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The Benefits Of Fasting Are Due To Lowering Endotoxin (LPS), Not Less Calories

Discussion in 'Scientific Studies' started by haidut, Sep 5, 2018.

  1. haidut

    haidut Member

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    As many of you know, the argument for/against fasting has been raging on the forum for several years at this point. While Ray has spoken several times favorably about potentially skipping a meal or two, he has repeatedly said that chronic fasting is not something he recommends due to its negative effects on metabolism. When asked to elaborate on any possible benefits of caloric restriction (CR), he said that any real benefit is likely due to the lower endotoxin (LPS) levels and reduced PUFA stores, and not the actual reduction in calories. He also said that some additional benefits may be due to reduced intake of tryptophan, methionine and cysteine.
    Well, this new study sides with Peat on the topic of fasting. The study found that reducing calories by about 40% led to changes in the microbiome that resulted in less endotoxin (LPS) synthesis and release in the bloodstream. As a result, the fasted animals had less fat mass while preserved lean mass and at the same time improved insulin sensitivity. Doing a fecal transplant from the fasted mice to naive mice provided the same benefits as CR while keeping their food intake unchanged. Conversely, administering endotoxin (LPS) to the fasted mice quickly reversed the benefits of CR and restored the mice to their previous levels of "health". Perhaps even more importantly, the study found that mice with higher levels of endotoxin (LPS) did NOT benefit from caloric restriction! This could explain why dieting/fasting does not benefit so many people that attempt it. To further confirm that the benefits of CR were due to lower endotoxin (LPS) levels, the authors did an experiment with a group of mice that had regular daily caloric intake but was given a TLR4 antagonist. Those regular, unfasted mice given a TLR4 antagonist enjoyed the same reduction/prevention of obesity, insulin resistance and chronic inflammation as the mice subjected to CR. In fact, as the study mentions itself, administering TLR4 antagonist may one day become an effective method to treat obesity and other metabolic conditions. I posted a few other studies showing that endotoxin (LPS) overload is probably involved in many (most) chronic conditions, so an effective blocker of endoxotin (LPS) signalling may become quite successful as a true cure for many diseases.
    Endotoxin And Iron Finally Recognized As Potential Causes Of Many Diseases
    Endotoxin (LPS) May Be A Causative Factor In Alzheimer Disease (AD)
    Endotoxin (LPS) Theory Of Atherosclerosis (CVD)
    Gut Bacteria May Cause ALL Autoimmune Conditions; Antibiotics Can Cure

    The TLR4 antagonist used in the study was the rather obscure chemical CLI-095. It has not been approved for human use and even in animal studies it is relatively unknown. However, there are already quite a few other TLR4 antagonists with much longer track record of usage in humans and likely better side effect profile.
    TLR4 - Wikipedia

    Among those antagonists, the most widely used ones that Peat has spoken about include cyproheptadine, ketotifen, naltrexone and the caffeine derivative propentofylline. Ketotifen is already being tested in human trials for other conditions associated with TLR4 overactivation including systemic sclerosis (scleroderma), Lupus, RA, and even IBD conditions like Crohn's.
    Emodin, progesterone, niacinamide, vitamin D, vitamin A and vitamin B3 would probably be the most applicable OTC ones.

    Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements - ScienceDirect
    How gut bacteria may help you diet and stay healthy

    "...In order to see what role gut bacteria might play in the process of becoming healthier following a calorie-restricted diet, the scientists transferred some of these bacteria from the dieting mice to a group of mice bred not to have gut microbiota...The researchers found that simply performing this microbiota transfer allowed the mice to become leaner and produce more beige fat, despite staying on their regular diets. After analyzing the composition and behavior of these microbiota, Prof. Trajkovski and team observed that they produced fewer toxic molecules known as lipopolysaccharides (LPS). However, when the researchers tried to boost LPS levels so that they would reach their usual levels, they noticed that the mice with higher LPS saw fewer health benefits, despite dieting."

    "...The researchers point out that LPS actually trigger an immune response as they activate a protein known as toll-like receptor 4 (TLR4). In the recent study, they noticed that mice that had been genetically engineered not to express TLR4 actually enjoyed similar health benefits to the ones seen by the rodents on the calorie-restricted diet. "Clearly the immune system not only combats infections, it also plays a key role in regulating metabolism," notes Prof. Trajkovski. Without activated TLR4, the mice not only produced more beige fat and thus saw more weight loss, but they also reacted better to insulin. These rodents' livers were also more effective at processing sugar and fat, and the mice became better at adjusting to colder temperatures. "This is turning into an entirely new field of research," Prof. Trajkovski says. After identifying these mechanisms, the team decided to test the effectiveness of two different compounds: one aimed at reducing LPS production, and the other aiming to block TLR4. Both of these drugs were effective in mice and induced a similar health outcome as that produced by calorie-restricted dieting."

