PUFAs Better Than Saturated Fats?

[CLASH]

@RWilly
Here is an excerpt from the book I've been slowly writing on the topic:

“High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects”

High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects


“RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05).”


Layman’s terms for those who want to see a reality show about clinical researchers: “Keeping up with the clinicians”:Giving people, especially glucose tolerance impaired individuals, obese individuals and type II diabetic individuals, large boluses of saturated fat like cream, their endotoxin levels in the blood went up. Interestingly, in type II diabetics, glucose tolerance impaired individuals and obese individuals the endotoxin levels where much higher than the normal individuals. In the type II diabetics the endotoxin levels were reported to be 60.6% higher than the normal people. Now something to note, if this was pure endotoxin by itself hitting the bloodstream then the inflammatory response these people had gotten should have been massive. However, as you’ll see in this response below by other researchers the inflammatory response from this increased endotoxin in the blood is relatively trivial. They even imply to some extent that the researchers who produced the article above didn’t effectively measure the endotoxin levels (researcher dis “you can’t even measure endotoxin the right way bro”):


“Comment on: Harte et al. High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects. Diabetes Care 2012;35:375–382”



Comment on: Harte et al. High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects. Diabetes Care 2012;35:375–382


“Harte et al. have reported levels of endotoxin to be between 3.3 and 14.2 EU/mL, but these concentrations are known to increase levels of tumor necrosis factor α (TNFα) in plasma and induce a massive inflammatory response in humans. Low-grade inflammation has been induced in human volunteers by intravenous injection or infusion of lipopolysaccharide (4,5), and as little as 60 pg/kg body weight given as a bolus resulted in a significantly increased plasma level of TNFα (4). This dose would be expected to result in a peak concentration of endotoxin in a 70 kg human of 1 pg/mL being equivalent to around 0.003 EU/mL. Furthermore, a concentration of >0.25 EU/mL is indicative of endotoxemia in humans, and endotoxin levels of around 450 pg/mL (= 4.5 EU/mL) are found in patients with Gram-negative infection.”


“In the study by Harte et al. (1), endotoxin was reported to increase from 3.3 to 6.3 EU/mL in normal subjects and from 5.3 to 14.2 EU/mL in the type 2 diabetic group. At the same time, there was no increase in levels of the inflammatory marker TNFα in plasma in both groups. So whatever the authors are measuring with the limulus amebocyte lysate assay, it does not represent endotoxin that is bioactive in humans. Furthermore, the lack of such bioactive endotoxin questions the suggestion that gut-derived endotoxin is a contributing factor for development of low-grade inflammation in adipose tissue or in other tissues that seems to be a hallmark for development of type 2 diabetes.”


Layman’s terms for those who think it’s funny that implying someone can’t measure endotoxin correctly in the blood is even a dis:The endotoxin content measured in these subjects blood following the cream ingestion was between 3.3 and 14.2 EU/mL (Don’t worry about the units, just look at the numbers here if your confused or inebriated). A concentration of greater than 0.25 EU/mL is indicative of endotoxemia in humans, and a concentration greater than 4.5 EU/mL is indicative of a full blown bacterial infection. Both endotoxemia and bacterial infections are considered pretty significant inflammatory states measured by high levels of an inflammatory marker called Tumor necrosis factor alpha. Endotoxin in the blood is one of the main initiators of septic shock via the release of the inflammatory mediators, so high levels is no joke. Yet despite having blood levels of endotoxin close to the level of a bacterial infection (4.5 EU/ml) or even more than 3x the level of a bacterial infection (14.2 EU/ml) these participants didn’t seem to have massively elevated inflammatory markers such as tumor necrosis factor alpha. With this in mind the researchers responding to the article effectively stated “So whatever the authors are measuring with the limulus amebocyte lysate assay, it does not represent endotoxin that is bioactive in humans” (this was the covert implied researcher dis lol; quick somebody get these guys a safe space so they don’t melt). My perspective on this was that the saturated fat in the cream was actually protecting the participants from the endotoxin and as I’ll show you in the rest of the book, and from what I’ve shown already, this seems to be the case.

----------------------------------------------------------------------------------------------------------------
EDIT:

Fair to tag me on the rat studies, however considering the effects saturated fats should have on the rats/mice considering the digestive physiology/anatomy differences, the fact that they are still protective and the lipoprotein system is evident in their species as well as ours, I think, serves to further bolster my original point.

I actually go over the reasoning for the protective effect of fruits/ juice in the book (its not the just the OJ. I also don't think its the vit C I'm pretty certain its actually the polyphenols.

Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition
Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition


“Polyphenols can be ingested by humans from the consumption of fruits, vegetables, and plant derived beverages. The consumption of diets rich in polyphenol have usually been associated with beneficial effects to human health [4]. Despite controversies, epidemiological studies suggest that dietary polyphenols could lower risk of cardiovascular disease, prevent obesity, cancer and type 2 diabetes, attenuate brain aging and Alzheimer’s disease, as well as maintain gut health [5,6]. These benefits have usually been associated with their diverse biological activities, such as anti-oxidation, anti-inflammation, anti-bacteria, enzyme inhibition, glycation inhibition, immunomodulation and miRNA interference [7,8,9].”


“Polypenols, especially flavonoids, have been suggested to exert their antibacterial effects in three ways; namely, direct killing of bacteria, synergistic activation of antibiotics, and attenuation of bacterial pathogenicity [11]. More importantly, flavonoids have been shown to be capable of inactivating efflux pump, destabilizing cytoplasmic membrane, and inhibiting β-lactamases and topoisomerase, and thus can prevent the development of antibiotic resistance in bacteria [12].”


Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: a Comprehensive Review.
Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: a Comprehensive Review. - PubMed - NCBI


“Several polyphenols: phenolic acids, flavonoids (especially flavonols), tannins, lignans, stilbenes and combinations of these in botanical mixtures, have exhibited significant antibacterial activity against resistant and non-resistant Gram-positive bacteria at low µg/mL range MIC values. Their mechanism of action is quite diverse, targeting cell wall, lipid membrane, membrane receptors and ion channels, bacteria metabolites, and biofilm formation. Synergic effects were also demonstrated for some combinations of polyphenols and antibiotics.”

Purple Sweet Potato (Ipomoea batatas L.) Anthocyanins: Preventive Effect on Acute and Subacute Alcoholic Liver Damage and Dealcoholic Effect
https://www.researchgate.net/public...Alcoholic_Liver_Damage_and_Dealcoholic_Effect


“This study aimed to investigate dealcoholic effect and preventive effect of anthocyanins from purple sweet potato (PSPAs) on acute and sub-acute alcoholic liver damage (ALD). Seven-week old male inbred mice were grouped into five groups: control group (without PSPAs and ethanol treatments), model group (with ethanol treatment only), low-dose group (50 mg PSPAs / kg body weight), middle-dose group (125 mg PSPAs / kg body weight) and high-dose group (375 mg PSPAs / kg body weight), and the mice in all groups were administered intragastrically. Biochemical parameters of serum and liver were determined, and the histopathological changes of liver tissue were also analyzed. Results showed that all tested parameters were ameliorated after consumption of PSPAs. Therefore, PSPAs have preventive effect on acute and sub-acute ALD. It is suggested that PSPAs could be used as a supplementary reagent during prophylactic and curative managements of ALD.


Polyphenols and gastrointestinal diseases
Polyphenols and gastrointestinal diseases


“A wealth of evidence suggests that luminal concentrations of polyphenols might be much higher than serum concentration [4]. Because of poor intestinal absorption, large quantities of polyphenol compounds are delivered to the colon, where many undergo extensive metabolism via colonic flora. High levels of dietary polyphenols actually alter colonic flora [8].”


“Green tea polyphenols have been used extensively in experimental models of liver injury. Our laboratory showed that the green tea polyphenols protected against endotoxin-induced hepatotoxicity and lethality [35]. In this study, green tea also decreased endotoxin-induced NF-κB activation and TNF production. Similarly, green tea polyphenols have been shown to protect against experimental alcohol-induced hepatic fibrosis in rats and to concomitantly decrease endotoxin levels [36].”

 

[boris]

If Vitamin E can offset the damage from PUFAs, then wouldn't nuts and seeds be OK, since they contain high amounts of Vitamin E to offset the PUFAs in them?

Why would they have more Vitamin E than is necessary to keep the PUFA from oxidizing inside the seed? After that, there are still: Anti-nutrients, phytic acid, gluten + feed bad gut bacteria I assume (don't quote me on that ). It is hard to find a reason to eat nuts and seeds.

Personally, I think nuts and seeds are okay in moderation. There are many health studies out there that show that nuts and seeds reduce the risk of cardiovascular mortality and type 2 diabetes.

@RWilly could you point to those studies please?

 

[RWilly]

Mostly reasonable choices like cheese, eggs, beef, coconut oil, etc. Occasionally from a cheat meal of pizza or something (that's where those high #'s greater than 10g come from).

Those sound like saturated fatty acid foods.

 

[CLASH]

@RWilly

Here are some more studies on my point:

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.
Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death. - PubMed - NCBI


“The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.”

Lipids: a key player in the battle between the host and microorganisms
Lipids: a key player in the battle between the host and microorganisms


“For example, lipoproteins including HDL, chylomicrons, VLDL, and LDL can bind and neutralize LPS, lipoteichoic acid, and viruses. The binding of LPS by lipoproteins has been shown to protect animals from LPS induced death. Numerous studies have shown that animals that have elevations in serum lipid/lipoprotein levels are protected from the toxicity of LPS, whereas animals with low circulating lipid/lipoprotein levels are more sensitive to the toxic effects of LPS. Studies have shown that HDL may inhibit the ability of certain viruses to penetrate cells. Moreover, lipoproteins can block the adhesion of bacteria to host cells and reduce tissue invasion (2). Another example involves cell-to-cell communication between bacteria, which coordinates gene expression and the production of virulence factors (3). Studies have shown that Staphylococcus aureus produce an autoinducing peptide that binds to surface receptors on the bacteria increasing the production of toxins and invasive enzymes (3). Apo B-containing lipoproteins sequesters the autoinducing peptide and reduces the infectivity of S. aureus (3, 4).”


The role of lipid peroxidation in liver damage.
The role of lipid peroxidation in liver damage. - PubMed - NCBI


“The consequences of the peroxidative breakdown of membrane lipids have been considered in relation to both the subcellular and tissue aspects of liver injury. Mitochondrial functions can be impaired by lipid peroxidation probably through the oxidation of pyridine nucleotides and the consequent alteration in the uptake of calcium. Several enzymatic functions of the endoplasmic reticulum are also affected as a consequence of peroxidative events and among these are the activities of glucose 6-phosphatase, cytochrome P-450 and the calcium sequestration capacity. Moreover, a release of hydrolytic enzymes from lysosomes and a decrease in the fluidity of plasma membranes can contribute to the liver damage consequent to the stimulation of lipid peroxidation. Extensive studies carried out in vivo and integrated with the use of isolated hepatocytes have shown that lipid peroxidation impairs lipoprotein secretion mainly at the level of the dismission from the Golgi apparatus, rather than during their assembly.However, such an alteration appears to give a late and not essential contribution to the fat accumulation. A more critical role is played by peroxidative reactions in the pathogenesis of acute liver necrosis induced by several pro-oxidant compounds as indicated by the protective effects against hepatocyte damage exerted by antioxidants. In addition, even in the cases where lipid peroxidation has been shown not to be essential in causing cell death there is evidence that it can still act synergistically with other damaging mechanisms in the amplification of liver injury.”

