Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the JNK pathway

nanonug

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https://www.ncbi.nlm.nih.gov/pubmed/26740179

Abstract
Chronic inflammation augments the deleterious effects of several diseases, particularly diabetes, cancer, and sepsis. It is also involved in the process of metabolic shift from glucose oxidation to lactate production. Although several studies suggest that the change in activity of the pyruvate dehydrogenase complex (PDC) is a major factor causing this metabolic change, the exact mechanism of the inflammatory state remains unclear. In this study, we investigated the effect of lipopolysaccharide (LPS) on the expression of pyruvate dehydrogenase kinase 4 (PDK4), which is strongly associated with inactivation of the PDC in C2C12 myoblasts. In C2C12 myoblasts, LPS exposure led to increased PDK4 mRNA and protein expression levels as well as lactate production in culture medium. However, the expression levels of other PDK isoenzymes (PDK1 - 3) remained unchanged. Additionally, we observed that LPS treatment induced phosphorylation of Jun N-Terminal Kinases (JNK). To confirm the role of JNK, we inhibited the JNK pathway and observed that PDK4 expression and lactate production were decreased, but p38 and ERK were not significantly changed. Taken together, our results suggest that LPS induces PDK4 expression and alters glucose metabolism via the JNK pathway.

COMMENT: The increased expression of PDK4 by lipopolysaccharides establishes a link between gut issues and the hypometabolic state model of SEID by Naviaux et al. It may not be, and probably isn't, the whole story but has the feel of a piece of the puzzle.
 

nanonug

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Now, wouldn't it be nice if there were a drug able to block the effects of lipopolysaccharides on PDK4? Too bad it has such nasty side effects, though...

Peroxisome proliferator-activated receptor γ agonism attenuates endotoxaemia-induced muscle protein loss and lactate accumulation in rats

Abstract
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg-1·day-1) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg-1·h-1) or saline. Rosi blunted LPS-induced increases in muscle tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% (P<0.05) and 64% (P<0.01) respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the up-regulation of muscle RING finger 1 (MuRF1; P<0.01) mRNA and the LPS-induced increase in 20S proteasome activity (P<0.05). Accordingly, LPS reduced the muscle protein: DNA ratio (∼30%, P<0.001), which Rosi offset. Increased muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA (P<0.001) and muscle lactate accumulation (P<0.001) during endotoxaemia were suppressed by Rosi. Thus, pre-treatment with Rosi reduced muscle cytokine accumulation and blunted muscle protein loss and lactate accumulation during endotoxaemia, and at least in part by reducing activation of molecular events known to increase muscle protein breakdown and mitochondrial pyruvate use.
 

Jackb23

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https://www.ncbi.nlm.nih.gov/pubmed/26740179

Abstract
Chronic inflammation augments the deleterious effects of several diseases, particularly diabetes, cancer, and sepsis. It is also involved in the process of metabolic shift from glucose oxidation to lactate production. Although several studies suggest that the change in activity of the pyruvate dehydrogenase complex (PDC) is a major factor causing this metabolic change, the exact mechanism of the inflammatory state remains unclear. In this study, we investigated the effect of lipopolysaccharide (LPS) on the expression of pyruvate dehydrogenase kinase 4 (PDK4), which is strongly associated with inactivation of the PDC in C2C12 myoblasts. In C2C12 myoblasts, LPS exposure led to increased PDK4 mRNA and protein expression levels as well as lactate production in culture medium. However, the expression levels of other PDK isoenzymes (PDK1 - 3) remained unchanged. Additionally, we observed that LPS treatment induced phosphorylation of Jun N-Terminal Kinases (JNK). To confirm the role of JNK, we inhibited the JNK pathway and observed that PDK4 expression and lactate production were decreased, but p38 and ERK were not significantly changed. Taken together, our results suggest that LPS induces PDK4 expression and alters glucose metabolism via the JNK pathway.

