tyw
Member
I wanted to state a couple of opinions regarding endotoxin in the context of 3 papers:
There are going to be many papers like this, but these 3 papers represents the points that I want to make, which I state up front:
Personal Interpretations
We cannot take observed high endotoxin levels in serum to mean that we are burning in a pit of destruction. Knowing how the endotoxin got there is an important question to ask.
If the intestinal barrier is compromised through whatever means -- be it infection, or gluten consumption , then we get a fairly free-flow of endotoxin from the gut into the bloodstream. This is undoubtedly bad, and if high endotoxin is observed in conjunction with intestinal barrier compromise, then things are bad
Note that what was described in the previous section are just mechanics. Mechanics need to be applied to a particular context to become useful.
In the real world, we need to explain situations where eating something like Coconut Oil "improves gut health" in some people, and then in others makes the gut worse (eg: comment by @Ewelina -- Why Does Starch Make Me Extremely Sick?). We also need to explain why diabetics seem to transport even more endotoxin.
In my opinion, this comes down to the Robustness and Sensitivity of the Immune Response.
All that eating fat does, is to provide the mechanical pathway for a "as safe as possible" endotoxin-mediated immune response to whatever endotoxin is already present in the gut. ie: Bundling up endotoxin into chylomicrons, is like a "quarantine function", whereby the invaders are then delivered to immune cells to be dealt with.
However, what happens when your immune system breaks down? For whatever reason, this transported endotoxin is not able to be dealt with. The endotoxin in chylomicrons will now only serve to keep asking the immune system for something it cannot provide, and the system is put into further stress.
This may be why some people find that saturated fat causes them to have "an immune shock", with symptoms like anxiety, nausea, shivering, etc ....
It is plausible that this cascade leads to breakdown of gut barrier function, which would then allow for even more un-regulated endotoxin entry into the bloodstream, making the immune over-reaction even worse.
Again, note the assumptions:
Conversely, if dietary fat is only transporting manageable quantities of endotoxin from the gut, I can see a situation whereby this leads to gradual clean-up of endotoxin and gut flora excess. This scenario can be achieved, again, by reduction of existing gut endotoxin levels, and bolstering of the immune system through all the usual Bio-energetic-enhancing strategies.
Also, this will explain why PUFAs like DHA seem to help the situation in the short term. These PUFAs shut down any sort of immune response, an isolate all endotoxin to the gut. The gut may be having a bad time, but there will be no systemic effect . One wonders how well an acute administration of DHA + antibiotics will work (DHA to transiently shutdown immune response, and then antibiotics to kill the gut-localised bacteria in hopes of reducing endotoxin formation)
Another interesting note will be the context of very low fat diets. In this case, you do not get as much of the Chylomicron-mediated endotoxin transport. You can still potentially feed the gut bacteria if you choose fermentable / slow-digesting foods, but you're not going to get as much endotoxin-triggered immune effects.
In light of this, my personal opinion is that if one has some sort of clear immune dysfunction, a lowered fat intake of all forms is preferred. Until sufficient energetics are restored, it is not a good thing to push more endotoxin from the gut into the bloodstream and lymphatic system, and ask the immune system to do more than it can.
....
(a) Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia (Mani et. al., 2013)
(b) High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects (Harte et. al, 2012)
(c) Endotoxin in the gut and chylomicrons: translocation or transportation? (Carl Grunfeld and Kenneth R. Feingold, 2008)
(b) High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects (Harte et. al, 2012)
(c) Endotoxin in the gut and chylomicrons: translocation or transportation? (Carl Grunfeld and Kenneth R. Feingold, 2008)
There are going to be many papers like this, but these 3 papers represents the points that I want to make, which I state up front:
(1) Eating Dietary Fat increases the observed gut-derived endotoxin in the bloodstream. The effect usually starts 2-4 hours after eating fat, and lasts for up to 12 hours in healthy subjects [see paper (a)]
(2) The more double bonds in a fat, the LESS endotoxin gets into the serum. A PUFA like DHA will cause less endotoxin to be transferred into the bloodstream, as compared to a Saturated Fat like Coconut Oil. [paper (a)]
(3) In Diabetics, this effect is much more pronounced -- 60% greater levels of circulating endotoxin in serum after eating fat, as compared to "healthy" subjects [paper (b)]
(4) Endotoxin is transported by chylomicrons -- the lipoprotein "Fat Carriers" which transport dietary fat from the GI tract, and deliver them to tissues.