    "It may one day become possible to treat obese people with a drug that simulates caloric restriction. We are currently investigating the precise changes in bacterial communities, and we are also testing other compounds that reduce LPS production and signaling." -- Prof. Mirko Trajkovski
     
  2. schultz

    schultz Member

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    Endotoxin/LPS is such an interesting topic and yet I never really hear anyone outside the "Peat-o-sphere" talking about it.

    Great post Haidut.
     
  3. Mito

    Mito Member

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    There are others around the web that have been writing about. Before I knew who Peat was I read about endotoxin here Endotoxin: Part 1 - How Opportunistic Bacteria Damage Your Heart
     
  4. schultz

    schultz Member

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    Thanks for the link!

    Have you ever run across any "mainstream" sources discussing endotoxin? It just seems like such an important topic that is not often discussed, though I suppose "gut health" has become a popular topic. Even just typing it into Pubmed gave me over 100,000 hits. I've noticed that, like carageenan, they use LPS to study the effects of inflammation, so it's obviously well known in the scientific community as something that can cause predictable systemic problems. One of the first studies that comes up (ordered by publication date) is this one where they use LPS to cause anxiety and depression so that they can test some product called Crocin. The abstract states...

    "Depression is one of the foremost psychological illness which is closely leagued with inflammation. Crocin is a natual product that exhibits both anti-inflammatory and anti-oxidant activities. However, little is known about anti-inflammatory mechanisms of crocin on LPS-induced anxiety and depressive-like behaviors. The objective of this study is emphasized on neuroprotective role of crocin against LPS-induced anxiety and depressive-like behaviors in mice."

    So apparently it is well known to cause anxiety and depressive symptoms. I knew about the anxiety, as Ray has talked about it on the podcasts. I wasn't aware of the "depressive like behaviour".

    This one, also one of the most recent on pubmed, studies the effect of L-theanine on chickens that have been injected with LPS. It seemed to have a similar action to antibiotics. Interestingly it increased the "feed to gain" ratio, which I think suggests a slowing of the metabolic rate (not surprising, but interesting nonetheless).

    "Lipopolysaccharide decreased feed intake (FI) and body weight gain (BWG) from d 22 to 28 (P < 0.05), BWG and feed to gain ratio (F:G) from d 29 to 56 (P < 0.05), increased mortality in different growth periods (P < 0.05), elevated the levels of serum cortisol, α1-acid glycoprotein (α1-AGP), interleukin-6 (IL-6) on d 24 and 25 (P < 0.05), reduced immune organ indexes and contents of jejunal mucosal secretory immunoglobulin A (sIgA) on d 28 (P < 0.05)."
     
  5. Mito

    Mito Member

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    No
     
  6. OP
    haidut

    haidut Member

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    There are quite a few things known well to the research community that nonetheless are complete taboo in pharma/industry/medical circles, mostly for political reasons. There is something called "chronic unpredictable mild stress" (CUMS) which is known to induce depression/anxiety/psychosis in ANY animal model. Google it or search Pubmed for it. Yet we still get fed the typical BS by FDA and its marketing arms in pharma companies that mental health issues are either genetic or with largely unknown causes. There is also the well-proven carcinogenicity and castration-like effects of various endocrine disruptors used in pretty much all plastics sold to the general population and present everywhere in the environment around us. Yet EPA says the evidence about their risks is "controversial", as if that somehow means unreliable or wrong. There is now evidence that the highest scientific body in US (the NAS) engaged in fraud to convince the world ionizing radiation is safe, yet most doctors I have talked to flatly deny that X-rays are dangerous and still talk about the "threshold" for inducing damage.
    NAS falsified data on radiation safety to justify widespread use!

    Then there is the well-publicized fact that the clinical trials for the blockbuster clotting drug Xarelto were fraudulent and FDA knows about it, but when asked it refuses to comment. Then there are the literally millions of animal studies with aspirin stopping pretty much any type of cancer, but there is zero talk about trying this in humans. But behind the scenes the powers that be know what's up and even worry that if the news about aspirin gets out of hand the pension system will collapse.
    Terms of Service Violation
    "...Aspirin’s use fighting cancer has the potential to increase pension liabilities by as much as $100 billion by extending lifespans, a risk modeler said in a report."

