Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.

[ljimbo423]

For generality, a relativism also appears in other circumstances (hope this comparison makes sense): Ducks or other birds which are prone to get eaten by say eagles, develope a flight-reflex, reasonably. It has been shown that it´s the frequency of the appearance of the shape in the sky, which makes the imprint, not the shape itself.

I think I understand what you are saying. The more frequently the microglia are exposed to whatever is causing their sensitization, the more sensitized they become. So lower and lower amounts of LPS could trigger them, as they become more sensitized. Is that what you are saying here?

 

[Hip]

If the BBB is compromised or the microglia sensitized, then even the LPS levels in healthy people would probably be enough to cause sickness behavior.

So in this case it's not high levels of LPS that would be the cause, but the microglial sensitization or BBB disruption.

 

[ljimbo423]

If the BBB is compromised or the microglia sensitized, then even the LPS levels in healthy people would probably be enough to cause sickness behavior.

Wouldn't that depend on the degree the BBB is compromised and/or the degree the microglia are sensitized?

So in this case it's not high levels of LPS that would be the cause, but the microglial sensitization or BBB disruption.

What I'm suggesting is it's both, the higher levels of LPS and microglial sensitization and/or BBB disruption.

 

[percyval577]

I think I understand what you are saying. The more frequently the microglia are exposed to whatever is causing their sensitization, the more sensitized they become. So lower and lower amounts of LPS could trigger them, as they become more sensitized. Is that what you are saying here?

To my own surprise to read it like so seems to be possible, but I didn´t want to put the comparision such detailed ...

I only wanted to say that the a characteristic (obviously LPS or eagle) might not be the first cause in the machinery.
And here it´s not the shape of eagles etc. but the low frequency these shapes appeare that has made the duck to know "this is dangerous". Or it wouldn´t be the LPS itself, but something other which would have come along the LPS, which would make/have made the microglia act too much.

If a lower frequency of LPS would fascilitate the senzitation, I don´t know, it might depend on the mathmatical function? However, that lower and lower LPS could be part of the whole story I would agree, eg Ron Davis told something about low infectious agents in me/cfs, didn´t he? So this could be mathmatical described, but I don´t know if only two parameters would be suficiant. Possibly?

I see, what you may also say, low appearance of LPS might lead to overreaction when finally LPS appear (because the microglia have waited for so long for some LPS which should come along), and this might become a new level. (I think such is basically one theory of allergy).

 

[nandixon]

Could be, and that's why I would like others to look at it. Perhaps @nandixon might be able to throw some light on this issue (as I detailed in this post).

It's not even the ME/CFS patients that are the issue here; it's the healthy controls. According to your 2nd study study, heathy people with no symptoms have on average around 75 pg/ml of LPS in their blood.

Then in the 1st study you inject healthy people with 1000 pg of LPS per kilo, which by my above calculation will increase their blood LPS levels by just 5 pg/ml, and all of a sudden these healthy people start experiencing sickness behavior symptoms.

It does not make sense that they can be symptom-free at 75 pg/ml, but then develop symptoms at 80 pg/ml.

It may have to do with the rate of change. If the additional 5 pg/mL of LPS were infused slowly over several hours the subjects might not have had much of a response, but it was given all at once and so apparently activated the body's usual defense mechanisms against potential bacterial pathogens involving the TLR4 receptor.

But again a similar issue applies: Average LPS levels in healthy people are 75 pg/ml, whereas in ME/CFS they are 119 pg/ml, which is not even twice the healthy control level.

It makes no sense that you could be perfectly healthy at 75 pg/ml, but then at 119 pg/ml the LPS suddenly causes all the sickness behavior symptoms found ME/CFS.

If ME/CFS patients had for example LPS levels that were 10 or 20 times higher than healthy people, then it might make sense that this greatly elevated level of LPS could be causing these sickness behavior symptoms of ME/CFS.

But when the level in ME/CFS patients is not even 2 times the level of healthy people, it does not look like the LPS can be the cause of the ME/CFS sickness behavior symptoms.

I'm not sure in this case but depending on the particular test only a small percentage change may be necessary to go from a healthy state to a pathological one. For example, people can be healthy with a HbA1c of 5.5% but be diabetic at 6.5%.

 

[Hip]

What I'm suggesting is it's both, the higher levels of LPS and microglial sensitization and/or BBB disruption.

Well if there is some condition making LPS much more potent than usual, then to my mind that would be the main cause.


But it seems that there is something here we do not understand, if the relatively small amount of LPS injected into healthy people in the study caused such substantial sickness behavior symptoms.