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Here is another excerpt from my book:


Now we’ll move onto some of bile acids more specific effects on bacteria in the small intestine:

Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts
Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts


“However, bile salts are antibacterial compounds that disrupt bacterial membranes, denature proteins, chelate iron and calcium, cause oxidative damage to DNA, and control the expression of eukaryotic genes involved in host defense and immunity. Bacterial species adapted to the mammalian gut are able to endure the antibacterial activities of bile salts by multiple physiological adjustments that include remodeling of the cell envelope and activation of efflux systems and stress responses.”


Layman’s terms for those who aren’t even reading the study excerpts: This study is discussing, among other things, the effects of bile acids directly on bacteria. Bile acids seem to have a general antibacterial effect in and of themselves. Some of these effects include breaking down the protective outer layer of the bacteria, stealing minerals from the bacteria, damaging the DNA of the bacteria and causing the bacteria to increase or decrease the activation of certain genes in the presence of bile that can have different effects on their overall function. It goes on to discuss the specific bacteria that are adapted to survive bile acids and certain bad bacteria like salmonella that have learned to adapt to bile and cause damage to the body. This isn’t in the article but even before bile acids, we have stomach acid. So in order for bacteria to successfully to the intestine, bacteria have to first get past stomach acid and then make it past bile acids.


As you can see, bile has some direct anti-bacterial effects, but that’s not all:


[Bile acids and endotoxins: physico-chemical defense of the body]. - PubMed - NCBI



[Bile acids and endotoxins: physico-chemical defense of the body]. - PubMed - NCBI


“If the common bile ducts of rats were chronically cannulated (bile deprived animals) perorally administered endotoxin was absorbed from the intestinal canal into blood circulation and provoked endotoxin shock. The translocation of endotoxins and consequent shock can be prevented by sodium deoxycholate or natural bile. The bile acids can split the endotoxin macromolecule (atoxic fragments).”


Layman’s terms:In this article bile acids are shown to breakdown endotoxin and protect rats from endotoxin in the GI tract. The researchers tested this by putting a pipe (more or less) into the rats bile ducts to drain the bile away from reaching the small intestine. Then the researchers gave the rats bacterial toxin orally. When the rats got the toxin they developed a very strong inflammatory response. When the researchers gave the rats bile orally with the oral bacterial toxin the inflammatory response (shock) was avoided. This is because, according to the researchers the bile acids actually can break endotoxin into what the researchers call “atoxic fragments” or in ordinary people terms, pieces that aren’t toxic. Just an FYI for anyone interested on how to induce bile release into the intestine; fats are excellent stimulators of bile acid release into the intestine. Just in case anyone doubts this, here is some direct evidence.


Effects of various food ingredients on gall bladder emptying
Effects of various food ingredients on gall bladder emptying


“We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively.”



“The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK.”



“Maximum % gall bladder volume change between t=−5 and t=65 min for healthy volunteers after they consumed each of the 10 test ingredients in Study 1. Values are mean±s.e.m., n=8. A=25 ml dairy emulsion; B=25 ml dairy emulsion+300 mg potato protease inhibitor; C=67.5 g yogurt drink; D=67.5 g yogurt drink+3 g protein; E=67.5 g yogurt drink+80 mg curcumin; F=250 ml coffee; G=250 ml tea; H=250 ml semi-skimmed milk; I=20 ml high-fat emulsion; and J=4 ml high-fat emulsion. aSignificant difference versus ingredient J, 4 ml high-fat emulsion (P<0.05); bSignificant difference versus ingredient J, 4 ml high-fat emulsion (P<0.01).”



Layman’s terms: The researchers here used MRI imaging to assess the change in the gallbladder volume after a series of different test meals (they were more like an assortment of weird snacks). The 250ml of semi-skimmed milk containing 4.5g of fat (H), 20ml of high fat emulsion containing 10g of fat (I), and 4ml of high fat-emulsion containing 2g of fat (J) stimulated the largest change in gallbladder volumes (41% for the skimmed milk, 42% for the 10ml fat emulsion, 27% for the 4ml fat emulsion). The change in volume is indicative of the gallbladder contracting to release its stored bile, where the contraction causes the bile to be released into the intestine thus decreasing the volume of the gallbladder.


So, Bile acids, besides being directly antibacterial can actually breakdown endotoxin into non-toxic pieces. There’s even more though:



Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor



Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor


“Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier.”


Layman’s terms for those who pictured a PVC pipe after reading the section above (if you didn’t picture it your probably bourgeoisie and steal bread from soup kitchens, 70% income tax for you):In this article, its shown that bile acids increase small intestine defense and protect against excess bacterial growth. The researchers in this one blocked bile flow into the rats intestine. When they did this the bacteria in the rats intestine not only increased their overall growth but they started to move across the small intestinal wall (#No_microbe_is_illegal). The researchers figured that part of the protective effect of bile was via the induction of a receptor in the intestine that increases the defense of the intestinal lining against bacterial (we’re going to rename this receptor the ICE receptor AKA the immigration and customs enforcement receptor). They confirmed their hypothesis by looking at mice that lack this specific receptor, which lead to an increase in bacterial overgrowth and a compromise of the intestinal barrier. Again, FYI fats stimulate bile acid release into the intestine.


So for bile overall, we see that it enhances protein and fat digestion, it is directly anti-bacterial, it can breakdown toxic bacterial products and it increases the overall defensive measures of the body in the small intestine.


Besides bile there is another component to this intestinal fat based system that shines, this is alkaline phosphatase. Alkaline phosphatase is an enzyme produced in the small intestine, liver and bile ducts among other areas of the body, it functions, at least in the areas specifically mentioned, in the detoxification of bacterial compounds and in the regulation of pH. It also seems to aid in fat absorption. As for its effects on bacterial toxins, one of its main effects within this system see below:


Dephosphorylation of endotoxin by alkaline phosphatase in vivo.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858034/

“The results show that inhibition of endogenous AP (alkaline phosphatase) by levamisole significantly reduces survival of rats intraperitoneally injected with E. coli bacteria, whereas this drug does not influence survival of rats receiving a sublethal dose of the gram-positive bacteria Staphylococcus aureus. In view of the endotoxin-dephosphorylating properties of AP demonstrated in vitro, we propose a crucial role for this enzyme in host defense. The effects of levamisole during gram-negative bacterial infections and the localization of AP as an ecto-enzyme in most organs as well as the induction of enzyme activity during inflammatory reactions and cholestasis is in accordance with such a protective role.”

Layman’s terms for those who don’t even know what bourgeoisie is, I didn’t until 3 days ago:This article shows that alkaline phosphatase, another component of the “fat system”, detoxifies and destroys endotoxin directly. As per this study when alkaline phosphatase is inhibited by a drug called levamisole it increases rats death after injection with endotoxin (bacterial toxin). Also interesting, the researchers note that the enzyme is upregulated in cholestasis which basically means the bile isn’t moving, its stuck. It seems the body is upregulating this protective enzyme to deal with endotoxin when bile is missing in action.


“Increase in alkaline phosphatase activity in small intestine mucosa in high fat diets”



https://www.ncbi.nlm.nih.gov/m/pubmed/7467486/?i=5&from=/7325238/related


“The activity of alkaline phosphatase in small intestine mucosa was increased by about 40% in rats adapted to a high fat diet in comparison to high-carbohydrate-adapted animals.”


Layman’s terms:A study showing increases in Alkaline phosphatase in the small intestine with high fat feeding.


Effect of fat feeding on intestinal alkaline phosphatase activity in tissue and serum. - PubMed - NCBI



https://www.ncbi.nlm.nih.gov/m/pubmed/7325238/


“Therefore, serum intestinal alkaline phosphatase activity rises in response to a single fat feed as a result of increased delivery of the enzyme to the blood and not as a result of an increase in its normally short biological half-life. This rise cannot be directly linked to an increase in the amount of brush-border-bound enzyme, and it appears that the serum enzyme is derived directly from a pool of soluble intracellular enzyme in the small bowel mucosa.”


Layman’s terms:In this study alkaline phosphatase is shown to be increased in serum (blood levels) by the feeding of fats. The interesting part is that the enzyme is transported into the bloodstream with the chylomicrons (peanut M&M’s) from the small bowel.

 

[Cirion]

Those sound like saturated fatty acid foods.

Yes, I don't eat foods that are primarily PUFA foods anymore. The PUFA I get is incidental from other foods, including primarily SFA foods. All fats, even coconut oil, contain PUFA. The only exception is hydrogenated coconut oil, which isn't a natural food.

Even hydrogenated coconut oil, which I've experimented with in the past, I've only seen mixed results with, and not enough experimentation to make final conclusions admittedly. But theoretically, HCO should be the safest fat.

I think part of the issue is when you're already PUFA toxic, even the 1-2 gram added PUFA from a SFA rich diet is unhelpful.

 

[RWilly]

@RWilly
Here is an excerpt from the book I've been slowly writing on the topic:

“High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects”

High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects


“RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05).”


Layman’s terms for those who want to see a reality show about clinical researchers: “Keeping up with the clinicians”:Giving people, especially glucose tolerance impaired individuals, obese individuals and type II diabetic individuals, large boluses of saturated fat like cream, their endotoxin levels in the blood went up. Interestingly, in type II diabetics, glucose tolerance impaired individuals and obese individuals the endotoxin levels where much higher than the normal individuals. In the type II diabetics the endotoxin levels were reported to be 60.6% higher than the normal people. Now something to note, if this was pure endotoxin by itself hitting the bloodstream then the inflammatory response these people had gotten should have been massive. However, as you’ll see in this response below by other researchers the inflammatory response from this increased endotoxin in the blood is relatively trivial. They even imply to some extent that the researchers who produced the article above didn’t effectively measure the endotoxin levels (researcher dis “you can’t even measure endotoxin the right way bro”):


“Comment on: Harte et al. High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects. Diabetes Care 2012;35:375–382”



Comment on: Harte et al. High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects. Diabetes Care 2012;35:375–382


“Harte et al. have reported levels of endotoxin to be between 3.3 and 14.2 EU/mL, but these concentrations are known to increase levels of tumor necrosis factor α (TNFα) in plasma and induce a massive inflammatory response in humans. Low-grade inflammation has been induced in human volunteers by intravenous injection or infusion of lipopolysaccharide (4,5), and as little as 60 pg/kg body weight given as a bolus resulted in a significantly increased plasma level of TNFα (4). This dose would be expected to result in a peak concentration of endotoxin in a 70 kg human of 1 pg/mL being equivalent to around 0.003 EU/mL. Furthermore, a concentration of >0.25 EU/mL is indicative of endotoxemia in humans, and endotoxin levels of around 450 pg/mL (= 4.5 EU/mL) are found in patients with Gram-negative infection.”


“In the study by Harte et al. (1), endotoxin was reported to increase from 3.3 to 6.3 EU/mL in normal subjects and from 5.3 to 14.2 EU/mL in the type 2 diabetic group. At the same time, there was no increase in levels of the inflammatory marker TNFα in plasma in both groups. So whatever the authors are measuring with the limulus amebocyte lysate assay, it does not represent endotoxin that is bioactive in humans. Furthermore, the lack of such bioactive endotoxin questions the suggestion that gut-derived endotoxin is a contributing factor for development of low-grade inflammation in adipose tissue or in other tissues that seems to be a hallmark for development of type 2 diabetes.”