COMMENT: The increased expression of PDK4 by lipopolysaccharides establishes a link between gut issues and the hypometabolic state model of SEID by Naviaux et al. It may not be, and probably isn't, the whole story but has the feel of a piece of the puzzle.

It brings me great happiness to know that even though there aren’t a ton of Dr.s researching me/cfs right now, we have a ton of well versed and articulate members on this site that are dedicated to digging as far as they can into this problem.
 

ljimbo423

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Here is another paper that shows LPS causing a switch to glycolysis, supporting Naviaux' position.

How does LPS promote Warburg metabolism in macrophages and DCs?
Activation of macrophages or DCs with a range of stimuli, including LPS10, the TLR3 ligand poly(I:C)11, and type I interferon (IFN)11, induces a metabolic switch from OXPHOS to glycolysis, in a phenomenon similar to the Warburg effect10.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493277/

Jim
 

JadeD

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Thank you both for these fascinating papers. These are the foundation of what Prof De Meirleir has been saying for years. A large subset of ME patients having increased bacterial translocation, causing higher scd14 than healthy controls. The lps causes all of these downstream hypometabolic effects - shifts in oxophos, inhibition of ampk, immune dysregulation, reactivation of viruses, increased pro-inflammatory cytokines, NO and ros production causing many of our symptoms.

With his treatment my PGE2 (which is stimulated by lps) has fallen considerably as has my serum ammonia, lactate and il-8. However I'm still in the early stages of treatment so it takes time and treatment is not yet optimal until we have new drugs to suppress cytokine production/effects as confirmed by Jose Montoya as well. Whether bacterial translocation is a consequence which perpetuates the disease or is the root cause (triggered by an infection in genetically susceptible people) remains to be confirmed.

In my humble opinion we can't treat all of the downstream individual metabolic effects like using ampk activators etc if the root cause/perpetuater is not addressed. All of the effects that naviaux are confirming are secondary downstream effects. In theory it means our disease is reversible, I hope.
 

kangaSue

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There's a lot of nutritional protocols that are supposed to help as an alternative to meds if that's any use to you.
https://www.naturalmedicinejournal....t-intestinal-permeability-defects-and-related

Intestinal ischemia is a known model for increased intestinal permeability so meds aimed at treating this should technically help with intestinal permeability, allopurinol (xanthine oxidase inhibitor) is a lesser known thing that springs to mind.

Having increased levels of LPS is suggested as a possible marker for intestinal ischemia. Often, the ischemia is restricted to the mucosa layer and doesn't produce any overt pathology. Usual measures of inflammation won't often be triggered (sed rate and c-reactive protein) but fecal Calprotectin level, as an indicator of mucosal inflammation, can be elevated.
 

Hip

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A large subset of ME patients having increased bacterial translocation
What evidence is there for bacterial translocation in ME/CFS? Bacterial translocation is when bacteria from the gut move into the lymph nodes, liver, spleen, kidney and blood.

According to this paper, this is how you can detect bacterial translocation:
Bacterial translocation ... can be measured both directly by culture of mesenteric lymph nodes and indirectly by using labeled bacteria, peripheral blood culture, detection of microbial DNA or endotoxin and urinary excretion of non-metabolisable sugars.
The paper also points out that:
Bacterial translocation may be a normal phenomenon occurring on frequent basis in healthy individuals without any deleterious consequences. But when the immune system is challenged extensively, it breaks down and results in septic complications at different sites away from the main focus.
Are there any studies showing bacterial translocation in ME/CFS patients? I am aware of this study by Maes, but that only provides indirect evidence.



If ME/CFS were due to bacterial translocation, then antibiotics would presumably work well in ME/CFS. Whereas there are no studies I can remember seeing indicating benefits from antibiotics, except perhaps azithromycin (but azithromycin is an immunomodulator), and except in cases where the ME/CFS is associated with the bacteria Chlamydia pneumoniae or Coxiella burnetii.