This DOES NOT involve any compromise to intestinal barrier function [paper (c)], but as a result, it is a completely inevitable side effect of consuming fat. ie: if you eat fat, existing endotoxin in the gut can and will be transported into the bloodstream within chylomicrons.
Quote from paper (c):
It is important to remember that you must have acute inflammation in order for proper immune responses to be established.
Quote from paper (c):
This is faulty logic -- the pro-PUFA stance claims that suppressing the alarm bells (stuff like NF-kB and TNF-alpha) is equivalent to decreasing the harm caused by the objects that are raising the alarm in the first place. I will elaborate more in the "Personal interpretations" section below.
----(2) The more double bonds in a fat, the LESS endotoxin gets into the serum. A PUFA like DHA will cause less endotoxin to be transferred into the bloodstream, as compared to a Saturated Fat like Coconut Oil. [paper (a)]
(3) In Diabetics, this effect is much more pronounced -- 60% greater levels of circulating endotoxin in serum after eating fat, as compared to "healthy" subjects [paper (b)]
(4) Endotoxin is transported by chylomicrons -- the lipoprotein "Fat Carriers" which transport dietary fat from the GI tract, and deliver them to tissues.
This DOES NOT involve any compromise to intestinal barrier function [paper (c)], but as a result, it is a completely inevitable side effect of consuming fat. ie: if you eat fat, existing endotoxin in the gut can and will be transported into the bloodstream within chylomicrons.
Quote from paper (c):
The paper of Ghoshal et al. (20) in this issue of the Journal of Lipid Research addresses these important questions. Using both animal models and polarized, cultured gut cells, they show that endotoxin, which is internalized into gut cells, is secreted into the circulation during the formation and secretion of chylomicrons.
Polarized CaCo-2 cells secrete endocytosed endotoxin when incubated with oleate, which forms chylomicrons in those cells, but not when incubated with butyrate, which does not. Importantly, Pluronic L-81, an inhibitor of chylomicron formation, blocked the effect of oleate.
Thus endotoxin is transported into the circulation in conjunction with chylomicron formation and secretion, not just translocated due to breakdown of the intestinal barrier.
(5) This transport of endotoxin by Chylomicrons is a normal immune response. Chylomicrons "neutralise" endotoxin during transport (endotoxin is not free to disperse like in a case of sepsis), while simultaneously stimulating the inflammatory cascade required for healthy immune response.Polarized CaCo-2 cells secrete endocytosed endotoxin when incubated with oleate, which forms chylomicrons in those cells, but not when incubated with butyrate, which does not. Importantly, Pluronic L-81, an inhibitor of chylomicron formation, blocked the effect of oleate.
Thus endotoxin is transported into the circulation in conjunction with chylomicron formation and secretion, not just translocated due to breakdown of the intestinal barrier.
It is important to remember that you must have acute inflammation in order for proper immune responses to be established.
Quote from paper (c):
Mesenteric lymph nodes are activated by the endotoxin on chylomicrons. Mesenteric lymph nodes likely play an important role of scavenging the loosely attached endotoxin and decreasing the amount that reaches the systemic circulation. But scavenging means activating the cells in the lymph nodes to secrete cytokines, hence inducing systemic inflammation.
Systemic administration of chylomicrons and chylomicron-like particles have been shown to bind endotoxin and not only protect from the toxicity of administered endotoxin (19), but also to protect from cecal ligation and puncture (23), a model of gut sepsis that even anticytokine agents fail to block.
Paper (a) will elaborate on why PUFAs do not cause as big of a response -- they suppress the initial inflammatory cascade within intestinal cells. The pro-PUFA observer sees this as a "good thing", because "less inflammation bro".Systemic administration of chylomicrons and chylomicron-like particles have been shown to bind endotoxin and not only protect from the toxicity of administered endotoxin (19), but also to protect from cecal ligation and puncture (23), a model of gut sepsis that even anticytokine agents fail to block.
