In this fifth and final post on gut dysbiosis, endotoxemia and heart disease, I want to explore the role cholesterol plays in all of this. As you know, I consider cholesterol an innocent bystander in this piece, not the villain.
So what is cholesterol?
Cholesterol is an alcohol but not the same type of alcohol you drink. The stuff you knock back during the weekend has two carbon, one oxygen and six hydrogen atoms. In contrast, the cholesterol molecule is composed of 27 carbon, one oxygen and 46 hydrogen atoms. That’s a lot of molecule so it’s termed a high-molecular weight alcohol. Technically, it’s a sterol which is a subgroup of steroids.
Cholesterol is fat soluble like fatty acids and triglycerides (triacylglycerols) but unlike the latter two, is not used by the body for energy. In food, the levels between fat and cholesterol are vastly different. Cholesterol is measured in milligram quantities whereas fats are eaten in gram amounts. For my metrically challenged American readers, one gram is equal to one thousand milligrams. A three ounce serving of salmon, for example, would contain anywhere from three to ten grams of fat and about thirty to seventy milligrams of cholesterol.
To paraphrase Anthony Colpo, without cholesterol you would be a pile of unsightly mush gumming up the linoleum. Cholesterol is essential to life and without it you would not exist. All cells in the body have it and can produce it.
Cholesterol is the building block for steroid and sex hormones, bile acids and vitamin D synthesis when your skin is exposed to sunlight. It builds and maintains cellular membranes and moderates their fluidity. Within the cell, it has functions important for intracellular transport, cell signaling and nerve conduction. And as I mentioned here, cholesterol is an extremely important part of your immune system.
Contrary to what you may have been told, it’s impossible to meet your daily cholesterol needs by diet alone. To make up the difference between what your body needs and what you take in through diet, your liver and other organs get busy synthesizing it. If you eat very little of it, your body produces more, and if you have a cholesterol-rich diet, your body produces less, which is why dietary changes are, with some exceptions that I’ll get to shortly, typically useless for affecting cholesterol concentrations in the blood. (1) (2) And you thought all those egg-white omelets were lowering your levels.
Associations between total cholesterol and heart-disease risk are U-shaped as I noted in part three of this series:
While this graph charts cholesterol and death rates in men, it is equally indicative of cholesterol’s effects on women. To reiterate, people with total cholesterol levels between 200 and 240 have the lowest rates of death from all causes. Those with total cholesterol levels between 190 and 220 have the lowest incidence of cardiovascular disease but note the sharp increase in death from infections and heart disease the lower your levels of cholesterol go, a bit of a conundrum no? This is, of course, rarely mentioned by the medical community or your nightly news “health” reporter.
For now, I want to focus on the rising upward slope of this cholesterol-cardiovascular-disease curve. How could gut dysbiosis and the translocation of gut pathogens or endotoxemia raise cholesterol levels? There are several mechanisms I can think of although there are no doubt others.
First, endotoxemia increases the production of cortisol, the stress hormone as described here. Cortisol requires cholesterol for its production, so an increase in its adrenal output will require more production of cholesterol. Cortisol levels are associated with increased levels of LDL. (3) Cortisol increases intestinal permeability, which adds to increased gut pathogen translocation, further raising cortisol levels.
A second reason LDL cholesterol may go up is because a quantity of long-chain fatty acids that would normally be incorporated into chylomicrons and enter the lymphatic system, may instead leach into the portal vein where they end up in the liver and are incorporated into VLDL lipoproteins. As roughly half of these particles will turn into LDL cholesterol, this will cause an increase in cholesterol concentrations. This assumes, however, that lipoproteins are capable of being manufactured by the liver, an assumption that is not always true as you’ll read later in this post.
A third reason is that endotoxemia-induced inflammation appears to down-regulate the enzyme lipoprotein lipase. As I explained in my post on chylomicrons, as lipid-rich lipoproteins circulate throughout the body, this enzyme breaks down the triglycerides they contain so they can be absorbed into various tissues throughout the body. If lipoprotein lipase is suppressed, triglyceride levels rise and HDL falls. (4)
A fourth reason cholesterol may increase is to repair vascular damage. In its role as a repair substance, it will be produced in larger quantities to heal whatever damage is being done.