Layman’s terms for those who think it’s funny that implying someone can’t measure endotoxin correctly in the blood is even a dis:The endotoxin content measured in these subjects blood following the cream ingestion was between 3.3 and 14.2 EU/mL (Don’t worry about the units, just look at the numbers here if your confused or inebriated). A concentration of greater than 0.25 EU/mL is indicative of endotoxemia in humans, and a concentration greater than 4.5 EU/mL is indicative of a full blown bacterial infection. Both endotoxemia and bacterial infections are considered pretty significant inflammatory states measured by high levels of an inflammatory marker called Tumor necrosis factor alpha. Endotoxin in the blood is one of the main initiators of septic shock via the release of the inflammatory mediators, so high levels is no joke. Yet despite having blood levels of endotoxin close to the level of a bacterial infection (4.5 EU/ml) or even more than 3x the level of a bacterial infection (14.2 EU/ml) these participants didn’t seem to have massively elevated inflammatory markers such as tumor necrosis factor alpha. With this in mind the researchers responding to the article effectively stated “So whatever the authors are measuring with the limulus amebocyte lysate assay, it does not represent endotoxin that is bioactive in humans” (this was the covert implied researcher dis lol; quick somebody get these guys a safe space so they don’t melt). My perspective on this was that the saturated fat in the cream was actually protecting the participants from the endotoxin and as I’ll show you in the rest of the book, and from what I’ve shown already, this seems to be the case.

----------------------------------------------------------------------------------------------------------------
EDIT:

Fair to tag me on the rat studies, however considering the effects saturated fats should have on the rats/mice considering the digestive physiology/anatomy differences, the fact that they are still protective and the lipoprotein system is evident in their species as well as ours, I think, would serve to further bolster my original point.

I actually go over the reasoning for the protective effect of fruits/ juice in the book (its not the just the OJ. I also don't think its the vit C I'm pretty certain its actually the polyphenols.

Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition
Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition


“Polyphenols can be ingested by humans from the consumption of fruits, vegetables, and plant derived beverages. The consumption of diets rich in polyphenol have usually been associated with beneficial effects to human health [4]. Despite controversies, epidemiological studies suggest that dietary polyphenols could lower risk of cardiovascular disease, prevent obesity, cancer and type 2 diabetes, attenuate brain aging and Alzheimer’s disease, as well as maintain gut health [5,6]. These benefits have usually been associated with their diverse biological activities, such as anti-oxidation, anti-inflammation, anti-bacteria, enzyme inhibition, glycation inhibition, immunomodulation and miRNA interference [7,8,9].”


“Polypenols, especially flavonoids, have been suggested to exert their antibacterial effects in three ways; namely, direct killing of bacteria, synergistic activation of antibiotics, and attenuation of bacterial pathogenicity [11]. More importantly, flavonoids have been shown to be capable of inactivating efflux pump, destabilizing cytoplasmic membrane, and inhibiting β-lactamases and topoisomerase, and thus can prevent the development of antibiotic resistance in bacteria [12].”


Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: a Comprehensive Review.
Antimicrobial Capacity of Plant Polyphenols against Gram-positive Bacteria: a Comprehensive Review. - PubMed - NCBI


“Several polyphenols: phenolic acids, flavonoids (especially flavonols), tannins, lignans, stilbenes and combinations of these in botanical mixtures, have exhibited significant antibacterial activity against resistant and non-resistant Gram-positive bacteria at low µg/mL range MIC values. Their mechanism of action is quite diverse, targeting cell wall, lipid membrane, membrane receptors and ion channels, bacteria metabolites, and biofilm formation. Synergic effects were also demonstrated for some combinations of polyphenols and antibiotics.”

Purple Sweet Potato (Ipomoea batatas L.) Anthocyanins: Preventive Effect on Acute and Subacute Alcoholic Liver Damage and Dealcoholic Effect
https://www.researchgate.net/public...Alcoholic_Liver_Damage_and_Dealcoholic_Effect


“This study aimed to investigate dealcoholic effect and preventive effect of anthocyanins from purple sweet potato (PSPAs) on acute and sub-acute alcoholic liver damage (ALD). Seven-week old male inbred mice were grouped into five groups: control group (without PSPAs and ethanol treatments), model group (with ethanol treatment only), low-dose group (50 mg PSPAs / kg body weight), middle-dose group (125 mg PSPAs / kg body weight) and high-dose group (375 mg PSPAs / kg body weight), and the mice in all groups were administered intragastrically. Biochemical parameters of serum and liver were determined, and the histopathological changes of liver tissue were also analyzed. Results showed that all tested parameters were ameliorated after consumption of PSPAs. Therefore, PSPAs have preventive effect on acute and sub-acute ALD. It is suggested that PSPAs could be used as a supplementary reagent during prophylactic and curative managements of ALD.


Polyphenols and gastrointestinal diseases
Polyphenols and gastrointestinal diseases


“A wealth of evidence suggests that luminal concentrations of polyphenols might be much higher than serum concentration [4]. Because of poor intestinal absorption, large quantities of polyphenol compounds are delivered to the colon, where many undergo extensive metabolism via colonic flora. High levels of dietary polyphenols actually alter colonic flora [8].”


“Green tea polyphenols have been used extensively in experimental models of liver injury. Our laboratory showed that the green tea polyphenols protected against endotoxin-induced hepatotoxicity and lethality [35]. In this study, green tea also decreased endotoxin-induced NF-κB activation and TNF production. Similarly, green tea polyphenols have been shown to protect against experimental alcohol-induced hepatic fibrosis in rats and to concomitantly decrease endotoxin levels [36].”

I would agree about the protective effects of fruit, and that polyphenols play a huge role. And vitamin C (in it's natural form, which may include bioflavonoids such as rutin) as well as other phytonutrients (even things like phytic acid) are huge when it comes to the health and management of the gut biome.

Also, the points you made about saturated fat is what I'm saying too. Saturated fat, for the person who is prone to diabetes behaves differently than saturated fat intake on a healthy person. I personally think this has to do with iron and bacteria, with the likely culprits being h. pylori or e.coli. Here is an article I wrote on that topic: Is Diabetes an Infection? A New Perspective on the Cause of Weight Gain and Type 2 Diabetes

 

[RWilly]

Yes, I don't eat foods that are primarily PUFA foods anymore. The PUFA I get is incidental from other foods, including primarily SFA foods. All fats, even coconut oil, contain PUFA. The only exception is hydrogenated coconut oil, which isn't a natural food.

Even hydrogenated coconut oil, which I've experimented with in the past, I've only seen mixed results with, and not enough experimentation to make final conclusions admittedly. But theoretically, HCO should be the safest fat.

I think part of the issue is when you're already PUFA toxic, even the 1-2 gram added PUFA from a SFA rich diet is unhelpful.

So if I'm understanding the graph then, that's not PUFA by itself. That is fat in general ... correct?

 

[Cirion]

Saturated fat, for the person who is prone to diabetes behaves differently than saturated fat intake on a healthy person.

Excellent point, and is something I was trying to say but didn't articulate properly.

If one has a large amount of body fat and thus FFA's, and especially a lot of PUFA, then shifting the mitochondria to burning fat (Which all fats will do, including SFA), is a bad move because you'll be burning lots of PUFA and the high SFA content is not enough to counteract the PUFA's in this case. It's like putting Kevlar on and expecting that you can get shot at all day and not get injured/die.

Now, take that same high SFA intake, with someone with way less body fat / less FFA's / less PUFA stored, and we have a different story entirely. Burning fats is infinitely safer if the body fat contains primarily SFA, and there isn't much body fat to begin with. Going along with my maybe terrible analogy, the healthful person has now put on a full iron man suit and can indeed get shot at all day.

So I want to be clear I'm not demonizing fats across the board 100%. I'm demonizing it for the sick / unwell person.

 

[CLASH]

@RWilly
I think the nuanced different in our interpretations is that I would say the saturated fat would be helpful in the type 2 diabetes/ obesity situation, especially in the long run as it detoxes the endotoxin over time and helps to clear the intestinal infection. It raises the serum levels of LPS, but I think this is actually a benefit as it is binding LPS, functioning in its detox, protecting the liver, and stimulating the clearance of the infection. I think this is specifically why Keto diets are "curing" peoples chronic diseases/ features of chronic diseases such as obesity, hyperlipidemia, dysregulated blood sugar. I also think this explains the period of the "keto flu", in which an immune response is triggered to this initial detox and then the person stabilizes. A high proportion of saturated fats in the diet, especially long chain from butter, tallow, cocoa butter will slowly displace PUFA from the tissues as the PUFA' are somewhat preferentially liberated from fat stores due to their hydrophilic structure in stark contrast to saturated fats mostly hydrophobic structure.

I'm on board with you in obesity, type 2 diabetes and pretty much every chronic disease having an infective component marked by a degree of endotoxemia or some other post infective metabolites. See here (More studies i used in the book):

Serum Zonulin and Endotoxin Levels in Exceptional Longevity versus Precocious Myocardial Infarction
Serum Zonulin and Endotoxin Levels in Exceptional Longevity versus Precocious Myocardial Infarction

“Endotoxemia-induced inflammation has been associated with insulin resistance and atherosclerosis, ultimately increasing the risk of coronary heart disease. Increased intestinal permeability is an important event leading to endotoxemia. This study aims to elucidate the possible association between endotoxin (lipopolysaccharide) and zonulin (a biomarker of intestinal permeability) levels and the risk of coronary heart disease, and thus healthy aging. Serum levels of zonulin, lipopolysaccharide and soluble CD14 (a protein that binds lipopolysaccharide) were measured in disease-free centenarians, young healthy controls and patients with precocious acute myocardial infarction. Disease-free centenarians had significantly lower levels of serum zonulin (P<0.01) and lipopolysaccharide (P<0.001) than young patients with acute myocardial infarction, and had significantly lower concentrations of serum lipopolysaccharide than young healthy controls (P<0.05). No significant differences were found for soluble CD14 between groups. Our findings may stimulate further research into the role played by intestinal permeability and endotoxemia not only in coronary heart disease but also in lifespan modulation.”


Table 1
Serum biochemical parameters in the three study groups.

Biomarkers

Young AMI patients

Healthy young controls

Centenarians

P-value

LPS (EU/mL)

15.4 ± 5.2

6.1 ± 7.3

4.2 ± 5.3

<0.001

Soluble CD14 (ng/mL)

1,489 ± 339

1,438 ± 312

1,341 ± 274

ns

Zonulin (pg/mL)

7.6 ± 3.1

5.2 ± 2.7

4.0 ± 2.1

<0.001

Abbreviations: AMI, acute myocardial infarction; LPS, lipopolysaccharide: ns, not significant (P>0.05).



Circulating Endotoxemia: A Novel Factor in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease
Circulating Endotoxemia: A Novel Factor in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease


“Circulating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality.”


“There were gradated increases in endotoxemia with increasing CKD stage (Figure 1a). Endotoxin levels were not statistically significantly different between CKD stage 3 and non-CKD controls, but they were significant between the other groups and controls. There was no evidence of a linear relationship between eGFR and endotoxin levels (Figure 1b). Patients receiving maintenance dialysis had grossly elevated levels (0.64 EU/ml in HD and 0.56 EU/ml in PD, P = 0.06). Pediatric HD patients were particularly endotoxemic (1.12 EU/ml, P = 0.008 compared with adult patients, Figure 1a). Serum endotoxin levels were nearly 6 times higher in CKD patients receiving dialysis compared with those that were not (0.62 ± 0.37 versus 0.11 ± 0.68 EU/ml, P < 0.001).”




Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age
Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age. - PubMed - NCBI


“To test this hypothesis, we analyzed the relationship between serum levels of lipopolysaccharide-binding protein (LBP), an indirect measure of endotoxin exposure, against male reproductive hormones, inflammatory markers (C-reactive protein, IL-1β, IL-6, TNF-α), and adiposity in 75 men. Adiposity was positively correlated with endotoxin exposure (LBP) and inflammation (C-reactive protein, IL-6) and negatively correlated with testosterone. Furthermore, endotoxemia (LBP) was negatively correlated with serum testosterone but positively correlated with IL-6. Multivariate analysis revealed a significant, negative correlation between serum IL-6 and free testosterone. In a second interventional study, low-dose endotoxin challenge in lean men produced a transient inflammatory response that was followed by a decline in serum testosterone, without changes in LH or FSH, providing further evidence that endotoxin-driven inflammation may result in impaired Leydig cell function.”


Metabolic endotoxaemia related inflammation is associated with hypogonadism in overweight men
Metabolic endotoxaemia related inflammation is associated with hypogonadism in overweight men. - PubMed - NCBI


“Overall increasing adiposity (% body fat) was positively associated with metabolic endotoxaemia (LBP, r = 0.366, p = 0.009) and inflammation (CRP r = 0.531, p < 0.001; IL-6 r = 0.463, p = 0.001), while also being negatively correlated with serum testosterone (r = -0.403, p = 0.004). Serum testosterone levels were significantly negatively correlated with inflammation (CRP r = -0.471, p = 0.001; IL-6 r = -0.516, p < 0.001) and endotoxaemia (LBP) after adjusting for serum LH levels (p = -0.317, p = 0.03).”


4) PCOS:

Serum LBP Is Associated with Insulin Resistance in Women with PCOS
Serum LBP Is Associated with Insulin Resistance in Women with PCOS


“In this cross-sectional study, 117 PCOS patients and 121 age-matched controls were recruited. Hyperinsulinemic-euglycemic clamp was performed with an expression of M value for insulin sensitivity. Fasting serum samples were collected to detect LBP, lipids, insulin, sex hormones and high sensitive C reactive protein (hs-CRP). Pearson’s correlation and multiple linear regression was used to analyze the associations between M value and LBP level.”


“Compared with controls, PCOS subjects had a significantly higher LBP concentration (33.03±14.59 vs. 24.35±10.31 μg/ml, p<0.001), and lower M value (8.21±3.06 vs. 12.31±1.72 mg/min/kg, p<0.001). Both in lean and overweight/obese individuals, serum LBP level was higher in PCOS subjects than that in controls. M value was negatively correlated with body mass index (BMI), fasting serum insulin, triglycerides, low-density lipoprotein cholesterol (LDL-c), free testosterone, high sensitive C reactive protein (hs-CRP) and LBP, whereas positively correlated with high-density lipoprotein cholesterol (HDL-c) and sex hormone binding globulin (SHBG). Serum LBP level was associated with M value after adjusting for BMI, fasting serum insulin, SHBG, as well as hs-CRP.”



Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation?
Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? - PubMed - NCBI


“Data found in literature have reported that bacterial endotoxins may be involved in the inflammatory and pathological processes associated with amyloidosis and Alzheimer's disease (AD). In fact, it has been observed that the chronic infusion of the bacterial lipopolysaccharide, the outer cell wall component of Gram negative bacteria, into the fourth ventricle of rats reproduces many of the inflammatory and pathological features seen in the brain of AD patients. In this context, a key player in the pathogenesis of AD is the amyloid-β peptide (Aβ) that is capable of aggregating in fibrils that represent the main component of amyloid plaques. These deposits that accumulate among brain cells are indeed one of the hallmarks of AD.”


Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer’s Disease Brain
Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer’s Disease Brain


“Here, we provide evidence that an intensely pro-inflammatory bacterial lipopolysaccharide (LPS), part of a complex mixture of pro-inflammatory neurotoxins arising from abundant Gram-negative bacilli of the human gastrointestinal (GI) tract, are abundant in AD-affected brain neocortex and hippocampus. For the first time, we provide evidence that LPS immunohistochemical signals appear to aggregate in clumps in the parenchyma in control brains, and in AD, about 75% of anti-LPS signals were clustered around the periphery of DAPI-stained nuclei. As LPS is an abundant secretory product of Gram-negative bacilli resident in the human GI-tract, these observations suggest (i) that a major source of pro-inflammatory signals in AD brain may originate from internally derived noxious exudates of the GI-tract microbiome; (ii) that due to aging, vascular deficits or degenerative disease these neurotoxic molecules may “leak” into the systemic circulation, cerebral vasculature, and on into the brain; and (iii) that this internal source of microbiome-derived neurotoxins may play a particularly strong role in shaping the human immune system and contributing to neural degeneration, particularly in the aging CNS.”


“Multiple aspects of increased inflammatory signaling and an altered innate-immune system are consistent features of AD neuropathology; however, it is not well understood where these pathogenic signals originate or how they progressively contribute to the AD process (1–5). AD is characterized by the appearance of complex networks of many different kinds of chemokines and cytokines including, prominently, interleukin 1β (IL-1β) and tumor necrosis factor (TNFα), 40 and 42 amino acid amyloid beta (Aβ40, Aβ42) peptides, and adhesion molecules, in addition to the progressive deposition of these Aβ peptide containing amyloid plaques and neurofibrillary tangles (NFT) in the parenchyma of AD brain (6, 7). Activated microglia, astrocytes, or neurons appear to mediate the release of these pro-inflammatory molecules and cellular immune components (6, 8–12). Indeed, chemokines, cytokines, the insoluble Aβ42-enriched peptide deposits, NFTs, apoptotic, damaged and vanishing neurons, and activated microglia, and other related pro-inflammatory signals are potent neuropathological stimulants that appear to maintain the AD brain in a “chronic state of self-reinforcing inflammation” (2, 7, 10–13). Very recent studies that evaluated the pro-inflammatory potential of several different chemokines, cytokines, Aβ peptides, and lipopolysaccharides (LPS), either alone or in combination, have indicated that when compared, bacterial LPSs exhibit the strongest induction of pro-inflammatory signaling in human neuronal–glial cells in primary coculture of any single inducer, and different LPS extracts from different gastrointestinal (GI)-tract resident Gram-negative bacteria appeared to have different pro-inflammatory potential (12, 14–16). For example, exposure of LPS from the Gram-negative GI-tract abundant Bacteroides fragilis to primary human neuronal–glial cells in coculture was found to be an exceptionally powerful inducer of the NF-κB p50/p65 dimer, a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation (15, 16). In both neocortex and hippocampus, LPS has been detected to range from a ~7- to ~21-fold increase abundance in AD brain (Figures (Figures1A–D).1A–D). Along with an avalanche of very recent work from independent laboratories, these observations prompted us to further examine the presence and anatomical location of LPS in AD brains versus age- and gender-matched controls (12, 17, 18).”


“To cite other recent examples, a secreted, highly pro-inflammatory zinc metalloprotease metalloproteinase B. fragilis endotoxin called fragilysin (BFT) derived from enterotoxigenic strains of B. fragilis have been recently shown to contribute to: (i) anaerobic bacteremia, sepsis and systemic inflammatory distress, diarrheal disease; (ii) systemic inflammation, GI-tract, and colorectal cancers; (iii) inflammatory neurodegeneration in part via the disruption of epithelial cell-based GI-tract barriers via cleavage of the synaptic adhesion zonula adherens protein E-cadherin; and (iv) enterotoxigenic microbes specifically impact microglial-mediated innate-immune responses, detoxifying and phagocytic mechanisms, and amyloidogenesis characteristic of inflammatory aspects of neurodegeneration (12, 15, 16, 30–34).”


“These recent findings indicate that AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable (12, 28, 38).”

Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review
Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review


“This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer’s disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains.”


“Rare early-onset familial forms of Alzheimer’s disease (AD) are associated with autosomal dominant mutations in the amyloid beta precursor protein (AβPP), presenilin 1 and presenilin 2 genes (Goate and Hardy, 2012). Mouse models based upon these mutated human genes have guided much of the drug discovery for AD (Belkacemi and Ramassamy, 2012; Hall and Roberson, 2012). However, clinical trials based upon these models have yet to lead to successful treatments (Selkoe, 2011; Huang and Mucke, 2012; Cavanaugh et al., 2014).”


“The presence of one or more infections over a 5-year follow up period increased the odds of developing AD, and risk increased with age (Dunn et al., 2005). Receiving DPT vaccines early in life as well as other vaccines later in life significantly reduces the risk of subsequent AD (Tyas et al., 2001; Verreault et al., 2001). Protection by DPT vaccine may be due in part to preventing infection by the Gram-negative Bordetella Pertussis bacterium which causes whooping cough. Tooth loss (Stein et al., 2007) and oral infections (Poole et al., 2013; Abbayya et al., 2015; Chen et al., 2017) have been associated with AD. Furthermore, Porphyromonas gingivalis (Ishida et al., 2017) and LPS from Porphyromonas gingivalis (Wu et al., 2017) produce AD-like phenotypes in mice. In addition, Spirochetes (Miklossy, 1993; Miklossy et al., 1994, 2004; Riviere et al., 2002), chlamydophila pneumonia (Hammond et al., 2010), Helicobacter pylori (Kountouras et al., 2009), fungi (Pisa et al., 2015), herpes viruses (Civitelli et al., 2015) and cytomegalovirus (Lovheim et al., 2018) are also reported to be involved in with AD pathology. Interestingly, previous in vitro studies demonstrate that amyloid-like morphological changes occur following Borrelia burgdorferi spirochetes or LPS exposure. These studies suggest that AD might be a neurological disorder associated with infectious agents.”





Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies
Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies


“Methods: Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimens: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined.
Results: Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall.”


Pathophysiology of psoriasis: coping endotoxins with bile acid therapy.
Pathophysiology of psoriasis: coping endotoxins with bile acid therapy. - PubMed - NCBI


“The authors have tested the hypothesis that the deficiency of bile acids and the consequent endotoxin translocation might play a role in the pathogenesis of psoriasis. Under normal conditions the bile acids act as detergents (physico-chemical defense) and can protect the body against enteric endotoxins by splitting them into nontoxic fragments and thus preventing the consequent release of cytokines [Persp. Biol. Med. 21 (1977) 70]. A total of 800 psoriasis patients participated in the study and 551 were treated with oral bile acid (dehydrocholic acid) supplementation for 1-8 weeks. The efficacy of the treatment was evaluated clinically and also by means of the Psoriasis Area Severity Index (PASI score). During this treatment, 434 patients (78.8%) became asymptomatic. Of 249 psoriatics receiving the conventional therapy, only 62 (24.9%) showed clinical recovery during the same period of time (P<0.05). The curative effect of bile acid supplementation was more pronounced in the acute form of psoriasis (95.1% of the patients became asymptomatic). Two years later, 319 out of the 551 acute and chronic psoriasis patients treated with bile acid (57.9%) were asymptomatic, compared to only 15 out of the 249 patients (6.0%) receiving the conventional treatment (P<0.05). At the end of the 2-year follow-up, only 10 out of 139 acute psoriasis patients (7.2%) receiving the conventional therapy and 147 out of 184 bile acid treated patients (79.9%) were asymptomatic (P<0.01).To conclude, the results obtained suggest that psoriasis can be treated with success by oral bile acid supplementation presumably affecting the microflora and endotoxins released and their uptake in the gut.”