 

[ljimbo423]

Well if there is some condition making LPS much more potent than usual, then to my mind that would be the main cause.

I guess you could look at it like that.

But it seems that there is something here we do not understand, if the relatively small amount of LPS injected into healthy people in the study caused such substantial sickness behavior symptoms.

Maybe nandixons post above yours could shed some light on this?

 

[Hip]

It may have to do with the rate of change. If the additional 5 pg/mL of LPS were infused slowly over several hours the subjects might not have had much of a response, but it was given all at once and so apparently activated the body's usual defense mechanisms against potential bacterial pathogens involving the TLR4 receptor.

That's an interesting suggestion, and seems quite plausible.

I'm not sure in this case but depending on the particular test only a small percentage change may be necessary to go from a healthy state to a pathological one. For example, people can be healthy with a HbA1c of 5.5% but be diabetic at 6.5%.

Certainly if there were a non-linear LPS concentration-response curve, small changes might create large effects. But the wide variation in blood LPS levels we see in healthy controls (from around 10 to 180 pg/ml looking at the earlier graph) does not suggest non-linearity, because if it were non-linear, you would expect the controls with higher levels to experience a lot of sickness behavior.


Could it perhaps be that the body accustoms itself to its normal basal level of LPS, and ceases to respond to this level, but then starts responding when LPS increases above the basal level?

That's similar to the idea you suggested, where it's the rapid change in LPS level that causes the immune response.

 

[Hip]

Endotoxin tolerance is a known phenomenon where the body's inflammatory response to LPS becomes diminished with repeated exposure to LPS. So it may be that the body does get accustomed to whatever basal levels of LPS are present, down-regulating the immune response accordingly.

Michael Maes et al in a recent paper suggested ME/CFS might involve endotoxin tolerance. The paper says:

endotoxin tolerance which involves profound systemic immune and metabolic downregulation, with the latter phenomenon involving sequential shifts in energy production via glycolysis and oxidation of fatty acids, following prolonged TLR upregulation in macrophages and monocytes

The paper then goes on to describe the complex way in which endotoxin tolerance induces a down-regulation of energy production.

 

[percyval577]

Could it perhaps be that the body accustoms itself to its normal basal level of LPS, and ceases to respond to this level, but then starts responding when LPS increases above the basal level?

And the problem would not only be which levels are normal (or indicating a possible dangerous change)
for which body in which time,


but also which perecentage of the stuff that is needed for the possible sickness responses
should be used for these very reactions (that could be illness responses) -
and this will be important under pysiological conditions, before any danger might suddenly come up,
because to some low degree (some of) these very reactions will take place as well.

I ever like to tell: nitric oxide is made from arginine, so the concentration of arginine too is important along LPS which induce nitric oxide
(and then I ever like to tell, that eg it´s manganese which might serve as one gauging,
because in the liver arginine is life important, and arginine will be released into the blood,
and it will reach the brain as well, and it will lead to a production of nitric oxide in this everyday case,
but also manganese is released into the blood from the liver,
because the arginase in the liver doesn´t need only arginine but manganese as well,
"so," might have said evolution in the brain, "if there is a lot of manganese
I should use more arginine as well,
otherwise the brain has too less normal nitric oxide from microglia" -

or must it be the other way round? - please correct me. )

The studies I've posted here make a connection to ME/CFS researcher Chris Armstrong's theory that a "slow sepsis" is the cause of ME/CFS and Jarred Younger's theory that sensitized microglia, causing low grade brain inflammation, is the main cause of symptoms.

According to the first part of my post, I would think it just in the other direction,
sensitized microglia would be the cause of mecfs,
and slow sepsis might be a consequence which could worsen symptoms.

Maybe the gut could be
a consequence plus a further cause but also also a first cause.
Microglia might react in both cases, because of elevated LPS or sensitization.
In the latter case it might be required to say elevated LPS would lead to microglia sensitization,

(at least according to your differenciation "mecfs and symptoms",
suggesting that without any LPS there wouldn´t be any symptoms, which is reasonable, I think).

 

[Murph]

... the problem with trying to explain the symptoms of ME/CFS in terms of LPS is simply that ME/CFS patients do not have a substantially higher blood level of LPS compared to healthy controls. The average patient LPS level is not even double that of the controls.

As you say, if the microglia of ME/CFS patients are sensitized, then they may respond even to the low amounts of LPS present in the blood. But if that were the case, then would not be the LPS that is the cause of ME/CFS (as the LPS is also present in healthy people), but the fact that microglia are sensitized.