A fifth reason cholesterol may rise is in response to infection: bacterial, viral and parasitic. As part of our immune system, an increase in infection will cause the liver to produce more cholesterol to counter it. Lipopolysaccharides from gram-negative bacteria, for example, are inherently dangerous and you can expect the liver to produce more cholesterol to neutralize this threat. The fireman coming to put out the fire, so to speak. (5) (6) But again, there is an exception to this that I’ll cover shortly.
A sixth reason is that gut dysbiosis in the ileum or final section of the small intestine can interfere with the production of a protein necessary for HDL cholesterol formation. By inhibiting the secretion of a gut hormone called PYY, production of HDL is negatively impacted. Lower levels of HDL increase levels of circulating triglycerides.
A seventh reason that gut dysbiosis and endotoxemia raises cholesterol is by causing fatty liver. Fatty liver impairs this organ’s ability to take up LDL from circulation increasing LDL concentrations in the blood.
A final reason, and one that underlies all causes of cholesterol dysregulation, is an increase in inflammation. Atherosclerosis is consistently associated with higher levels of tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), and C-reactive protein. TNF-a and IL-6 are inflammatory cytokines and C-reactive protein is a marker for inflammation. In persons with this pattern, LDL and triglyceride levels are elevated in relation to HDL. (7) TNF-a, and especially IL-6, are also associated with low-thyroid function or hypothyroidism which itself is a risk factor for heart disease, not to mention obesity. (8)
The increase in levels of LDL cholesterol and triglycerides coupled with decreased levels of HDL are a sign of bacterial translocation from the gut. Cholesterol is not the cause of this problem, it’s merely responding to the endotoxemia.
If you have high levels of HDL cholesterol (over 40 to 50 milligrams per deciliter or mg/dl for men, 50-60 mg/dl for women ) and low triglyceride levels (under 150 mg/dl), I don’t believe elevated total cholesterol is of any concern. In fact, this pattern shows appropriate uptake of fat and cholesterol from both chylomicrons and LDL lipoproteins and HDL transport back to the liver, suggesting proper cholesterol handling and a healthy immune system.
But how do we reconcile what I just described with the left side of the slope that also sees an association between increasing rates of cardiovascular disease, but this time due to lower levels of total cholesterol?
I want to offer a hypothesis that makes solving this contradiction even more of a challenge, but hey, I like challenges. I believe the left-side of this slope would be steeper than it is were it not for one major reason. Many of those who would develop heart disease were they to live long enough instead die of numerous other causes first; a fact illustrated by the steeply curved blue line that tracks death from all causes as cholesterol levels decline.
One of the reasons heart disease was rare before the 20th century was because death from infections was the number-one killer of people in the developed world before the age of sanitation, rising living standards, vaccines and antibiotics. If you die young, you’ll never grow old enough to have a heart attack and be counted in the statistics. Many who argue that heart disease rates in certain parts of the underdeveloped world are low due to their low-animal protein or saturated-fat diets usually fail to mention the abysmal life expectancy rates that kill many of these people well before heart disease has a chance to do the same. Heart disease is typically a disease of old age:
Before resolving this seeming contradiction, I want to review an old study that may offer us a clue. The year was 1965, June to be exact, and your humble blogger and future probiotic/prebiotic peddler was just about to turn five years old when it came out.
Famously known as the Rose Corn Oil trial, it was one of the first studies that tried using a reduced saturated-fat-intervention diet to lower the incidence of heart disease in the treated group(s). (9) It was based on the assumption that Ancel Keys was right and saturated fat was the cause of heart disease launching the entire lipid-cholesterol-heart disease
industry era that we are all still living with today.
What I like about this study is that it was a randomized, controlled trial unlike the confounder-prone
crappy population studies that are always touted by the anti-saturated-fat and lower-cholesterol-is-always-good-for-you crowd. Unfortunately, due to its length, it was not a live-in study. Not much chance you can ever convince a group of people to check themselves into a hospital for three years leaving their lives and family behind, I’m afraid.
In the study intro, the authors remarked on the lower cardiovascular-disease rates in olive-oil consuming nations like Italy and Greece, so they wanted to see if it was protective against heart disease. They were also curious to see if polyunsaturated vegetable oils offered similar protection.