“Microbiota, a key player in alcoholic liver disease”
Microbiota, a key player in alcoholic liver disease


“Only 20% of heavy alcohol consumers develop alcoholic liver cirrhosis. The intestinal microbiota (IM) has been recently identified as a key player in the severity of liver injury in ALD. Common features of ALD include a decrease of gut epithelial tight junction protein expression, mucin production, and antimicrobial peptide levels. This disruption of the gut barrier, which is a prerequisite for ALD, leads to the passage of bacterial products into the blood stream (endotoxemia). Moreover, metabolites produced by bacteria, such as short chain fatty acids, volatile organic compounds (VOS), and bile acids (BA), are involved in ALD pathology.”


“Comparing the effects of acute alcohol consumption in germ-free and conventional mice: the role of the gut microbiota”
Comparing the effects of acute alcohol consumption in germ-free and conventional mice: the role of the gut microbiota


“There was no liver injury after alcohol consumption, and there was less neutrophil infiltration and lower pro-inflammatory cytokine levels (CXCL-1/KC and interleukin (IL)-6) in the liver in germ-free mice compared with alcohol-fed conventional mice. Additionally, conventionalization of germ-free mice with intestinal contents from alcohol-fed conventional mice induced injury and inflammation in both the liver and the intestine, suggesting that alcohol intake successively caused a perturbation of the intestinal microbiota (dysbiosis) and liver injury. Finally, previous treatment with a high-fiber diet decreased liver injury and gut permeability in alcohol-fed conventional mice.”



Metabolic endotoxemia with obesity: is it real and is it relevant?
Metabolic endotoxemia with obesity: is it real and is it relevant?


“Complimentary cross-sectional evidence indicates that the LPS-TLR4 pathway is responsible, at least in part, for the heightened pro-inflammatory milieu in human obesity. For example, Creely et al.48 reported that TLR4 mRNA expression and protein content is elevated in adipose tissue from obese and T2D compared to lean donors. In addition, similar findings have been reported, in tandem with increased TLR4 signaling, in skeletal muscle from obese and T2D compared to normal weight donors41, 49. Furthermore, cross-sectional analyses have shown an elevation in circulating endotoxin in obese individuals compared to their lean counterparts.”


“Large prospective population based studies highlight the clinical relevance of elevated circulating endotoxin and proteins of the LPS-TLR4 pathway as they relate to cardio-metabolic disease development. For example, elevated baseline fasting serum endotoxin concentrations predicted coronary heart disease events at follow up (10 years) in middle aged, otherwise healthy individuals25. In addition, the risk of incident diabetes is increased at follow up (10 years) in healthy adults aged 25–75 with elevated serum endotoxin69. Furthermore, the risk for developing metabolic syndrome and most of its components (including central adiposity) is increased in middle aged and older healthy Chinese adults with elevated fasting plasma LPS binding protein (LBP) at baseline 70.”



Elevated endotoxin levels in non-alcoholic fatty liver disease
https://journal-inflammation.biomedcentral.com/articles/10.1186/1476-9255-7-15


“Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008).”

 

[RWilly]

@RWilly could you point to those studies please?

Here's a few:
Nut Consumption in Relation to Cardiovascular Disease Incidence and Mortality Among Patients With Diabetes Mellitus. - PubMed - NCBI
The effect of nuts on inflammation. - PubMed - NCBI
Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance). - PubMed - NCBI
Nuts as a Replacement for Carbohydrates in the Diabetic Diet
Nuts May Lower Risk of Heart Disease and Death in Diabetics

 

[CLASH]

@RWilly
Most of those nut studies were purely observational and used statistical correlation with no intervention. The correlations they found in the studies also weren't very strong. We already know the PUFA is bad, and if eating nuts for polyphenols why not just eat fruit? The overall nutritional value provided by nuts is marginal when all factors are considered.

The only intervention study you posted was 1) retracted and 2) the endpoints for the outcomes don't really prove anything of value (Lowering hbAC1 [by 0.21% I might add] by going on a lower carb diet doesn't prove an increase in ability to handle blood glucose, also as shown above lowering LDL doesn't really mean much for heart disease [this is considering the findings of the study weren't significant and were marginal at best]. For further proof of the lack of proof for the LDL- heart disease hypothesis see here:

Omega-6 vegetable oils as a driver of coronary heart disease: the oxidized linoleic acid hypothesis

https://openheart.bmj.com/content/openhrt/5/2/e000898.full.pdf

“A systematic review of studies measuring the changes in linoleic acid concentration in subcutaneous adipose tissue in the USA revealed an approximate 2.5-fold increase in linoleic acid increasing from 9.1% to 21.5% from 1959 to 2008.2 Importantly, the concen- tration of linoleic acid in adipose tissue is a reliable marker of intake as the half-life of linoleic acid is approximately 2 years in adipose tissue. The authors of the study also noted that the increase in adipose tissue linoleic paralleled the increase in the preva- lence of diabetes, obesity and asthma.”

“Importantly, linoleic acid concentra- tions in both serum cholesteryl esters and phospholipid fatty acids are in fact higher in patients with CAD compared with those without CADcoronary artery disease. Again, since linoleic acid cannot be synthesised in the body, this suggests that patients who have heart disease consume more omega-6 linoleic acid than those without heart disease. Indeed, the authors of the study concluded, “(...) cholesteryl linoleate is widely believed to decrease in patients with CAD. Such decreases, however, represent decreases only in relative terms. We have shown in this study that linoleate actually is present in a higher concentration in individuals with CAD than in those without CAD”.

“The low-density lipoprotein (LDL) oxidation hypothesis gained traction during the 1980s because it was noted that in general, native unoxidised LDL does not cause foam cell formation. In other words, LDL had to become oxidised first in order for atherosclerosis to develop. Indeed, it was later discovered that oxidised LDL (oxLDL) caused direct toxic effects to the cell, recruitment and entry of monocytes into the subendothelial layer and increased foam cell formation5 leading to increased atherosclerosis and inflammation.6 Moreover, oxLDL was found to be higher in patients with CAD compared with normal patients and oxLDL was able to better identify patients at an elevated risk of heart disease. Moreover, OxLDL and auto antibodies to oxLDL are found in atherosclerotic lesions. Furthermore, patients with progressive carotid atherosclerosis have more antibodies to oxLDL versus those without progression.9 Thus, the evidence is resounding that oxLDL is important in the formation of atherosclerosis.”

“It was later discovered that the oxidation of LDL was initiated by the oxidation of linoleic acid contained within the LDL parti- cles.13 Indeed, linoleic acid is the most common oxidised fatty acid in LDL.14 Once linoleic acid becomes oxidised in LDL, aldehydes and ketones covalently bind apoB, creating LDL that is no longer recognised by the LDL receptors in the liver but is now recognised by scavenger receptors on macrophages leading to the classic foam cell formation and atherosclerosis.13 15 16 Hence, the amount of linoleic acid contained in LDL can be seen as the true ‘culprit’ that initiates the process of oxLDL formation as it is the linoleic acid that is highly susceptible to oxida- tion. Additionally, an increase in the intake of linoleic acid intake increases the linoleic acid content of very-low- density lipoprotein (VLDL) and high-density lipoprotein (HDL) increasing their susceptibility to oxidise, which further increases the risk of cardiovascular disease. Thus, expanding on the oxLDL theory of heart disease, a more comprehensive theory, the ‘oxidised linoleic acid theory of coronary heart disease’, is as follows: dietary linoleic acid, especially when consumed from refined omega-6 vegetable oils, gets incorporated into all blood lipoproteins (such as LDL, VLDL and HDL) increasing the susceptibility of all lipoproteins to oxidise and hence increases cardiovascular risk.”

“However, oxidised cholesterol was also considered a culprit as it was contained in atherosclerotic plaque, which led to the demonisation of dietary cholesterol as a cause of coronary heart disease (CHD). However, choles- terol bound to saturated fat does not readily oxidise; this is not the case with linoleic acid.21 Moreover, lipids from human atherosclerotic plaques have been found to contain oxidised cholesteryl linoleate (cholesterol esters containing linoleic acid).21–24 Moreover, the severity of atherosclerosis is noted to increase with increasing oxidised cholesteryl linoleate.21 25 In other words, choles- terol was protected from oxidation if bound to saturated fat but susceptible to oxidation when bound to linoleic acid. Again, this suggests is that eating more linoleic acid increases the oxidation of cholesterol within LDL particles further increasing atherosclerosis formation and the risk of coronary heart disease. Indeed, healthier regions of aortas have been found to have less oxidised cholesteryl linoleate (5.8%–9.5%) compared with athero- sclerotic regions (12.4%–21%).”

“The most prevalent fatty acid contained in LDL is linoleic acid.14 On LDL oxidation, linoleic acid is converted to hydroperoxides, which can then be converted to hydroxy acids, such as 9-HODE (9-hydroxy-10,12-octadecadienoic acid). 9-HODE is extremely prevalent in oxidised LDL and is a good indicator of lipid peroxidation. In fact, 9-HODE is 20 times higher in young patients with athero- sclerosis compared with healthy volunteers and 30-fold to 100-fold greater in patients with atherosclerosis aged 69 to 94 compared with young healthy individuals.14 9-HODE levels may be a novel way to determine some- one’s cardiovascular risk and further studies should be performed to test if 9-HODE could be a good risk factor for coronary heart disease, particularly in those over the age of 50.”

“In 1952, Glavlind and colleagues published a paper showing that aortic lipid peroxides positively correlated with atherosclerosis.25 These findings were confirmed in 1970 by Brooks et al who found large amounts of 9-HODE and 13-hydroxy-9,11-octadecadienoic acid (13-HODE) derived from linoleic acid hydroperoxides in aortic plaques.22 In 1991, Wang and Powell found increased amounts of 9-HODE and 13-HODE in the aortas and LDL of atherosclerotic rabbits.26 That same year, Belkner and colleagues found oxygenated cholesterol esters (cholesteryl linoleate) in atherosclerotic plaques of human aortas, the degree of which correlates with the stage of atherosclerosis.21To sum up, the increase in linoleic acid hydroperoxides in atherosclerotic plaques coincide with a greater severity of atherosclerosis versus normal regions. In other words, the more oxidised linoleic acid you have in atherosclerotic plaque, the worse the severity of CAD.”

“In 1984, both Steinbrecher et al and Morel et al discov- ered that endothelial cells can oxidise LDL and that this process involves lipid peroxidation.28 29 Oxidised LDL was found to be atherogenic and toxic to endothelial cells. In 1990, Miyazawa et al confirmed elevated levels of hydroperoxides from linoleic acid in human LDL,30 which was also elevated in human plasma.31 32 Later in 1992, it was discovered by Weisser et al that patients with atherosclerosis have more oxidised LDL versus healthy patients. Thus, numerous lines of evidence implicate the oxidation of linoleic acid as a major cause for increased oxidised LDL and hence an increased risk for coronary heart disease.”

“A study by Mozaffarian and colleagues found that post- menopausal women with a higher saturated fat intake had less coronary atherosclerosis progression (when measured as per cent stenosis as well as minimal coronary artery diameter),38 whereas polyunsaturated fatty acid (PUFA) intake was associated with worsening (a decline) in the diameter of the coronary artery. For each 5% increase in energy intake from PUFA, there was a 0.17 mm greater decline in minimal coronary artery diameter and a 5.8% greater progression in mean percentage stenosis. The intake of PUFA was also associated with greater atherosclerosis progression when replacing saturated fat (p=0.02). Moreover, a greater intake of saturated fat was not associated with adverse cardiovascular outcomes (myocardial infarction (MI) or CHD death or unstable angina). In summary, the consumption of omega-6 PUFA is associated with coronary atherosclerosis progression, whereas the intake of saturated fat is associated with less plaque progression.”

