calcium flux ( could this be related to ion channel issues?)

    It rate limits steps in fatty acid metabolism and sterol synthesis as it is the upstream kinase for acetyl- coA carboxylase and TMG(?) Reductase

    It' s involved in adaptive reprogramming if metabolism via transcriptional changes

    It regulates activity of SIRT1 in some tissues via effects on NAD+ levels ( promoting fatty acid oxidation when ATP low)

    It is linked to circadian clock regulation via regulation of clock component CRY1 SER 71

    It may control cell polarity in some settings and is needed for repolarisation and tight junction formation following calcium switch.

    So potentially a modulating molecule for many functions ( many of which i do not yet understand ) ....
     

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