aquariusgirl
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Welcome to Phoenix Rising!
Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.
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Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the JNK pathway
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aquariusgirl
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University of Manchester have conducted a series of studies that are drastically changing the way scientists think about the effect bacteria have on a number of diseases including Alzheimer’s disease, Parkinson’s disease, Sepsis, Rheumatoid Arthritis, and most recently Type 2 diabetes (T2D).
Previously, Pretorius and Kell have established that these chronic inflammatory diseases also have a microbial origin. “If the bacteria were active, or replicating, as in the case of infectious diseases, we would have known all about that,” says Kell. “But the microbes are not replicating, they’re mainly actually dormant.”
Because their dormant nature meant that they did not manifest under standard microbial test conditions, bacteria were previously thought to be absent from human blood, consistent with the view that blood is ‘sterile’. However, high levels of iron in blood (typical of inflammatory diseases) can effectively bring these bacteria back to life. Previous research suggested that under these conditions, the bacteria start replicating and secreting lipopolysaccharides (LPS), leading to increased inflammation.
The one thing these chronic diseases have in common is constantly elevated levels of inflammation. Pretorius and Kell had already established that anomalous amyloidogenic blood clotting, a cause of inflammation, is linked to and can be experimentally induced by bacterial cell wall constituents such as LPS and Lipoteichoic acid (LTA). These are cell wall components of Gram-negative and Gram-positive bacteria, respectively. Read more at previous research article on this topic.
These coagulopathies (adverse blood clotting) are also typical of inflammatory diseases and the researchers have long shown that they lead to amyloid formation, where the blood clotting proteins (called fibrinogen) are structurally deformed from a-helixes to a flat b-sheet-like structures, potentially leading to cell death and neuro-degeneration.
Previously, Pretorius and Kell have established that these chronic inflammatory diseases also have a microbial origin. “If the bacteria were active, or replicating, as in the case of infectious diseases, we would have known all about that,” says Kell. “But the microbes are not replicating, they’re mainly actually dormant.”
Because their dormant nature meant that they did not manifest under standard microbial test conditions, bacteria were previously thought to be absent from human blood, consistent with the view that blood is ‘sterile’. However, high levels of iron in blood (typical of inflammatory diseases) can effectively bring these bacteria back to life. Previous research suggested that under these conditions, the bacteria start replicating and secreting lipopolysaccharides (LPS), leading to increased inflammation.
The one thing these chronic diseases have in common is constantly elevated levels of inflammation. Pretorius and Kell had already established that anomalous amyloidogenic blood clotting, a cause of inflammation, is linked to and can be experimentally induced by bacterial cell wall constituents such as LPS and Lipoteichoic acid (LTA). These are cell wall components of Gram-negative and Gram-positive bacteria, respectively. Read more at previous research article on this topic.
These coagulopathies (adverse blood clotting) are also typical of inflammatory diseases and the researchers have long shown that they lead to amyloid formation, where the blood clotting proteins (called fibrinogen) are structurally deformed from a-helixes to a flat b-sheet-like structures, potentially leading to cell death and neuro-degeneration.
ljimbo423
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This screenshot, from Maureen Hanson's study, shows the increase in LPS plasma levels in ME/CFS patients over controls.
Note the difference in the upper ranges of the CFS patients verses the controls. They are very substantial. The range of LPS plasma levels in CFS patients was 34.32-279.30 The range of LPS plasma levels of the control group was 32.21-187.32
Reduced diversity and altered composition of the gut microbiome in individuals with ME.png
Jim
Note the difference in the upper ranges of the CFS patients verses the controls. They are very substantial. The range of LPS plasma levels in CFS patients was 34.32-279.30 The range of LPS plasma levels of the control group was 32.21-187.32
Reduced diversity and altered composition of the gut microbiome in individuals with ME.png
Jim
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nanonug
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This is consistent with the idea that SEID is a mild form of sepsis: Could Chronic Fatigue Syndrome (ME/CFS) Be a Chronic Form of Sepsis?