Participants were randomized to three groups. A control group whose members were given no advice to change eating behavior, and two other intervention groups that I’ll get to in a minute. The trial was expected to last three years. However, by the end of the second year, only half of the original participants were around, either because they had died, had another incapacitating heart attack or just stopped showing up. For that reason, only results from the first two years of the study were published.
Criteria to be admitted to the trial included 1) evidence of having had a heart attack or having angina, 2) being under the age of seventy, 3) absence of heart failure or other disease that would threaten life within two years and 4) absence of personal factors that would interfere with study participation.
As the control group was not instructed to change anything, they went about their “artery clogging”, saturated-fat ways eating bangers and mash, Shepard’s Pie and black pudding (it was a British study after all). The other two groups were not so lucky, errr…I mean…not so unlucky to miss out on the “heart-healthy” nutritional advice to avoid fried foods, fatty meats, sausages, pastry, ice-cream, cheese, cake and to restrict milk, eggs and butter. In other words, both intervention groups were advised to restrict their consumption of saturated fat. Sound familiar?
Apart from being instructed to limit these foods, one group was told to consume 80 grams of olive oil daily while the other was instructed to consume 80 grams of polyunsaturated corn oil per day. That’s about 3 ounces. The patients in these two groups soon learned that nothing gets the plumbing moving quicker than a swig of fat as diarrhea was a common complaint along with distaste and nausea.
What did the diet and oils do to total cholesterol levels in these two groups?
The control, or saturated-fat group, showed pretty consistent results throughout the two-year period which is remarkable given all the sugar and wheat-laden garbage they were no doubt eating along with their animal fats, all probably washed down with quite a few pints at the local pub with cigarette in hand.
The olive-oil group was all over the lot. First up, then down, but nonetheless, relatively consistent over the two years. However, look at the corn-oil group. Their cholesterol levels went down and stayed there. The negative 19.9 figure recorded in the last six months in this group was apparently an aberration because according to the researchers, levels fell again during the third year of the study.
Hallelujah! We’ve found a dietary substance that consistently lowers cholesterol! Praise the Lord and kiss the baby! Time to slap that bought-and-paid for American Heart Association “Heart Healthy” seal on all those inviting amber-colored bottles lining the grocer’s shelf.
But wait! What’s this? Two participants in both “heart-healthy” oil groups developed glycosuria. And what pray tell is that? From Taber’s Medical Dictionary we learn:
“The presence of a reducing sugar found during routine urinalysis is suggestive but not diagnostic of diabetes mellitus. It is found when the blood glucose level exceeds the renal threshold (about 170 mg/dl of blood). The fasting level of blood glucose is normally between 70 and 99 mg/dl of blood.”
Oh dear! That doesn’t sound good now does it? Now one of the two people so afflicted entered the trial with mild diabetes, but oil made it worse. It’s not clear which oil group this patient was in, however. Oil was stopped, and the glycosuria went away but restarted once oil was added back to the diet.
And what about cardiac events? Certainly the corn-oil group must have fared the best what with all that low cholesterol coursing through their saturated-fat deprived and maize-coated arteries. Well, at two years, the group that was the least likely to have a cardiac episode (75% to be exact) was the I’m-going-to-eat-anything-I-damn-well-want-with-lots-of-saturated-fat-so-screw-you-and-your-medical-degree group. Only 57% of the “heart healthy” olive-oil group remained free of cardiac disease. And what of our low-cholesterol champs? The corn-oil group fared worst of all with a 25% increase in heart attacks and death in contrast to the control group.
Now to be fair, compliance with this distasteful oil regimen and diet declined with the researchers estimating that by year two, both groups were probably only taking 60% of the recommended oil dose. Nevertheless, that cholesterol levels remained so low in the corn-oil group suggests compliance was high enough to keep levels depressed throughout the study.
In typical British understatement the authors stated:
“It is concluded that under the circumstances of this trial corn oil cannot be recommended as a treatment of ischaemic heart disease. It is most unlikely to be beneficial, and it is possibly harmful.”
Well said old chaps!
