The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Interferon gamma (IFNγ)

Discussion in 'Immunological' started by Thewonders92, Sep 12, 2017.

  1. Thewonders92

    Thewonders92

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    What do inflammatory bowel disorders, Chronic Fatigue Disorder, Parkinsons and Alzheimers have in common?

    Chronic Fatigue Syndrome
    • Fatigue
    • Loss of memory or concentration
    • Sore throat
    • Enlarged lymph nodes in your neck or armpits
    • Unexplained muscle pain
    • Pain that moves from one joint to another without swelling or redness
    • Headache of a new type, pattern or severity
    • Unrefreshing sleep
    • Extreme exhaustion lasting more than 24 hours after physical or mental exercise

    Alzheimers
    Parkinsons
    • Tremor.
    • Slowed movement (bradykinesia).
    • Rigid muscles.
    • Impaired posture and balance.
    • Loss of automatic movements.
    • Speech changes.
    • Writing changes.

    The basal ganglia, specifically the substantia nigra is known as the motivating factor in the reward pathway of the human brain. The substantia nigra is implicated in many degenerative diseases, in Parkinson's it will show as tremors, decreased motor function and severe depression, in chronic fatigye this means ceaseless fatigue, pain, depression, anxiety and muscle weakness.

    In alzheimers it gets advanced neurologically of course to completely losing ones memories and brain function over time.

    "Regional neuronal loss in the substantia nigra (SN) was studied in relation to extrapyramidal symptoms and dementia in 27 patients with Alzheimer's disease (AD), 12 patients with idiopathic Parkinson's disease (PD) and 18 controls. Four areas of the right SN were investigated at the level of the caudal red nucleus. In AD the number of neurons were reduced to 97%, 79%, 83% and 78% of the control values from the medial to lateral SN respectively.

    https://www.ncbi.nlm.nih.gov/pubmed/2602422

    Moreover, activation of microglia in the SNpc and striatum is profound in various types of PD animal models [1517]. Further biochemical analysis reveals higher levels of pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interferon-gamma (IFN-γ) in the midbrain of PD patients. These data strongly suggest the involvement of immune components in PD pathogenesis.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603346/#!po=7.77778

    The basal ganglia has also been highlighted in Chronic Fatigue syndrome.

    "The findings show that patients with chronic fatigue syndrome have decreased activation of an area of the brain known as the basal ganglia in response to reward. Additionally, the extent of this lowered activation was associated with each patient's measured level of fatigue."

    "The researchers showed that patients with chronic fatigue syndrome experienced significantly less change in basal ganglia blood flow between winning and losing than the healthy volunteers. When the researchers looked at scores for the Multidimensional Fatigue Inventory, a survey often used to document fatigue for chronic fatigue syndrome and various other conditions, they also found that the extent of a patient's fatigue was tightly tied with the change in brain activity between winning and losing. Those with the most fatigue had the smallest change."

    "Dr. Unger says that she and her colleagues became curious about the role of the basal ganglia after previous studies by collaborators at Emory University showed that patients treated with interferon alpha, a common treatment for chronic hepatitis C and several other conditions, often experienced extreme fatigue."

    https://www.sciencedaily.com/releases/2012/04/120424142109.htm

    The observation was incredibly fortuitous but was given very little consideration. The basal ganglia does become damaged over time in those with CFS, and other conditions. Not in a similar manner to interferon treatment (in my opinion) but exactly as one would undergoing longterm, indefinite low dose interferon treatment.

    Our source for this ceaseless interferon treatment? The gut.

    "IFN-γ gene, its transcription factor T-bet, IFN-γ protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-γ downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS."

    https://www.ncbi.nlm.nih.gov/pubmed/26744473

    Why is this an issue? Sure low serotonin could bring mood down, but how does that explain feeling as though I have the flu 24/7 365 days a year?

    Well, Tryptophan is a lot more complex than people realize.

    It isn't just the serotonin precursor, in fact very little Tryptophan is used to make serotonin. What were concerned with is the other side of Tryptophan metabolism.

    The kynurenine pathway.

    Kynurenine is produced from Tryptophan via IDO Indoleamine 2,3 Dioxygenase. Kynurenine along with several or its metabolites are incredibly damaging to our bodies, and must be regulated. When we get sick, interferon gamma is released, when interferon gamma is released, IDO is stimulated to overutilize Tryptophan to manufacture kynurenine, when the infection is gone and Tryptophan has been used up, our gut begins to repair, the biome starts to replenish to regulate Tryptophan as a fuel source to lower inflammation.