Hip
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I did Google, but could not find the study, that's why I asked for a link.
Thanks for posting that (when I was looking a while ago for LPS translocation studies, I couldn't find anything).
Your study states that LPS is translocated from the gut into the bloodstream during exercise under heat stress, though does not provide any supporting evidence, apart from citing this study, which itself provides no evidence, but interestingly states:
So I'd like to see some evidence for this LPS translocation.
But anyway it's interesting the study says translocated LPS activates TLR4, as this could explain why low-dose naltrexone sometimes helps ME/CFS (LDN blocks TLR4).
One point that occurred to me: your study says translocation of LPS into the bloodstream is greatly exacerbated by exercising under heat stress, due to the fact that blood is diverted away from the intestines:
So if translocated LPS from exercise is playing a causal role in ME/CFS, this might be mitigated any drugs or supplements which increase intestinal blood flow.
@kangaSue might have something to say about the vasodilating effects of the drug nicorandil in the intestines.
@Hip as others have previously said gut dysbiosis and potential bacterial translocation or the role of intracellular bacteria is a common research area atm for many ME researchers/clinicians. Whether or not they have published yet is a separate thing but Hanson, Armstrong, Lipkin, Staines, Maes, KDM and now Jonas Bloomberg (see recent article below) are all looking into this and I'm sure there's more that I haven't thought of. Most of them have presented these findings at the conferences.
Given the close links with the microbiome and immunity/inflammation it has to play a key role in the pathogenesis of the disease and in time treatment will be centered around it most likely. Hopefully the pieces of the puzzle will fit together soon.
https://translate.googleusercontent...700201&usg=ALkJrhg6vh2FyJQhS1e8gQGJRv2zwQkHYw
Given the close links with the microbiome and immunity/inflammation it has to play a key role in the pathogenesis of the disease and in time treatment will be centered around it most likely. Hopefully the pieces of the puzzle will fit together soon.
https://translate.googleusercontent...700201&usg=ALkJrhg6vh2FyJQhS1e8gQGJRv2zwQkHYw
ljimbo423
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I couldn't agree more, well maybe a little more,
with this theory. This video is from the OMF symposium last September. At 14:00 minutes into this video it shows a 100% genetic expression match of ME/CFS to Systemic inflammatory response syndrome (SIRS). Which is the same response as in sepsis.
nanonug
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The 100% match with SIRS is absolutely amazing. Considering that sepsis is basically "SIRS due to infection" the link is almost spooky.
nanonug
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The mechanism is not fully understood but this review paper entitled "Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation" provides some clues. Fig 2. on page G9 illustrates the possible mechanisms.
https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-016-0171-4
Third result when googling Hanson me cfs lps.
Third result when googling Hanson me cfs lps.
nanonug
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I have on hand Miyarisan (Clostridium butyricum) that I recently acquired from Japan. Clostridium butyricum is a butyrate-producing organism and has the potential to help with intestinal hyperpermeability. I'm going to start supplementing today and see what happens.
Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2
https://www.ncbi.nlm.nih.gov/pubmed/28893958
Abstract
Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2.
https://www.ncbi.nlm.nih.gov/pubmed/28893958
Abstract
Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2.
nanonug
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"We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum."
Interestingly enough, Firmicutes are apparently the main producers of butyrate.
Murph
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253991/
I found the above link to be a very good read on intestinal permeability. It is one of those things that has gone from being a fringe hypothesis to a part of mainstream medicine in the last few years.
Here's a short excerpt that also suggests bacteria are being translocated to the bloodstream (nb I think the idea that me/cfs is wholly explained by something that big and easy to detect is unlikely to be true. It will likely be more nuanced. And we now know the gut microbiota is more than just bacteria. Viruses, which are far smaller, outnumber gut bacteria by an order of magnitude. The complexities of the gut are very much still being discovered. For a long time science thought they knew what it did so they didn't much study it.)