KDM often treats ME/CFS with long term antibiotics, but I have not seen any evidence from him that this leads to improvements in ME/CFS symptoms.
 
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kangaSue

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According to this paper, this is how you can detect bacterial translocation
As is mentioned in your reference, mesenteric lymph fluid is the only transport system I have come across too as a means for bacterial translocation but due to the invasive nature of testing for this (involving the need for laparotomy), it's rarely done.
 

ljimbo423

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What I found very interesting about this study is that the higher blood levels of bacterial sequences (DNA) were maintained 72 hours post exercise in the CFS group but not the control group. The worst PEM symptoms often are felt in the first 24-72 after exercise or over-doing it physically.

These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

One current model of disease suggests that a trigger event (e.g. infection) results in a chronic inflammatory state characterized by increased proinflammatory cytokine production, increased reactive oxygen and nitrogen species, altered intracellular signaling, increased intestinal permeability and systemic activation of innate immune receptors, altered glutaminergic and dopaminergic neurotransmission, mitochondrial dysfunction, and aberrant autoimmune responses

Particularly germane to this study, only 3 of the 10 patients and 2 of the 10 controls reported gastrointestinal symptoms and all participants reported mild severity and symptoms present “a little of the time.”

There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684203/

Jim
 
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sb4

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Does anyone know if, besides the investigational drug Larazotide (a zonulin receptor antagonist), there is anything out there able to reverse increased intestinal permeability?
There is a lot of talk on the RayPeat forums about reducing endotoxin. One member came up with a way that worked for him that involved eating very high carb, very low fat, with the main source of calories being short grain rice. Short grain rice is pretty much all amylopectin which is absorbed very fast, high up the small intestines, leaving nothing for gut bacteria to feed on / attach to. Fat requires chylomicrons to be absorbed which bring LPS with them, so very low fat would obviously avoid this.

Of course, many of us have problems tolerating carbs so that could be an issue. You could always experiment with waxy potatoes instead of rice.
 

tyson oberle

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There is a lot of talk on the RayPeat forums about reducing endotoxin. One member came up with a way that worked for him that involved eating very high carb, very low fat, with the main source of calories being short grain rice. Short grain rice is pretty much all amylopectin which is absorbed very fast, high up the small intestines, leaving nothing for gut bacteria to feed on / attach to. Fat requires chylomicrons to be absorbed which bring LPS with them, so very low fat would obviously avoid this.

Of course, many of us have problems tolerating carbs so that could be an issue. You could always experiment with waxy potatoes instead of rice.
Don't wazy potatoes have lots of carbs also?
 

sb4

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Don't wazy potatoes have lots of carbs also?
Yers they do. This is the idea, get most of calories from fast absorbing sources that involve the least amount of endotoxin.

That is INSANE! I stopped paying attention to anything on Ray Peat forums a long time ago.
Why do you think it's insane? I understand RP forums, like all health forums, are limited in focusing on what they think leads to health, but this doesn't mean it's all junk, surely?
 

sb4

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High glycemic/high carb (which is what the dude at Ray Peat forums is doing) is a recipe for metabolic syndrome. It is basically high calorie malnutrition. Why wouldn't this be insane?
I don't believe this to be true. There are many people eating various diets (including high glycemic) that don't suffer metabolic syndrome. Diet can contribute to it, absolutely, however it's not the only variable, and in fact, I believe, you can be very healthy on high carb, in certain circumstances.

Interestingly enough, you can have relatively lower levels of insulin on very high carb than mod carb / mod fat. Basically, like I was saying in the other thread, fat drives reverse electron flow, which drives insulin sensitivity. If you have no fat coming in, all electron flow is going in at cytochrome 1, meaning RET is minimal. This makes your cell very insulin sensitive. The more insluin sensitive, the less insulin. It has been used with some success (though not as much as ketosis) to reverse diabetes.
If you add a decent amount of fat to this then you need more insulin as your cell becomes more insulin resistant. If you are healthy, your body can deal with this no problem. If you are sick, you would probably do better in keto.
 

msf

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What evidence is there for bacterial translocation in ME/CFS? Bacterial translocation is when bacteria from the gut move into the lymph nodes, liver, spleen, kidney and blood.

