Low dose endotoxemia (leaky gut) chronic inflammation and neuroinflammation

ljimbo423

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Abstract
Low-dose endotoxemia is prevalent in humans with adverse health conditions, and it correlates with the pathogenesis of chronic inflammatory diseases such as atherosclerosis, diabetes, and neurologic inflammation.

However, the underlying molecular mechanisms are poorly understood. In this study, we demonstrate that subclinical low-dose LPS skews macrophages into a mild proinflammatory state, through cell surface TLR4, IL-1R-associated kinase-1, and the Toll-interacting protein.

Unlike high-dose LPS, low-dose LPS does not induce robust activation of NF-κB, MAPKs, PI3K, or anti-inflammatory mediators. Instead, low-dose LPS induces activating transcription factor 2 through Toll-interacting protein-mediated generation of mitochondrial reactive oxygen species, allowing mild induction of proinflammatory mediators.

Low-dose LPS also suppresses PI3K and related negative regulators of inflammatory genes. Our data reveal novel mechanisms responsible for skewed and persistent low-grade inflammation, a cardinal feature of chronic inflammatory diseases. https://www.ncbi.nlm.nih.gov/pubmed/22706082
 

Hip

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This study talks about the immune priming effect of low-dose LPS.

Immune priming is the phenomenon in which an initial exposure to an inflammatory factor such as IFN-γ or LPS makes immune cells far more sensitive to reacting to any further exposures. Which means that later exposures to inflammatory factors create much stronger inflammatory responses from these immune cells than they otherwise would have done.

See here, here and here for info on immune priming.


So for example, if someone had these low levels of LPS in their circulation, that may sensitze the immune response. Then when a second inflammatory factor comes along, such as a viral infection which normally induces IFN-γ, the immune response will be much stronger.

This is the idea behind the immune priming theory of ME/CFS.
 

ljimbo423

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So for example, if someone had these low levels of LPS in their circulation, that may sensitze the immune response. Then when a second inflammatory factor comes along, such as a viral infection which normally induces IFN-γ, the immune response will be much stronger.
I agree that viral infections might be triggering the priming of the microglia in some with ME/CFS. What causes the primed microglia in those that don't get ME/CFS triggered by a viral infection? I think it might be chronic low levels of LPS.

I think the chronic increased levels of LPS found in ME/CFS, could be causing the sustained priming of the microglia and symptoms. When we physically over-do it, or try to exercise.

I think the increased activity increases the level of LPS in the bloodstream, causing the microglia to go into a fully activated state and cause an increase in inflammation/neuro-inflammation and PEM-

This is a quote from a study that showed a significant increase in LPS in the blood of ME/CFS patients over healthy people after exercise. They found a significant increase in LPS in the blood of ME/CFS patients over controls.

I don't think it's a coincidence that the high LPS levels were sustained for 72 hours or 3 days in ME/CFS patients. The time frame that most of us have our worst PEM-

In the present study, changes in microbiome and bacterial measures were accompanied by large changes in fatigue, pain, and confusion in ME/CFS patients.
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. These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684203/#sec011title

Chris Armstrong agrees with this study saying-

Well we all experience a bacteremia when we exercise. The type of bacteria that enter your bloodstream are usually quite controllable by your immune system but if your gut is further compromised they may release more bacteria into your blood or more pathogenic species or your immune system may already be depleted. This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM.
https://forums.phoenixrising.me/thr...20-2016-metabolomics.47485/page-6#post-791828

EDIT- There was also research done that showed ME/CFS had a 100% gene expression match with SIRS.
 
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