Regulation of gut permeability by diet, prebiotics and probiotics
Since we now know about the clinical implications, interest in understanding the regulation of this barrier is growing. Two major regulatory factors could be identified, diet/nutrients/prebiotics, and, secondly, the intestinal microbiota/probiotics. Both are related to life style, which suggests that environmental factors might influence the function of the intestinal barrier and thus gut health [6]. The molecular mechanisms that regulate the epithelial tight junction and the paracellular pathway in response to luminal nutrients as D-glucose are less well defined but have been proposed to involve the cytoskeleton including myosin light chain phosphorylation [87].
The effect of diet on intestinal permeability is dependent on individual factors such as the host’s genetic susceptibility, and also on the intestinal microbiota. For example, the increased gut permeability during metabolic adaptation to high fat diet (HFD) is associated to altered gut microbiota [13]. Dietetic factors that promote increased intestinal permeability and subsequent translocation of bacteria resulting in inflammatory reactions in the liver, the white adipose tissue, the brain, and other organs trigger metabolic diseases such as insulin resistance. This pathophysiological cascade is now accepted to be of major relevance for the development of metabolic diseases including type II diabetes, cardiovascular diseases and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) [88]-[93]. Therefore it is tempting to speculate that tools allowing a safe modulation of the intestinal microbiota such as prebiotic food components or probiotic bacteria might be of great interest for future therapy of intestinal barrier-related diseases.
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Gut issues are very much correlated with my personal wellbeing. I am lucky to have identified two brands of probiotic that make my life easier.
I found the above link to be a very good read on intestinal permeability. It is one of those things that has gone from being a fringe hypothesis to a part of mainstream medicine in the last few years.
Here's a short excerpt that also suggests bacteria are being translocated to the bloodstream (nb I think the idea that me/cfs is wholly explained by something that big and easy to detect is unlikely to be true. It will likely be more nuanced. And we now know the gut microbiota is more than just bacteria. Viruses, which are far smaller, outnumber gut bacteria by an order of magnitude. The complexities of the gut are very much still being discovered. For a long time science thought they knew what it did so they didn't much study it.)
Regulation of gut permeability by diet, prebiotics and probiotics
Since we now know about the clinical implications, interest in understanding the regulation of this barrier is growing. Two major regulatory factors could be identified, diet/nutrients/prebiotics, and, secondly, the intestinal microbiota/probiotics. Both are related to life style, which suggests that environmental factors might influence the function of the intestinal barrier and thus gut health [6]. The molecular mechanisms that regulate the epithelial tight junction and the paracellular pathway in response to luminal nutrients as D-glucose are less well defined but have been proposed to involve the cytoskeleton including myosin light chain phosphorylation [87].
The effect of diet on intestinal permeability is dependent on individual factors such as the host’s genetic susceptibility, and also on the intestinal microbiota. For example, the increased gut permeability during metabolic adaptation to high fat diet (HFD) is associated to altered gut microbiota [13]. Dietetic factors that promote increased intestinal permeability and subsequent translocation of bacteria resulting in inflammatory reactions in the liver, the white adipose tissue, the brain, and other organs trigger metabolic diseases such as insulin resistance. This pathophysiological cascade is now accepted to be of major relevance for the development of metabolic diseases including type II diabetes, cardiovascular diseases and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) [88]-[93]. Therefore it is tempting to speculate that tools allowing a safe modulation of the intestinal microbiota such as prebiotic food components or probiotic bacteria might be of great interest for future therapy of intestinal barrier-related diseases.
--
Gut issues are very much correlated with my personal wellbeing. I am lucky to have identified two brands of probiotic that make my life easier.
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Murph
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As a person on the FODMAP diet (low in Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols, i.e. things that break down into fructose in the gut) this bit really caught my eye:
Using TLR-4 mutant mice we showed that the onset of fructose-induced liver disease is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells [104]. Recently, we could also show in a mouse-feeding model that chronic consumption of 30% fructose solution for eight weeks was associated with the loss of the tight junction proteins occludin and ZO-1 in the duodenum and a subsequent increase of bacterial endotoxin in the portal vein.