“The Anti-Coronary Club trial found that more people died overall and due to heart disease when saturated fat was replaced with polyunsaturated fat.40 Recovered data from the Sydney Diet Heart Study also found that replacement of dietary saturated fats with omega-6 linoleic acid (from safflower oil and margarine) increased all-cause mortality, cardiovascular mortality and CHD mortality.41 Finally, recovered data from the Minnesota Coronary Experiment indicated that replacing saturated fat with omega-6 linoleic acid (from corn oil and margarine) significantly lowered serum cholesterol but did not reduce mortality and may have increased the risk of death in older adults.42 In fact, for each 30 mg/dL reduction in serum cholesterol, there was a 22% higher risk of death. More troubling was a significantly greater incidence of at least one MI confirmed by autopsy in the omega-6 inter- vention. The overall clinical trial evidence suggests no benefit of replacing saturated fat with omega-6 polyunsat- urated fat and even possible harm.”

Evidence implicating omega-6-rich vegetable oils as a causative factor in atherosclerosis and coronary heart disease

1. Greater amounts of linoleic acid oxidation products are found in LDL and plasma of patients with atherosclerosis.14

2. Greater amounts of linoleic acid oxidation products are found within atherosclerotic plaques and the degree of oxidation deter- mines the severity of atherosclerosis.22

3. A diet higher in oleic acid or lower in linoleic acid decreases LDL susceptibility to oxidation.14

4. Endothelial cells oxidise LDL forming linoleic acid hydroperoxides.14

5. Linoleic acid is the most abundant fatty acid in LDL and is ex- tremely vulnerable to oxidation being one of the very first fatty acids to oxidise.14

6. A meta-analysis of randomised controlled trials in humans found that when saturated fat plus trans-fat is replaced with omega-6 fat (high in linoleic acid), there is an increase in all-cause mortality, ischaemic heart disease mortality and cardiovascular mortality.41

7. The oxidation of linoleic acid in LDL leads to conjugated dienes (malondialdehyde and 4-hydroxynonenal), which covalently bind to apoB altering its structure creating oxidised LDL. oxLDL is no longer recognised by the LDL receptors on the liver but by scavenger receptors on macrophages causing monocyte infiltra- tion into the subendothelium, foam cell formation and eventual atherosclerosis.14

8. Oxidation products of linoleic acid (including 9-HODE and 13- HODE) are found in infarcted tissue.44

9. Ultrasound of the carotid arteries in healthy patients who have high 9-HODE in LDL have signs of atherosclerosis.14

10. The increase in 9-HODE begins between 40 and 50 years old prior to the clinical manifestation of atherosclerosis.14

11. 9-HODE is a good indicator of oxLDL, especially if other caus- es of inflammation are excluded. An increased oxidised LDL, and hence levels of 9-HODE and 13-HODE in LDL, found in patients with rheumatoid arthritis may explain why they have an increased risk of heart disease.45

12. 9-HODE and 13-HODE stimulate the release of interleukin 1B from macrophages.45

13. The linoleic acid metabolite 9-HODE is a strong promoter of in- flammation45 and hence may be both a marker and inducer of atherosclerosis.

14. Susceptibility of LDL to oxidation correlates independently with the extent of atherosclerosis.46

15. 15) Linoleic acid free fatty acids and hydroxy acids (such as 13- HODE) can induce direct toxic effects to the endothelium causing an increase inflammation, reactive oxygen species and adhesion molecules.33 34

16. Exposure of the endothelium to linoleic acid has been found to increase LDL transfer across the endothelium, an essential step in the atherosclerosis process.35

17. Oxidised linoleic acid metabolites (OXLAMs) are recognised by immune cells and can recruit monocytes/neutrophils to athero- sclerotic lesions.47 OXLAMs are considered a danger signal acti- vating innate immune cells, which are involved in atherosclerosis formation.48 49

18. Linoleic acid is the most abundant fat found in atherosclerotic plaques, and this has been known since at least the 1960s.50

19. Oxidised linoleic acid but not oxidised oleic acid is found in ather- osclerotic plaques.51

20. Consuming more linoleic acid increases the amount of linoleic acid in complicated aortic plaques.52

Continued

21. Linoleic acid in adipose tissue and platelets positively associates with CAD, whereas EPA and DHA in platelets are inversely correlated with CAD.3

22. Linoleic acid serum concentrations (as opposed to per cent of fatty acids) are higher in patients with CAD.4

23. Using the fat-1 transgenic mouse model, which converts ome- ga-6 to omega-3 creating an omega-6mega-3 ratio of around 1:1 in tissues and organs, reduces atherosclerotic lesions by in- hibiting systemic and vascular inflammation.53

24. Mice fed fish oil (high in omega-3) as compared with corn oil (high in omega-6) have a significant reduction in atherosclerotic plaque formation possibly due to an increase in antioxidant enzyme activity.54

25. There is more thin fibrous cap atheroma, less thick fibrous cap atheroma, less stable plaque and a greater percentage of plaque rupture in patients given sunflower oil (high in omega-6) versus control.55

26. An excess dietary intake of linoleic acid causes greater endothelial activation compared with an excess of saturated fat.56 Linoleic acid can activate vascular endothelial cells, a critical step for in- ducing atherosclerosis.57 58

27. Linoleic acid is inflammatory to the vascular endothelium.59

28. Linoleic acid metabolites promote cardiac arrhythmias, cell death, organ failure and cardiac arrest.60

29. Patients who have died from sudden cardiac death have more linoleic acid and less omega-3 polyunsaturated fats in their coro- nary arteries versus control patients who died mostly from traffic accidents.61 Box 2 summarises the opposing views for (1) why linoleic acid may reduce CHD and (2) why linoleic acid may in- crease the risk of CHD.


Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results
Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results


“Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.”



LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391


“If high total cholesterol (TC) causes atherosclerosis, people with high TC should have more atherosclerosis than people with low TC. In 1936, Landé and Sperry found that corrected for age, unselected people with low TC were just as atherosclerotic as people with high TC [4Landé KE, Sperry WM. Human atherosclerosis in relation to the cholesterol content of the blood serum. Arch Pathol. 1936;22:301–312. [Google Scholar]]. Since then, their seminal observation has been confirmed in at least a dozen studies [5Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002;95:397–403.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“In accordance, the positive association between TC and degree of atherosclerosis noted in the study by Solberg et al. disappeared when those with TC above 350 mg/l (9 mmol/l) were excluded [5Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002;95:397–403.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar],6Solberg LA, Hjermann I, Helgeland A, et al. Association between risk factors and atherosclerotic lesions based on autopsy findings in the Oslo study: a preliminary report. In: Schettler G, Goto Y, Hata Y, et al., editors. Atherosclerosis IV. proc 4. int. symp. Berlin: Springer Verlag; 1977. p. 98–100.[Crossref], , [Google Scholar]].”

“If high TC were the major cause of atherosclerosis, there should be exposure–response in cholesterol-lowering drug trials; for example, the arteries of those whose lipid values are lowered the most should benefit the most. However, in a review of 16 angiographic cholesterol-lowering trials, where the authors had calculated exposure–response, this correlation was only present in one of them, and in that trial, the only treatment was exercise [5Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002;95:397–403.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“If high TC was the major cause of CVD, people with high TC should have a higher risk of dying from CVD. The hypothesis that high TC causes CVD was introduced in the 1960s by the authors of the Framingham Heart Study. However, in their 30-year follow-up study published in 1987 [7Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the framingham study. JAMA. 1987;257:2176–2180.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], the authors reported that ‘For each 1 mg/dl drop in TC per year, there was an eleven percent increase in coronary and total mortality’.”


“During the years following the report of the Framingham Heart Study, numerous studies revealed that high TC is not associated with future CVD. with the strongest evidence of a lack of relation between TC and CVD in elderly people. For instance, a review published in 2002 included references to 12 such studies [12Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003;96:927–934.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. A 2004 Austrian study [13Ulmer H, Kelleher C, Diem G, et al. Why Eve is not adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health. 2004;13:41–53.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]] published 2004 including 67,413 men and 82,237 women who had been followed up for many years found that TC was weakly associated with coronary heart disease (CHD) mortality for men, except for those between age 50 and 64 years. For women, it was weakly associated among those below the age of 50 years, and no association was present after that age. No association was found between TC and mortality caused by other CVDs, except that low TC was inversely associated with CVD mortality for women above the age of 60 years.”


“Today, the general opinion is that TC is not the most useful or accurate predictor of CVD, and interest has increasingly focused on low-density lipoprotein cholesterol (LDL-C).”


*LDL is specifically raised in response to endotoxin, hence the focus here. The higher LDL in certain contexts may be an associative factor for increased endotoxin burden.


“If LDL-C is atherogenic, people with high LDL-C should have more atherosclerosis than those with low LDL-C. At least four studies have shown a lack of an association between LDL-C and degree of atherosclerosis [5Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002;95:397–403.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], and in a study of 304 women, no association was found between LDL-C and coronary calcification [16Hecht HS, Superko HR. Electron beam tomography and national cholesterol education program guidelines in asymptomatic women. J Am Coll Cardiol. 2001;37:1506–1511.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. One exception is a study of 1779 healthy individuals without conventional risk factors for CVD [17Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. JACC. 2017;70:2979–2991.[Crossref], , [Google Scholar]]. Here, the authors found that LDL-C was significantly higher among those with subclinical atherosclerosis (125.7 vs.117.4 mg/dl). However, association does not prove causation.”

“If high LDL-C causes CVD, LDL-C of untreated patients with CVD should be higher than normal. However, in a large American study [20Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. Am Heart J. 2009;157:111–117.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]] including almost 140,000 patients with acute myocardial infarction (AMI), their LDL-C at the time of admission to hospital was actually lower than normal. In another study with the same finding [21Al-Mallah MH, Hatahet H, Cavalcante JL, et al. Low admission LDL-cholesterol is associated with increased 3-year all-cause mortality in patients with non-ST segment elevation myocardial infarction. Cardiol J. 2009;16:227–233.[PubMed], [Web of Science ®], , [Google Scholar]], the authors decided to lower the patients’ LDL-C even more, but at a follow-up 3 years later, total mortality among those with LDL-C below 105 mg/dl (2 mmol/l) was twice as high compared to those with a higher LDL-C, even after adjustment for confounding variables (14.8% vs. 7.1%, p = 0.005).”

*LDL is protective against infection as seen above. Lowering LDL may remove its protective effects against endotoxin, this may be why the LDL was lower in patients at hospital admission; when the patients LDL was lowered their protection from endotoxin was removed leading to adverse events. This may also be why the mortality was higher in people with the lower LDL.