    But what happens when the inflammation doesn't stop? What if we lose too much of our good bacteria, are overcome by inflammatory and interferon stimulating bacteria and eventually lose our anti inflammatory Tryptophan processing bacteria? All of our food contains antibiotics right? Those will help to kill the intruders, well no, not without also killing many factors greater the good guys.

    IDO activity stays high in response to low levels of a constant stream of IF-y from intestinal inflammation, Tryptophan becomes inflammatory rather than incredibly antiinflammatory as a bacterial food source, kynurenine stays at the same level causing more oxidative and inflammatory stress, further increasing IF-y production, the antibiotics you're eating continue wiping out your good bacteria, and eventually there is nothing left to suppress IDO activity, kynurenine gets the emphasis, serotonin synthesis is in decline, interferon-y is slowly destroying your health and every bit of stress you put yourself through makes the inflammatory issues worse.

    IF-y eventually begins to destroy the substantia nigra, and you begin to lose your motivation, first it was energy now it's the will to have energy. Next you start losing your memory, you forget which pills are your morning pills, and which are the afternoon. What protocol am I on again?

    The gut inflammation increases, nutrient absorption goes down, you are now symptomatic for a thousand conditions. The good bacteria has declined heavily, unable to process toxins, nutrients or help you in any way but keep you going.

    Eventually your immune system fails to the point where it can barely damage you anymore, your blood tests all come back fine now, and you feel okay. You can't remember what feeling actually okay meant, but if you catch a glimpse it terrifies you, maybe this is 20 years on, now your IF-y reads normal, you've hardly got enough biotic cultures left to show up high anywhere on immune function.

    At this point it's got to be in your head right? You can't really be this sick if no one believes you are.

    Well, I'll tell you who believes you. The 100 trillion symbiotes living inside you having a much tougher time than you ever have. Well no, that's in a healthy person, let's say 50 to be safe.

    Well healthy people have interferon responses as well, they just also have probiotics in their bodies, and can handle getting sick without hospitalization.

    What can you do about the damage?

    Well L.Reuteri (not commonly found in humans, is severely limited and tied up/destroyed by fructose or high fructose corn syrup depending on your diet) combined with Tryptophan has been shown to do a great job at treating intestinal inflammation, lowering IDO activity, increasing serotonin and Tryptophan (weird coincidence huh?)

    https://www.sciencedaily.com/releases/2017/08/170803141045.htm

    Berberine is a powerful inhibitor of Tryptophan to Kynurenine, and lowers IF-y, also protects against substantia nigra damage (another coincidence I suppose)

    Jiaogulan or gynostemma works very strongly to repair the entire basal ganglia, and had shown great promise in all related disorders. It also lowers IF-y, suppresses gut inflammation and increases serotonin.

    Rosmarinic Acid is an IDO inhibitor.

    Probiotics must be used in at least several hundred billion CFUs to be considered therapeutic. Nothing short of 100 billion is going to put a drop in the bucket.

    So when I look around around and see some of the main research into CFS focusing on IF-y, gut inflammation, resultant dopaminergic dysfunction, kynurenine/tryptophan and nobody seems to be trying the most powerful substances relating to those connections I have to scratch my head.

    I think one person on here has mentioned trying gynostemma, they posted once and never came back.

    I don't see anyone taking reparative dosages of probiotics, Reuteri specifically with Tryptophan.

    Berberine is always hit or miss, well it's an antibiotic so if you're not using it with probiotics that's kind of antagonizing the underlying issue a bit.

    Rosmarinic acid I believe was mentioned once as a skin lotion.


    TL;DR
    There is a lot of research into CFS you may find promising.

    Some Google possibilities.

    Tryptophan/Kynurenine CFS
    Kynurenine CFS
    IDO CFS
    Interferon gamma CFS
    IBD Kynurenine
    Substantia Nigra CFS
    Basal Ganglia CFS
    Jiaogulan
    Gynostemma
    Berbeine
    Rosmarinic Acid IDO
     
  2. lansbergen

    lansbergen Senior Member

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    I think interferon gamma is importent and my immunesystem did not produce enough of it.
     
  3. Thewonders92

    Thewonders92

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    Well yeah, I have noticed there's a theory that probiotics are the issue, and one would want to take interferon treatments to cure their CFS. If the opposite approach to what I'm saying seems right, then you should pay me no mind and pursue it.

    Increasing IDO activity will help increase IF-y, anything pro inflammatory will help to increase IDO expression. Tryptophan is used in this. Anti inflammatory herbs, supplements and medications will lower IF-y and should be avoided.