(from the same link as above.) Eat fructose -> get bacteria in your little mousy veins.
If you wanted to go straight to super meta from this small murine experiment you could speculate on whether rising fructose consumption in the west might help explain the epidemic of autoimmunity?
Using TLR-4 mutant mice we showed that the onset of fructose-induced liver disease is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells [104]. Recently, we could also show in a mouse-feeding model that chronic consumption of 30% fructose solution for eight weeks was associated with the loss of the tight junction proteins occludin and ZO-1 in the duodenum and a subsequent increase of bacterial endotoxin in the portal vein.
(from the same link as above.) Eat fructose -> get bacteria in your little mousy veins.
If you wanted to go straight to super meta from this small murine experiment you could speculate on whether rising fructose consumption in the west might help explain the epidemic of autoimmunity?
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Murph
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Here are a few probiotics this study says have evidence behind them:
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Importantly, one study has shown that L. plantarum can regulate human epithelial Tight Junction (TJ) proteins in vivo and to confer protective effects against chemically induced disruption of the epithelial barrier in an in vitro model [122].
Administration of L. plantarum into the duodenum of healthy human volunteers was shown to significantly increase ZO-1 and occludin in the vicinity of TJ structures [122]. These results suggest that administration of L. plantarum can enhance the stability of TJ complexes in humans and may attenuate their disruption by cytokines, toxins and pathogens.
Apart from L. plantarum, other probiotic Lactobacillus strains seem to have protective effects on the intestinal barrier using different in vitro settings or mouse models of disease, namely L. salivarius strains UCC118 and CCUG38008, L. rhamnosus GG, Lactobacillus casei strain DN-114 001, and L. casei strain Shirota [123]-[127]. Also the probiotic E. coli Nissle 1917 up-regulates tight junction proteins such as claudin 14 expression and other components of the intestinal barrier [112],[113],[128].
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Importantly, one study has shown that L. plantarum can regulate human epithelial Tight Junction (TJ) proteins in vivo and to confer protective effects against chemically induced disruption of the epithelial barrier in an in vitro model [122].
Administration of L. plantarum into the duodenum of healthy human volunteers was shown to significantly increase ZO-1 and occludin in the vicinity of TJ structures [122]. These results suggest that administration of L. plantarum can enhance the stability of TJ complexes in humans and may attenuate their disruption by cytokines, toxins and pathogens.
Apart from L. plantarum, other probiotic Lactobacillus strains seem to have protective effects on the intestinal barrier using different in vitro settings or mouse models of disease, namely L. salivarius strains UCC118 and CCUG38008, L. rhamnosus GG, Lactobacillus casei strain DN-114 001, and L. casei strain Shirota [123]-[127]. Also the probiotic E. coli Nissle 1917 up-regulates tight junction proteins such as claudin 14 expression and other components of the intestinal barrier [112],[113],[128].
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Hip
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The association of intracellular bacterial infection like Chlamydia pneumoniae or Coxiella burnetii with ME/CFS is not really doubted, and these forms of ME/CFS respond to antibiotics.
But that's different to the hypothesis that gut dysbiosis or bacterial / LPS translocation plays a role in ME/CFS, which is more tenuous.
Interesting paper. It says:
So only if the liver is not up to scratch in detoxifying LPS will this toxin enter the systemic circulation. So for those who think translocation of LPS plays a role in ME/CFS, presumably this implies that there must an impairment in liver deacetylation in ME/CFS which allows LPS into the systemic circulation.
Murph
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Following a bit of reading I think @Hip is right to remain cautious on the role of lps translocation. There is evidence for it, yes, but the data doesn't seem especially strong. It could be one of those things that seems so obvious in theory (barrier failure lets bacteria in -> sickness!) that we focus on it a lot, but the process doesn't actually work like that in most cases.