Also, one thing that confuses me is the first study, where they injected 1 ng of LPS per kg body weight. This is a very small amount of LPS, much lower than the basal level of LPS in the blood of healthy people.

By my calculation, that 1 ng/kg LPS injection will increase the blood LPS concentration by just 5 pg/ml (this is based on the fact that extracellular fluid comprises 20% of body weight).

5 pg/ml is negligible given that basal LPS levels are on average 74.74 pg/ml (from your second study).

Yet the first study found that this tiny increase of 5 pg/ml caused measurable increases in brain inflammation, as well as in sickness behavior symptoms.

That just does not make sense at all.

Something is not right here.

@Hip you seem to be assuming a linear relationship between LPS and microglia reaction. I see no reason not to imagine a very non-linear one, e.g. strong reaction if rising above a reference level.

Re: biomodality, that could be explained by actiity lelevls. I'd imagine LPS could be higher in PEM and lower than controls in people that have been pacing well.

Edit: nandixon has made a related point above.

 

[Hip]

@Hip you seem to be assuming a linear relationship between LPS and microglia reaction. I see no reason not to imagine a very non-linear one, e.g. strong reaction if rising above a reference level.

If you look at the graph in this post, you see that in healthy controls, there is a wide range of basal blood LPS levels, from about 10 pg/ml to 180 pg/ml.

If there were a very strong reaction to LPS above a certain threshold LPS level, then when healthy controls are injected with a small amount of LPS, you would expect no reaction from people whose basal LPS level was well below the threshold. But as far as I can work out from the study, LPS injection (which I calculated only raised blood levels by 5 pg/ml) elicited a response in everyone. So it does not look like there is a specific threshold level.



If we factor things like endotoxin tolerance into the equation (as mentioned above), we see that if there is a threshold level, it may vary from person to person, depending on the amount of endotoxin tolerance in that individual (which in turn will probably relate to their basal level of LPS). Endotoxin tolerance is the degree to which LPS is ignored by the immune system.

Or there may be no threshold level at all, and perhaps as nandixon suggests, the system may respond to a sudden increase in LPS levels. A sudden increase would occur if a new infection appeared in the body.

 

[Hip]

Here is another study which injected 0.4 or 0.8 ng/kg of LPS into 42 volunteers. Again, they all responded to this small amount of LPS, yet in most cases this small amount would barely change their LPS level.

 

[sb4]

Could be massively wrong here, but perhaps its the injection that's causing the poor response. If the endotoxin comes from the gut perhaps the immune system handles it better?

 

[percyval577]

Alltogether and strangly, the absolut amount seems to be unimportant enough:

Some species, like humans and sheep, are very sensitive to LPS, whereas other species, such as mice or nonhuman primates are much more resistant.

page 12470, right column.

Equal blood levels of cytokines equal different levels of LPS, the LPS differ as much as
0.1 mg / kg (in their other study, mice I guess)
to 4 ng / kg in humans.

They mention, it´s 10^6 times a difference. Tell me that I am not be able to read.


I ever thought that LPS (via TLR-4) would be a key to immuneresponse.,
reflecting at least to an easy enough to grasp extent an infection,
which should be equal in different primates eg.
What´s now with this? The story gets more complicate, in terms of regulatory elements.

 

[Hip]

Could be massively wrong here, but perhaps its the injection that's causing the poor response. If the endotoxin comes from the gut perhaps the immune system handles it better?

Certainly perhaps LPS within the gut or gut lining might have effects of its own.

However, I don't think LPS in the gut is directly detected by the vagus nerve in the gut, as I believe this nerve only detects the inflammatiory cytokines IL-1beta and TNF-alpha, but does not directly detect LPS.

When the vagus nerve detects inflammation anywhere in the body (through elevated IL-1beta and TNF-alpha), the vagus nerve signals this to the brain, and in response in the brain will ramp up its own inflammation levels, and this will cause increased sickness behavior.

I would think the brain ramps up its own inflammation (immune activation) as a precaution: if there is an infection anywhere in the body (as detected by the vagus), then the brain may put its self on guard to prevent that infection taking a foothold in the brain.



But is not just brain inflammation that LPS could cause. In the subset of ME/CFS patients who do had raised LPS, the endotoxin tolerance that raised LPS might induce might also contribute to ME/CFS symptoms, as endotoxin tolerance down-regulates mitochondrial metabolism, according to the Maes paper.

Endotoxin tolerance also causes immune down-regulation.