    Antibiotics will also lead to increased IF-y release over time, at first they will suppress it and once the biome is impaired enough, the inflammation will increase and another IF-y storm will begin.

    I've heard of people trying antibiotics and interferon treatments at the same time, I'm not sure how effective it's been.

    Beyond this I've only come across tumors as being able to stimulate IF-y.

    Probiotics without berberine or antiinflammatory compounds will also produce IF-y on their own in response to inflammation, reintroducing them to a barren host will overwhelm them and overproduce IF-y, hence why people with longstanding CFS and chronic illness get much worse on probiotics alone.

    In inflammatory bowel disorders, the body overproduced IF-y in response to a threat that wasn't there, IDO activity is always upregulated in intestinal issues and convinces the body to release IF-y in response to inflammation caused by IDO, the snake eating itself kind of situation.
     
    Last edited: Sep 12, 2017
  4. lansbergen

    lansbergen Senior Member

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    The immune modulator levamisole I use has many effects . One is indirectly increase ofinterferon gamma but the main reason I think it helps is superoxide decrease.
     
  5. Thewonders92

    Thewonders92

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    Jiaogulan as far as I've been able to find is one of if not the most potent SOD Booster known.
     
  6. lansbergen

    lansbergen Senior Member

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    SOD2?
     
  7. Hip

    Hip Senior Member

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    Interferon gamma has no particular connection to the gut as far as I can see; according to Wikipedia, it is mainly produced by natural killer cells and natural killer T-cells in the blood:
    There are pathways through which intestinal inflammation results in signals being sent to the brain, which in turn ramp up brain inflammation; but those pathways work through the cytokines IL-1β and TNF-α in the gut, and the signal itself is mainly sent along the vagus nerve, which runs from the organs of the torso (including the gut) to the brain.

    So the idea of reducing gut inflammation by means of better diet, prebiotics, probiotics and so forth can pay dividends, in terms of reducing brain inflammation. However, not all ME/CFS patients are able to tolerate probiotics; some feel much worse on probiotics.



    There some studies linking indoleamine 2,3-dioxygenase (IDO) activation with increased cognitive impairment (see 1 2 3), and so I wondered whether interferon gamma-induced IDO activation might be responsible for the brain fog of ME/CFS. I also wondered whether IDO might be responsible for the depression symptoms I have, via its inhibition of serotonin synthesis.

    However, I did not notice much improvements in either brain fog or depression on taking pure andrographolide, the chemical component of Andrographis paniculata responsible for this herb's interferon gamma inhibition, nor from the herb itself.

    I did temporarily get amazing results from the antidepressant drug Wellbutrin (bupropion), which is a potent interferon gamma inhibitor, where my depression and brain fog were dramatically improved, and it felt like I was in near remission from ME/CFS. My chronic sore throat symptoms also disappeared while I took Wellbutrin, possibly as a result of its interferon gamma inhibition, or its IL-1beta or TNF-alpha inhibition. More info on my Wellbutrin experiences in this post.

    Unfortunately after two weeks, its amazing benefits disappeared, and I was not able to get Wellbutrin to work for me again. This is not uncommon in ME/CFS: quite a few patients experience initial benefits of a drug or supplement, only to find that those benefits wear off after some time.
     
  8. Learner1

    Learner1 Professional Patient

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    Very interesting discussion. When I read the original question, I thought "disturbed gut microbiome"?

    So, then, wouldn't the answer lie in manipulating the composition of the microbiome?

    Its more than just downing large quantities of probiotics. One needs an environment where what you put in will thrive, with insoluble fiber and certain dietary components that will promote the growth of targeted strains of bacteria, which likely differ for each one of us.

    I'm speaking from downing large quantities of very high quality probiotics consistently, only to find none of them on more than one stool test. Its a lot more sophisticated than we have been led to believe.

    The answer lies in figuring out what your microbiome constituents are, and then taking specific actions, by introducing targeted dietary components and strains of bacteria to improve the quality and diversity of our microbiome. Rotating different probiotics products is helpful.

    Additionally, solving issues like candida, SIBO, and any parasites is important, too.

    The diverse bacteria have different jobs to do in processing and converting nutrients our bodies need. If we lack certain strains, it'll be very difficult for our bodies to get these nutrients.