(Which is not to say that the gut itself is not an issue, I am confident it is, but the way it affects the body might not be so simple. e.g. the stuff leaking out might not be the gram negative bacteria that show LPS on their exteriors)
There's a section on approaches to measuring LPS translocation in the paper I just read. The key take-away is that they mostly use circumstantial evidence to find the LPS, and even then get mixed results...
(Which is not to say that the gut itself is not an issue, I am confident it is, but the way it affects the body might not be so simple. e.g. the stuff leaking out might not be the gram negative bacteria that show LPS on their exteriors)
There's a section on approaches to measuring LPS translocation in the paper I just read. The key take-away is that they mostly use circumstantial evidence to find the LPS, and even then get mixed results...
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kangaSue
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I think what's being debated here is the same thing that occurs even in healthy endurance athletes, exercise induced GI hypoperfusion that may provoke transient damage to the gut epithelium. Some studies have found significantly increased luminal permeability in untrained healthy volunteers too.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133117/
If you chuck sudomotor dysfunction into the mix, which is common in autonomic dysfunction (anhydrosis or hypohydrosis - Autonomic Neuropathy), you have the increased risk of getting heat stress with it too.
https://www.ncbi.nlm.nih.gov/pubmed/18565834
I'm thinking the difference ME/CFS is concerned is that most "normals" have an appropriate vasoconstriction/vasodilation autonomic function response so return to their normal base level without issue other than maybe a case of transient Ischemic Colitis here and there. Those "normals" that don't have a normal autonomic response can end having chronic Ischemic Colitis which, in about 80% of cases, is a microvascular intestinal ischemia problem.
Chronic Mesenteric Ischemia (CMI) is a similar thing to Ischemic Colitis. Blood flow to the bowel is compromised, usually as the result of mesentery artery stenosis, but up to 30% of cases are microvascular (non-occlusive). When it's a chronic issue, ischemic periods are relatively short lived so it doesn't usually cause any overt pathology to diagnose it from. Epigastric pain made worse by eating is the most common symptom for this but it can feel like just a dull ache for some people. You can be totally asymptomatic too.
It was because of suspecting I had CMI that I tried the drug nicorandil as a peripheral artery vasodilator. I didn't tolerate any of the usual remedies for intestinal permeability (NAC, glutamine, glutathione, colostrum, lactoferrin) or any of the other supplement type nitric oxide boosters (l-arginine or l-citrulline) but had no such issue with nicorandil (or a couple of other prescription nitrates).
I don't have ME/CFS here, just severe gastroparesis, and was almost totally reliant on a feeding tube because of this. The net result from taking nicorandil was that severe abdominal pain was mostly resolved, pretty much overnight, and I was able to ditch the feeding tube within two weeks to have everything orally again. I still have a severely restricted diet because the underlying cause of dysfunction hasn't been addressed, or found for that matter although it looks to be due to having a totally occluded left renal vein (Nutcracker Syndrome) and that causes a lot of autonomic dysfunction in many cases, including symptoms of fatigue mimicking CFS.
From doing more research into microvascular CMI, I find there is a lot of hypothesis out there that it is far more prevalent than is generally thought in cases involving chronic GI dysfunction and that can include IBS too.
There are no tests specific for chronic intestinal ischemia but there a couple of invasive things that holds some promise. Visible Light Spectroscopy during an endoscopy is the least invasive one. The other is a "challenge" Venogram where a vasodilator med is injected directly into the superior mesentery artery thereby decreasing vascular resistance in the sma to cause intestinal microvascular hypoperfusion. Or at least, that's what I think it's doing as it's originally a test for small vessel (microvascular) heart disease when injected into the main blood vessels in the heart.
https://www.ncbi.nlm.nih.gov/pubmed/21168842
https://www.ncbi.nlm.nih.gov/pubmed/18799501