According to this paper, this is how you can detect bacterial translocation:


The paper also points out that:

Are there any studies showing bacterial translocation in ME/CFS patients? I am aware of this study by Maes, but that only provides indirect evidence.



If ME/CFS were due to bacterial translocation, then antibiotics would presumably work well in ME/CFS. Whereas there are no studies I can remember seeing indicating benefits from antibiotics, except perhaps azithromycin (but azithromycin is an immunomodulator), and except in cases where the ME/CFS is associated with the bacteria Chlamydia pneumoniae or Coxiella burnetii.

KDM often treats ME/CFS with long term antibiotics, but I have not seen any evidence from him that this leads to improvements in ME/CFS symptoms.
Isn't this a little bit disingenuous? Since we only need the lps to translocate for this model to work? And I'm sure you are aware of Hansons study, which shows higher levels of LPS in patients with ME.
 
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Hip

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And I'm sure you are aware of Hansons study, which shows higher levels of LPS in patients with ME.
I have not seen that study; would you have a link?



Since we only need the lps to translocate for this model to work?
I have never come across any study which reliably demonstrates that LPS can cross the intestinal lining, even in those with leaky gut. LPS is a large molecule, with a molecular weight of over 100,000 daltons, so hard for this to cross the intestinal lining.

In fact it seems to me it might be harder for LPS to translocate across the intestinal lining than for bacteria to do so. Bacteria can secrete connective-tissue destroying enzymes to "burn" holes in our tissues so that they can spread around the body; but obviously LPS cannot do this.
 

msf

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Wow, I always thought you'd read everything. Just google Hanson, she's only published a couple of articles on ME.

As for how LPS gets into the body, I'm not sure exactly how it does it, but Im pretty sure it does.
 

nanonug

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I have never come across any study which reliably demonstrates that LPS can cross the intestinal lining
You may want to have a look at this study, but if you start digging on Pubmed, you'll find other studies claiming increases in serum LPS.

Heat stress, gastrointestinal permeability and interleukin-6 signaling - Implications for exercise performance and fatigue

Abstract
Exercise in heat stress exacerbates performance decrements compared to normothermic environments. It has been documented that the performance decrements are associated with reduced efferent drive from the central nervous system (CNS), however, specific factors that contribute to the decrements are not completely understood. During exertional heat stress, blood flow is preferentially distributed away from the intestinal area to supply the muscles and brain with oxygen. Consequently, the gastrointestinal barrier becomes increasingly permeable, resulting in the release of lipopolysaccharides (LPS, endotoxin) into the circulation. LPS leakage stimulates an acute-phase inflammatory response, including the release of interleukin (IL)-6 in response to an increasingly endotoxic environment. If LPS translocation is too great, heat shock, neurological dysfunction, or death may ensue. IL-6 acts initially in a pro-inflammatory manner during endotoxemia, but can attenuate the response through signaling the hypothalamic pituitary adrenal (HPA)-axis. Likewise, IL-6 is believed to be a thermoregulatory sensor in the gut during the febrile response, hence highlighting its role in periphery - to - brain communication. Recently, IL-6 has been implicated in signaling the CNS and influencing perceptions of fatigue and performance during exercise. Therefore, due to the cascade of events that occur during exertional heat stress, it is possible that the release of LPS and exacerbated response of IL-6 contributes to CNS modulation during exertional heat stress. The purpose of this review is to evaluate previous literature and discuss the potential role for IL-6 during exertional heat stress to modulate performance in favor of whole body preservation.​