“It has been suggested that inverse causation explains the inverse association between mortality and LDL-C; for example, that cancer and infections lower LDL-C. A more likely explanation is that CVD may be caused by infections and that LDL directly inactivates almost all types of microorganisms and their toxic products [12Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003;96:927–934.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar],22Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39:3–16.[PubMed], [Web of Science ®], , [Google Scholar],23Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci. 2012;344:391–394.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. Consistent with that finding is the observation that healthy individuals with low LDL-C have a significantly increased risk of both infectious diseases [23Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci. 2012;344:391–394.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]] and cancer [24Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM. 2012;105:383–388.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]; the latter possibly because microorganisms have been linked to almost 20% of all cancer types [25Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–3044.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“If high LDL-C was the major cause of atherosclerosis and CVD, people with the highest LDL-C should have shorter lives than people with low values. However, in a recent systematic review of 19 cohort studies including more than 68,000 elderly people (>60 years of age), we found the opposite [26Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6:e010401.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. In the largest cohort study [27Bathum L, Depont Christensen R, Engers Pedersen L, et al. Association of lipoprotein levels with mortality in subjects aged 50+ without previous diabetes or cardiovascular disease: a population-based register study. Scand J Prim Health Care. 2013;31:172–180.[Taylor & Francis Online], [Web of Science ®], , [Google Scholar]], those with the highest LDL-C levels lived even longer than those on statin treatment. In addition, numerous Japanese studies have found that high LDL-C is not a risk factor for CHD mortality in women of any age [28Hamazaki T, Okuyama H, Ogushi Y, et al. Towards a paradigm shift in cholesterol treatment. A re-examination of the cholesterol issue in Japan. Ann Nutr Metab. 2015;66(suppl 4):1–116.[PubMed], , [Google Scholar]].”

“Furthermore, the most important outcome – an increase of life expectancy – has never been mentioned in any cholesterol-lowering trial, but as calculated recently by Kristensen et al., statin treatment does not prolong lifespan by more than an average of a few days [71Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open. 2015;5:e007118.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“Furthermore, case–control and cross-sectional studies have shown that statin use is observed significantly more often among patients with cataracts [76Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010;340:c2197.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], hearing loss [77Chung SD, Chen CH, Hung SH, et al. A population-based study on the association between statin use and sudden sensorineural hearing loss. Otolaryngol Head Neck Surg. 2015;152:319–325.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], suicidal ideation [78Davison KM, Kaplan BJ. Lipophilic statin use and suicidal ideation in a sample of adults with mood disorders. Crisis. 2014;35:278–282.[Crossref], [PubMed], , [Google Scholar]], peripheral neuropathy [79Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58:1333–1337.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], depression [80Kang JH, Kao LT, Lin HC, et al. Statin use increases the risk of depressive disorder in stroke patients: a population-based study. J Neurol Sci. 2015;348:89–93.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], Parkinson’s disease [81Huang X, Alonso A, Guo X, et al. Statins, plasma cholesterol, and risk of Parkinson’s disease: a prospective study. Mov Disord. 2015;30:552–559.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], interstitial cystitis [82Huang CY, Chung SD, Kao LT, et al. Statin use Is associated with bladder pain syndrome/interstitial cystitis: a population-based case-control study. Urol Int. 2015;95:227–232.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], herpes zoster [83Antoniou T, Zheng H, Singh S, et al. Statins and the risk of herpes zoster: a population-based cohort study. Clin Infect Dis. 2014;58:350–356.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], impotency [84Solomon H, Samarasinghe YP, Feher MD, et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract. 2006;60:141–145.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], cognitive impairments [85Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy. 2009;29:800–811.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]–88Muldoon MF, Ryan CM, Sereika SM, et al. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117:823–829.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], and diabetes [89Cederberg H, Stančáková A, Yaluri N, et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–1117.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar],90Mansi I, Frei CR, Wang CP, et al. Statins and new-onset diabetes mellitus and diabetic complications: a retrospective cohort study of US healthy adults. J Gen Intern Med. 2015;30:1599–1610.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. In some of these studies, the side effects disappeared with discontinuation of the statins and worsened with rechallenge [74Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. 2004;57:525–528.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar],84Solomon H, Samarasinghe YP, Feher MD, et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract. 2006;60:141–145.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar],85Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy. 2009;29:800–811.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. As cholesterol is a vital substance for the renewal of all cells, and since statins also block the production of other molecules necessary for normal cell function [75Okuyama H, Langsjoen PH, Hamazaki T, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015;8:189–199.[Taylor & Francis Online], [Web of Science ®], , [Google Scholar]], it is not surprising that statin treatment may result in side effects from many different organs.”

According to Collins et al., statin treatment protects against cancer. However, in three trials, cancer occurred significantly more often in the treatment groups [24Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM. 2012;105:383–388.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], and there is much evidence that low cholesterol predisposes to cancer. For instance, several experiments on rodents with lipid-lowering drugs produced cancer [91Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA. 1996;275:55–60.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], and in nine human cohort studies, cancer rates were inversely associated with cholesterol levels measured in healthy people 10 to more than 30 years earlier [24Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM. 2012;105:383–388.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. Therefore, case–control studies in which the incidence of cancer in statin-treated patients was lower than in controls are invalid because many untreated individuals have low cholesterol, and those on statins have lived most of their lives with high cholesterol that may have provided protection from developing cancer.”

“For instance, according to the Simon Broome registry, only a small percentage of FH individuals die at an early age, and the mortality among the elderly does not differ from the mortality of the general population despite their high LDL-C [93Scientific steering committee on behalf of the simon broome register group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303:893–896.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“In a study by Mundal et al., 4688 individuals aged 0–92 years with FH were followed up for 18 years [94Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. JAMA. 2014;3:e001236. [Google Scholar]]. During that time, 113 died, whereas the expected number in the general population was 133. The mortality benefit cannot have been due to lipid-lowering treatment because there was no significant difference between the number on such treatment among those who died and those above the age of 18 years who survived (88.2% vs. 89.1%).”

“If high LDL-C causes premature CVD in FH, the LDL-C of those with CVD should be higher compared to others, but at least six studies of untreated FH individuals have shown no significant differences in LDL-C or age [95Seed M, Hoppichler F, Reaveley D, et al. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–1499.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]–100Cenarro A, Artieda M, Castillo S, et al. A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia. J Med Genet. 2003;40:163–168.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. It has also been shown that FH relatives without FH may have shorter lives than the general population [101Harlan WR, Graham JB, Estes EH. Familial hypercholesterolemia: a genetic and metabolic study. Medicine. 1966;45:77–110.[Crossref], [Web of Science ®], , [Google Scholar]].”

“In a Swedish study including 289 of the 290 municipalities, no association was found between statin use and the change in mortality from AMI [102Nilsson S, Mölstad S, Karlberg C, et al. No connection between the level of exposition to statins in the population and the incidence/mortality of acute myocardial infarction: an ecological study based on Sweden’s municipalities. J Negat Results Biomed. 2011;10:6.[Crossref], [PubMed], , [Google Scholar]]. Also, the American National Health and Nutrition Examination Survey [103Kuklina EV, Yoon PW, Keenan NL. Trends in high levels of low-density lipoprotein cholesterol in the United States, 1999–2006. JAMA. 2009;302:2104–2110.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]] found that during the period 1999–2006, the number of AMI and strokes increased from 3.4% to 3.7% and from 2.0% to 2.9%, respectively. During the same period, mean LDL-C level decreased from 126.1 to 114.8 mg/dl, and the self-reported use of lipid-lowering drugs increased from 8% to 13.4%. Furthermore, statin utilization in 12 European countries between 2000 and 2012 was not associated with reduced CHD mortality or its rate of change over the years [104Vancheri F, Backlund L, Strender LE, et al. Time trends in statin utilisation and coronary mortality in Western European countries. BMJ Open. 2016;6:e010500.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]].”

“The idea that high cholesterol levels in the blood are the main cause of CVD is impossible because people with low levels become just as atherosclerotic as people with high levels and their risk of suffering from CVD is the same or higher. The cholesterol hypothesis has been kept alive for decades by reviewers who have used misleading statistics, excluded the results from unsuccessful trials and ignored numerous contradictory observations.”

“The usual argument in support of the lipid hypothesis is that numerous studies of young and middle-aged people have shown that high TC or LDL-C predict future CVD. This is correct, but association is not the same as causation. Few authors have adjusted for other CVD-promoting factors such as mental stress, coagulation factors, inflammation, infections, and endothelial sensitivity, all of which are closely related to LDL receptor abnormalities [105Okuyama H, Hamazaki T, Hama R, et al. A critical review of the consensus statement from the European atherosclerosis society consensus panel 2017. Pharmacology. 2018;101:184–218.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]]. For instance, mental stress can raise TC [17Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. JACC. 2017;70:2979–2991.[Crossref], , [Google Scholar],18Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med. 1982;44:413–430.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]] possibly because cholesterol is necessary for the production of cortisol and other steroid stress hormones, and mental stress may cause CVD by an increased production of epinephrine and norepinephrine, which contribute to hypertension and hypercoagulation. The reason why high TC is a risk factor only for young and middle-aged people may be that mental stress is more common among working people than among retired senior citizens.”

“It is important to emphasize that LDL participates in the immune system by adhering to and inactivating all kinds of microorganisms and their toxic products and that many observations and experiments have incriminated infections as a possible causal factor of CVD [21Al-Mallah MH, Hatahet H, Cavalcante JL, et al. Low admission LDL-cholesterol is associated with increased 3-year all-cause mortality in patients with non-ST segment elevation myocardial infarction. Cardiol J. 2009;16:227–233.[PubMed], [Web of Science ®], , [Google Scholar]–23Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci. 2012;344:391–394.[Crossref], [PubMed], [Web of Science ®], , [Google Scholar]], and our results indicate that there may be better methods than cholesterol lowering to prevent atherosclerosis and CVD.”

 

[RWilly]

@RWilly
I think the nuanced different in our interpretations is that I would say the saturated fat would be helpful in the type 2 diabetes/ obesity situation, especially in the long run as it detoxes the endotoxin over time and helps to clear the intestinal infection. It raises the serum levels of LPS, but I think this is actually a benefit as it is binding LPS, functioning in its detox, protecting the liver, and stimulating the clearance of the infection. I think this is specifically why Keto diets are "curing" peoples chronic diseases/ features of chronic diseases such as obesity, hyperlipidemia, dysregulated blood sugar.

I can speak from anecdotal experience, that I was well on my way to diabetes after having been 4 years on a low-carb and ketogenic diet. I was putting on weight and found out I was very insulin resistant ... which is why I study this so much, and thus came up with what I think is the root cause ... iron and bacteria.

Also, study after study shows how a high fat diet is one of the causes of diabetes, and it's because of this absorption of endotoxins. Diabetes is endotoxemia. The entire body changes its blood chemistry to deal with infection. (Vitamin A, beta carotene, iron, copper, zinc, E, C, etc.).

But like I said, it depends on the type of bacteria one has in the gut. We get our main bacteria species from birth to about 2 years old. Many bacteria stay dormant until there is iron availability.

When researchers do a poop transplant from a fat mouse, and put it into a thin mouse, the thin mouse gets fat.

And study after study shows that a high fat diet increases the amount of pathogenic bacteria.

 

[RWilly]

@RWilly
Most of those nut studies were purely observational and used statistical correlation with no intervention. The correlations they found in the studies also weren't very strong. We already know the PUFA is bad, and if eating nuts for polyphenols why not just eat fruit? The overall nutritional value provided by nuts is marginal when all factors are considered.

The only intervention study you posted was 1) retracted and 2) the endpoints for the outcomes don't really prove anything of value (Lowering hbAC1 [by 0.21% I might add] by going on a lower carb diet doesn't prove an increase in ability to handle blood glucose, also as shown above lowering LDL doesn't really mean much for heart disease [this is considering the findings of the study weren't significant and were marginal at best]. For further proof of the lack of proof for the LDL- heart disease hypothesis see here:

I'm not saying vegetable oils and nut oils are good. And I'm not saying that one should eat nuts for PUFA, or for that matter make an effort to eat PUFA at all. I'm just saying that I believe the PUFA in the nut is protected by E, and other phytonutrients. I think one of the main values of nuts are its phytic acid, to help move iron out and deliver it to beneficial bacteria.