This is faulty logic -- the pro-PUFA stance claims that suppressing the alarm bells (stuff like NF-kB and TNF-alpha) is equivalent to decreasing the harm caused by the objects that are raising the alarm in the first place. I will elaborate more in the "Personal interpretations" section below.
Personal Interpretations
We cannot take observed high endotoxin levels in serum to mean that we are burning in a pit of destruction. Knowing how the endotoxin got there is an important question to ask.
If the intestinal barrier is compromised through whatever means -- be it infection, or gluten consumption , then we get a fairly free-flow of endotoxin from the gut into the bloodstream. This is undoubtedly bad, and if high endotoxin is observed in conjunction with intestinal barrier compromise, then things are bad
Note that what was described in the previous section are just mechanics. Mechanics need to be applied to a particular context to become useful.
Sidenote: Medium Chain Triglycerides (MCTs) do not stimulate chylomicron production, and thus do not provide this immune regulated endotoxin transport. They can be incorporated into chylomicrons, but do not actually stimulate the formation of chylomicrons.
Practically speaking, there is no MCT-only diet -- which is seen only rarely in certain hospitalisation cases where few other nutrients can be absorbed. Any naturally occurring fats will contain other types of fatty acids, which will stimulate chylomicron formation and the associated endotoxin transport.
Practically speaking, there is no MCT-only diet -- which is seen only rarely in certain hospitalisation cases where few other nutrients can be absorbed. Any naturally occurring fats will contain other types of fatty acids, which will stimulate chylomicron formation and the associated endotoxin transport.
In the real world, we need to explain situations where eating something like Coconut Oil "improves gut health" in some people, and then in others makes the gut worse (eg: comment by @Ewelina -- Why Does Starch Make Me Extremely Sick?). We also need to explain why diabetics seem to transport even more endotoxin.
In my opinion, this comes down to the Robustness and Sensitivity of the Immune Response.
All that eating fat does, is to provide the mechanical pathway for a "as safe as possible" endotoxin-mediated immune response to whatever endotoxin is already present in the gut. ie: Bundling up endotoxin into chylomicrons, is like a "quarantine function", whereby the invaders are then delivered to immune cells to be dealt with.
NOTE: eating fat only helps transport this endotoxin -- if there is little or no endotoxin in the first place (caused by too much gut flora), then there isn't anything to be Immune against .
IMO, this generally means that less gut flora is better in this regard. However, it may be a case whereby the key factor is less endotoxin-producing gut flora.
However, what happens when your immune system breaks down? For whatever reason, this transported endotoxin is not able to be dealt with. The endotoxin in chylomicrons will now only serve to keep asking the immune system for something it cannot provide, and the system is put into further stress.
This may be why some people find that saturated fat causes them to have "an immune shock", with symptoms like anxiety, nausea, shivering, etc ....
It is plausible that this cascade leads to breakdown of gut barrier function, which would then allow for even more un-regulated endotoxin entry into the bloodstream, making the immune over-reaction even worse.
Again, note the assumptions:
- There is already an existing high level of endotoxin in the gut
- Immune system cannot handle any incoming endotoxin
Conversely, if dietary fat is only transporting manageable quantities of endotoxin from the gut, I can see a situation whereby this leads to gradual clean-up of endotoxin and gut flora excess. This scenario can be achieved, again, by reduction of existing gut endotoxin levels, and bolstering of the immune system through all the usual Bio-energetic-enhancing strategies.
Also, this will explain why PUFAs like DHA seem to help the situation in the short term. These PUFAs shut down any sort of immune response, an isolate all endotoxin to the gut. The gut may be having a bad time, but there will be no systemic effect . One wonders how well an acute administration of DHA + antibiotics will work (DHA to transiently shutdown immune response, and then antibiotics to kill the gut-localised bacteria in hopes of reducing endotoxin formation)
Another interesting note will be the context of very low fat diets. In this case, you do not get as much of the Chylomicron-mediated endotoxin transport. You can still potentially feed the gut bacteria if you choose fermentable / slow-digesting foods, but you're not going to get as much endotoxin-triggered immune effects.
In light of this, my personal opinion is that if one has some sort of clear immune dysfunction, a lowered fat intake of all forms is preferred. Until sufficient energetics are restored, it is not a good thing to push more endotoxin from the gut into the bloodstream and lymphatic system, and ask the immune system to do more than it can.
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