    The list goes on and on and on. Bottom line - almost nothing that comes out as official announcement of public health policy can be trusted. In fact, most such announcements and programs have only one goal - increase profits for private companies and/or prevent the public from getting its hands on something that really works, since if a person's health (and food) cannot be controlled then that person is largely free. Nightmare for anybody in a position of power!
     
  7. nwo2012

    nwo2012 Member

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    Nice post Haidut.
    Does Pizotifen have similar properties?
     
  8. nwo2012

    nwo2012 Member

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    Also, @haidut does naloxone share similar properties to LPS as naltrexone?
     
  9. OP
    haidut

    haidut Member

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    Yes, pizotifen is basically considered the same as cypro/ketotifen in terms of pharmacology.
     
  10. OP
    haidut

    haidut Member

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  11. nwo2012

    nwo2012 Member

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  12. Vinero

    Vinero Member

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    It should also be mentioned for people who don't like/aren't able to take drugs to get TLR4 antagonist effects, that some vitamins also act as TLR4 antagonists. Haidut has posted studies in the past discussing Vitamins A,D, B2, and B3 as having TLR4 antagonist effects.
     
  13. nwo2012

    nwo2012 Member

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    That cant apply to............. (Opens can of worms)...... vitamin A, as it is not a vitamin at all, it is a toxin we have adapted to handle......
    Well I deserve a laugh, trying to get through a tough nightshift!

    Yes I agree. How about emodin. Good Peaty one.
     
  14. jb116

    jb116 Member

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    lol
     
  15. Vinero

    Vinero Member

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    Vitamin A deficiency - Wikipedia
     
  16. Elephanto

    Elephanto Member

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    I find that since I've been doing Intermittent Fasting (18:6), I'm able to do the fasting window without feeling any stress or intense hunger. Stress always prompts hunger for me.

    Seems like the Endotoxin perspective could explain it :
    Lipopolysaccharide directly stimulates cortisol secretion by human adrenal cells by a cyclooxygenase-dependent mechanism. - PubMed - NCBI

    Though from modifying my diet and being more active, I also feel like my glycogen storing capacity has increased. I keep progressing with muscle growth and my very low body fat % hint to no cortisol-induced catabolism happening.

    I don't think that fasting and using TLR4 antagonists is entirely the same though. In the first case you are starving bacterias, reducing the total endotoxin load, while in the second you are temporarily reducing their ability to trigger TLR4.
     
  17. Glassy

    Glassy Member

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    What I find most fascinating in this information is that reducing endotoxin (LPS) load seems to result in a increase/restored metabolism.

    Endotoxin is nasty stuff but I didn’t know that it was disrupting metabolism so much.

    I think this emphasises the importance of keeping your small intestines “clean” rather than the importance of TLR4 antagonists. I must admit I don’t know much about TLR4 antagonists though. From what I understand, TLR4 is responsible for some of the immune response to LPS but doesn’t necessarily affect LPS production by bacteria (although I guess it could affect absorption).

    It does seem to indicate how powerful cascara could be in keeping materials moving and combating some of the TLR4 immune response, particularly as a lot of the cascara seems to stay in the digestive tract.

    Edit: just been reading what Peat has to say on endotoxin and yeah he clearly points to the affects of it on mitochondrial functioning and metabolism. It’s amazing sometimes how on the money he is and how much info he packs into 1 article. He also seems to emphasise the carrot salad and ACV/CO dressing more than TLR4 antagonists.
     
  18. Malris

    Malris Member

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    Haidut,

    So, do you have or know of any posts outlining a comprehensive strategy to reduce endotoxins? I mean, is it as simple as take vitamin A/D/E/B3, cypro if you tolerate, look for improved symptoms in 2-3 weeks?
     
  19. Lejeboca

    Lejeboca Member

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    Not @haidut, but thought I'd chip in and see whether forum members can critique or add to this strategy:

    As was mentioned above, Peat prefers carrot salad (to be used as bottle brush for the existing endotoxin overload). I recall him giving an example of a woman, for whom this overload was reduced in ~1 week with carrot salad, and her symptoms disappeared.
    Then, I've read on this forum that some people prefer activated charcoal (AC), instead of carrot salad. I use AC myself, whenever I don't have access to carrots (and with potential heavy endotoxin outlook), such as while traveling.
    Finally, at all times, no or very reduced foods that digest slowly and may promote endotoxins. As a general rule here, no uncooked vegetables except for carrots.

    It's my understanding that all the vitamins and cypro, act on the consequences of endotoxins, such as serotonin.
     
  20. Regina

    Regina Member

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    I was surprised to hear this RP clip last night. Without caveat, he says that a healthy person can go not eating for 12-15 hours without a stress response.
     
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