And, it's those beneficial bacteria that are able to saturate PUFA for us. We take care of them, they take care of us.

 

[CLASH]

@RWilly
Keto diets induce a state of adapted insulin resistance, however it is reversible, and I don't think it is due to endotoxin. With this in mind, I am not a fan of keto diets, I was merely making a point.

Can you please post studies showing that a high saturated fat diet induces diabetes specifically because of endotoxin?

I don't think this is true at all and I have posted quite a bit of evidence directly to the contrary, with plausible mechanisms explained. Also, I think to be realistic we have to clairfy what a high saturated fat diet is? I highly doubt a diet based on fruit, juice, meat, specific seafood, possibly dairy, possibly tubers and saturated fat sources like butter, coconut oil, cocoa butter, beef tallow is going to induce diabetes. I would say even 30-40% of calories from mostly saturated fat sources would pose no real issue, especially not diabetes, heart disease or even obesity.

 

[Cirion]

So if I'm understanding the graph then, that's not PUFA by itself. That is fat in general ... correct?

Yes... more or less. All fats are unhelpful to me like I say. That said, my data suggests that one or two tablespoons of pure SFA may be helpful (some more data needed to be sure). This is what Ray Peat said as well. When he added one or two tbsp. a day of coconut oil to his diet, he lost weight. Everything I have experimented on has proven Ray Peat right. I respect the man more daily for this reason. He is the smartest dietician of our age. Truly iconic.

See this plot for why I believe this.

This is a 28 day (4 week) rolling average plot. X axis is SFA intake, Y axis is a parameter I spent an hour or so defining myself. MWM stands for Metabolic Weight Marker. The math is a little complex, but basically it is a single parameter that scores, on a scale of 0-100, the metabolic rate as a function of waking body temp, waking body pulse, and amount of weight loss. More weight loss = higher score. Better temps/pulses = higher score. If temps pulses are high, and a lot of weight is lost, this gives closer to 100 score. This means not only metabolic rate increased, but weight is lost. Win-win.

I can speak from anecdotal experience, that I was well on my way to diabetes after having been 4 years on a low-carb and ketogenic diet. I was putting on weight and found out I was very insulin resistant ... which is why I study this so much, and thus came up with what I think is the root cause ... iron and bacteria.

Hard to say what is truly the "root cause" once you're unwell, everything seems to go wrong. I agree tho that endotoxin, iron overload etc can all be unhelpful things for sure.

All of the millions of studies quoted are nice and all but I'm more interested in results "From the trenches" so to speak. And my own experience shows the same -- fats are not helpful, and exasperate my symptoms. I don't care if a study says otherwise, because its just not my experience.

 

[CLASH]

@RWilly
I know your not saying those things. What I'm asking is why eat nuts in the first place? We know that PUFA isn't good and they are a significant source of PUFA. They also have minimal nutrient supply considering all of the digestive inhibitors which includes the phytic acid. Thus, the only thing that is left is perhaps the fiber and the polyphenols, in which case why not just eat fruit/ juice/ tubers/ veg?

Also, Vit e does not fully protect against the effects of PUFA in the body. Also, any Vit E in the nuts is most likely mitigated by the PUFA present concurrently.

Effect of Long-Term Fish Oil Supplementation on Vitamin E Status and Lipid Peroxidation in Women

"Plasma vitamin E levels did not change significantly after supplementation; however, after 3 mo of supplementation by young women, plasma vitamin E was significantly lower than after 1 mo. The vitamin E:TG ratio was significantly increased and vitamin EEPA + DHA) significantly decreased. All women showed a significant increase in plasma lipid peroxide through mo 2 of supplementation. After 2 mo, older women had significantly higher lipid peroxide levels than young women. The lipid peroxide:TG ratio, which declined by mo 3, was still significantly higher than baseline. These data indicate that although long-term fish oil supplementation may be beneficial in reducing plasma total TG, susceptibility of plasma lipids to free radical attack is potentiated. Furthermore, the decrease in plasma vitamin EEPA + DHA) and increase in plasma lipid peroxide, particularly in the older subjects, indicates that vitamin E content of fish oil capsules may not be sufficient to provide adequate antioxident protection."

Lastly, the goal of using phytic acid to deliver it directly to bacteria seems contradictory to me and questionable. I can understand using phytic acid to lower iron absoprtion from meals (Among other valuable metals) but the goal of lowering iron overall is to limit bacterial growth not to sequester the iron from yourself and then give it to the so called "beneficial bacteria". Considering that phytic acid also lowers other valuable metals, and comes with a whole host of other negative factors in the foods that contain it, why not just use cranberries, pomegranates, aspirin, coffee, and blood donation to lower iron?

I don't see a positive argument for nuts in nutritional optimization.

 

[CLASH]

@Cirion
What have the trenches gotten you so far in the past year or so of experience? Have you lost significant weight? Have you solved any of your health issues? Are you even running true experiments or are you flip flopping all over the place and tracking pulse and temp without a baseline or any extent of controlled intervention?

Furthermore, have you actually read Peat or some of the people he quotes such as Broda Barnes? Besides discussing using coconut oil, Peat also talks about eating chicken wings, frying his eggs in butter and eating 150g of protein a day. These are all contradictory to what you have espoused in the last few days. Cherry picking Peats experiences to rationalize your own decisions can be a slippery slope.

Furthermore, some of the information in Broda Barnes book Hypothyroidism: The unsuspected illness, is directly contradictory to some of the things your write about, especially in regards to losing weight and raising temperature (which paradoxically is the core tennant of your current health philosophy).... Broda Barnes recommends an early form of a low carb diet for his obese patients in conjunction with thyroid supplementation. Once they lose weight, they can then slowly increase their carb intake. This is mirrored by the numerous people who use keto to lose weight and then add carbs (usually in the form fruit/ fruit juice and tubers) back into their diet. I'm not advocating keto here, just calling into question your statements and experiences, which on your own account haven't really gotten you anywhere objectively so far.

 

[RWilly]

I don't think this is true at all and I have posted quite a bit of evidence directly to the contrary, with plausible mechanisms explained. Also, I think to be realistic we have to clairfy what a high saturated fat diet is? I highly doubt a diet based on fruit, juice, meat, specific seafood, possibly dairy, possibly tubers and saturated fat sources like butter, coconut oil, cocoa butter, beef tallow is going to induce diabetes. I would say even 30-40% of calories from mostly saturated fat sources would pose no real issue, especially not diabetes, heart disease or even obesity.

Hopefully you read my article, as that really explains it all, and I list a ton of studies there too. But I'll add more research here that I didn't use in the article.

Also, keep in mind that it is going to depend on what kind of microbes the person has.

Low-Carb and Ketogenic Diets in Type 1 and Type 2 Diabetes
"Reducing CHO [carb] intake with an LCD [low carb diet] is effective in reducing body weight and, in patients with type 2 diabetes, improving glycemic control, with a stronger effect with a very low carb diet (KD). However, LCD [low carb diet] and KD [ketogenic diet] may not be appropriate for all individuals. Especially in patients with type 2 diabetes, it is necessary to balance the potential increase in cardiovascular risk because of the unfavorable lipid profile observed with KD with the benefits deriving from weight loss and improvement of glycemic control. Moreover, long-term compliance with low-CHO diets is still an issue."

https://www.hindawi.com/journals/jdr/2015/206959/
"The present study uncovered a significant relationship between dairy consumption and reduced insulin sensitivity in middle-aged, nondiabetic women, suggesting that higher intakes of dairy products may be associated with greater insulin resistance."

Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia
"In recent years accumulating research has investigated the link between dietary fat and endogenous endotoxin in relation to metabolic inflammation [12,13]. Current evidence suggests that dietary fat augments circulating endotoxin concentrations and the resultant postprandial endotoxemia leads to low-grade systemic inflammation which has been implicated in the development of several metabolic diseases [1,3,14]. Intestinal derived endotoxin and the subsequent acute endotoxemia are considered major predisposing factors for inflammation associated diseases such as atherosclerosis, sepsis, obesity, type 2 diabetes and Alzheimer's [15-17]. However, the ability of different types of oil and fatty acids to facilitate uptake of intestinal endotoxin has been poorly characterized. Interestingly, saturated and n-3 polyunsaturated fatty acids (PUFA) have been shown to reciprocally modulate the LPS receptor, TLR4, and cell membrane lipid rafts [18]. This is postulated to be due to saturated fatty acids (SFA) such as lauric and myristic acid being part of the fatty acyl side chain composition of Lipid-A component of endotoxin and the ability of n-3 PUFA to reduce the potency of endotoxin when substituted in place of saturated fatty acids in lipid-A [19,20]. Thus, there is clear linkage between fatty acids (saturated, n-3 polyunsaturated, monounsaturated etc. …) and endotoxin signaling.


Dietary Fat and Risk for Type 2 Diabetes: a Review of Recent Research
https://www.sciencedirect.com/science/article/abs/pii/S0026049598900804
High-Fat Diet Is Associated with Obesity-Mediated Insulin Resistance and β-Cell Dysfunction in Mexican Americans
https://physiology.org/doi/abs/10.1152/ajpendo.1986.251.5.E576
High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice
A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain
Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet. - PubMed - NCBI
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Are We Going Nuts on Coconut Oil? - PubMed - NCBI


I should also mention, that 'dairy fat' is a little too inclusive for all types of dairy. Cream for instance, has a high endotoxin response. I however think that the bacterial action done to make butter (thus butyrate), along with vitamin A to help deal with pathogenic bacteria, is different. Thus, reasons for mixed results. (And I'm still on the fence about butter by the way.)

 

[RWilly]

This is a 28 day (4 week) rolling average plot. X axis is SFA intake, Y axis is a parameter I spent an hour or so defining myself. MWM stands for Metabolic Weight Marker. The math is a little complex, but basically it is a single parameter that scores, on a scale of 0-100, the metabolic rate as a function of waking body temp, waking body pulse, and amount of weight loss. More weight loss = higher score. Better temps/pulses = higher score. If temps pulses are high, and a lot of weight is lost, this gives closer to 100 score. This means not only metabolic rate increased, but weight is lost. Win-win.

Something that I've recently learned is that temps are impacted by altitude and weather.

All of the millions of studies quoted are nice and all but I'm more interested in results "From the trenches" so to speak. And my own experience shows the same -- fats are not helpful, and exasperate my symptoms. I don't care if a study says otherwise, because its just not my experience.

Yeah... I get it. I'm researching the science, but still have to make it work in reality. Easier said than done ... as you know. It requires changing the biome, and also figuring out iron, which has no natural pathway for excretion when there is excess, making the body a more favorable environment for pathogenic microbes. (Which is why red meat can be problematic.) Our iron stores increase as we age ...

 

[Cirion]

Something that I've recently learned is that temps are impacted by altitude and weather.

Very true, environment also matters. I am not looking forward to winter as such. Just have to take extra care to keep home warm, and bundle up excessively if necessary whenever going outside. Last winter I was the "weird guy" who would wear a ski mask frequently to work on cold days. It kept my face warm, so I didn't care how I looked. I also like to double, triple, quadruple, quintuple up on layers to really stay warm on the torso in particular. I think most people under-dress for the cold. I feel like you should dress warmly enough to stay reasonably comfortable for upwards of an hour (or more) of being outside. Most people only dress warm enough to survive the 5 minute walk in the parking lots.