    This is a young science, but important, and the ME/CFS researchers seem to be finding that the microbiome is a component of our problem.
     
    ljimbo423 likes this.
  9. Thewonders92

    Thewonders92

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    If-y is increased in the mucosa of IBS patients as a result of altered serotonin signalling and impaired Tryptophan metabolism.
    https://www.ncbi.nlm.nih.gov/pubmed/26744473

    People with CFS will always get worse on probiotics before they get better (I'm talking about therapeutic dosages 500 billion+), this is because probiotics will ramp up the production of IF-y amongst other things if taken without berberine or anything to meditate the excessive resultant IF-y release. IDO will always be upregulated in the chronically ill, so taking probiotics will aggravate the situation in the begging without something like berberine as a buffer.
     
  10. Learner1

    Learner1 Professional Patient

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    Can you provide some info on this? I haven't gotten worse on probiotics, just haven't gotten any lacto & bifido to live there, no matter what high quality probiotics I take, and I need to further improve diversity...

    From what I've gathered, we need to improve the terrain to make it hospitable for new inhabitants and make sure the inhabitants are in healthy and not in healthy competition.
     
  11. Thewonders92

    Thewonders92

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    Taking probiotics will not result in recolonization. Prebiotics and reintroducing Ahr ligands will, and rebalancing your biome will. What dosage were you taking? What strains? The idea is to simulate a colony that most likely would exist naturally in your gut to help fight infection and to heal the damage done to the gastrointestinal tract, but doing this will generally cause a flare up, if done in therapeutic dosages, this is alongside Tryptophan refeeding to lactobacillus to restore it's natural food supply. Anti oxidants should be taken heavily as undesirable substances will be made while the lining and biome balance is being restored.

    I'm far from saying taking probiotics and get better, most likely people will get worse on probiotics alone, and should be heavily focused on antioxidants during the process of repairing the gut, the issue is we cannot ever come close to doing the job probiotics could at repairing our gut, the many compounds the produce and utilize would be too much to handle through supplementation and could never result in a suitable environment for our own bacteria to repopulate.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266036/#!po=18.7500
     
  12. wastwater

    wastwater Senior Member

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    Missing Interferon regulatory factor 4 (IRF4) might be at the root of my condition
     
  13. Learner1

    Learner1 Professional Patient

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    So, I don't have a kyurenine problem, am not short in tryprotophan, and take large amounts of antioxidants. Plus insoluble fiber, prebiotic foods, and GOS specfically. Still no progress.

    And some of the strains missing aren't in any commercial probiotic I've found.

    What do you recommend for probiotics?
     
  14. Thewonders92

    Thewonders92

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    So your serum Tryptophan Kyn/Trp & Kyna/Quin ratio is all good? No symptoms of excess Kynurenine and low gut serotonin? Constipation, general inflammation, brain fog, sore joints, depression or fatigue?

    https://ca.iherb.com/pr/renew-life-ultimate-flora-probiotic-150-billion-30-veggie-caps/57480

    This is the probiotic I recommend and the brand, specifically this one as it has 40 strains and 150 billion CFU's making reaching 500-3 or so trillion fairly cheap in rounds.

    But by the sounds of it your gut is doing well, Kynurenine excess only shows when Tryptophan metabolism has been impaired in the gut and IDO becomes overactive. I'm not sure that it will be necessary to take probiotics in this case.
     
  15. Jesse2233

    Jesse2233 Senior Member

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    I should note that after 4 rounds of IVIG my interferon gamma (IFN-y) fell from 80 to 5 pg/mL (normal range <=5)
     
    wastwater and Learner1 like this.
  16. Learner1

    Learner1 Professional Patient

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    All have been measured regularly and are fine.
    Fatigue only.
    Thanks, I appreciate the recommendation. Unfortunately, it contains dairy, which I'm allergic to. Also, I've been taking 100 billion of most of those strains for 3 years and still have no lactobacillus or bifidobacteria.

    Big mystery.

    It is more complex than just taking them. Something, obviously is making my gut inhospitable to them. Either other bacteria, some supplement, hormone, or drug I'm taking, or not enough good terrain. Its a head scratcher...

    I bring this up, not to be difficult, but I suspect others could have similar issues and not realize it. The researchers seem to think we do.

    Ken over on cfsremission.com has some interesting things to say about cultivating the right strains in one's gut.

    I'm looking at taking PrescriptAssist, Dr. Ohhiras, Symbioflor, or Equilibrium. Researching them first, though, and discussing with my doctor.

    Actually not. The big reason is there's a lot of undigested food... not a good thing, and I'm continually deficient in nutrients the strains I'm missing make.

    There are a lot of things that happen biochemically in the gut. Tryptophan metabolism is one. Certainly important, especially with any brain symptoms, but there's far more impact of our microbiomes on our biochemistry.

    This is a young science and no one has all the answers yet. Its good we can learn from one another.
     

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