Analysis of subsequent trials purportedly showing cardiovascular benefit from consuming omega-6 vegetable oils found these studies to be unreliable because they failed to distinguish between omega-3 and omega-6 polyunsaturated-fat intake. (10)
So what’s going on here. Why did polyunsaturated omega-6 corn oil do this and why would heart events go up even though cholesterol levels went down…way down?
If my last post is any clue, it’s because these fats increase gut dysbiosis, intestinal permeability and translocation of gut pathogens to the liver. This in turn increases inflammatory immune responses in that organ:
“Acute and chronic inflammation cause hypocholesterolemia [low cholesterol levels] in humans and nonhuman primates. Many of the effects of inflammation on lipoprotein metabolism appear to be mediated by cytokines [inflammatory proteins]. Injection of interleukin-2, colony stimulating factor, or interferon results in hypocholesterolemia in humans, whereas tumor necrosis factor-a (TNF-a) and interleukin (IL-6) cause a rapid fall in plasma cholesterol as well as the concentrations of apolipoprotein (apo) A-I and apoB in nonhuman primates.” (11)
Translation: inflammation in the liver lowers total cholesterol. The more severe the inflammation, the lower your cholesterol goes, including LDL cholesterol. With its negative effects on tight junctions in the small intestine and oxidation in the liver, you now know why the polyunsaturated omega-6 oil group had the outcomes they did and why focusing only on high cholesterol is a potentially deadly mistake.
But wait a minute Ray, didn’t you say that inflammation caused by endotoxemia raises cholesterol? Yes, dear reader, I did. The solution to this riddle comes down to the level of gut pathogen translocation. In a liver that is responding to chronic levels of gut bacteria, but protected somewhat by saturated fat, LDL cholesterol and triglycerides will rise and HDL fall for the reasons I explained above.
However, in a liver under a lot of oxidative stress brought about by ingesting lots of polyunsaturated omega-6 oils, not to mention gluten, refined fructose, and alcohol, coupled with reduced intake of liver-protecting saturated fatty acids, total cholesterol production of both HDL and LDL will go down while triglyceride levels rise.
This is a graphic of lipoproteins, the vehicles that transport cholesterol and fat throughout the bloodstream. Do you see the protein segment attached to the shell and colored purple? This is an essential component of all lipoproteins. These proteins come in classes labeled A, B, C, D, E, and H with variations within some groups. Apolipoprotein B or apo-B proteins are found in chylomicrons (apo-B-48) and VLDL, IDL and LDL cholesterol (apoB-100). Apolipoprotein A or apo-A is found in chylomicrons and HDL. What is important to take from all of this is that you cannot assemble cholesterol-transporting lipoproteins without them:
“The effects of cytokines on lipoprotein metabolism are complex, and the mechanisms by which cytokines cause hypocholesterolemia [low cholesterol] have not been studied extensively. However, at least two changes in lipoprotein metabolism appear to be important in the development of acquired hypocholesterolemia from inflammation in primate species. First, the metabolism of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles is altered by inflammation; concentrations of both particles fall rapidly after injection of lipopolysaccharide and cytokines. Data from Schectman et al suggest that inflammation causes a decrease in LDL production rates, as injection of interferon into normocholesterolemic [normal levels of cholesterol] humans reduced the LDL-apoB production rate but did not change the fractional catabolic rate. Second, injection of lipopolysaccharide and cytokines into nonhuman primates results in a significant reduction in the cholesterol ester content of HDL and LDL that is preceded by a rapid fall in the plasma concentration of lecithin: cholesterol acyltransferase (LCAT), suggesting that acute inflammation may result in lower production of cholesterol esters in plasma.” (11)
Translation: very low total cholesterol is not a sign of health, but of acute inflammation.
When the production of these proteins go down, fat that the liver produces from diet will largely stay there where it will tend to accumulate:
“Thus, it appears that cytokines may increase lipogenesis [fat production] in Hep G2 [liver] cells but reduce secretion of cholesterol due to the inhibition of the secretion of apolipoproteins.” (11)
Translation: inflammation increases the production of fat in the liver but prevents its export because your poor liver can’t produce adequate levels of these needed proteins to assemble the vehicles that would otherwise cart the fat away.
Fatty liver anyone?
Oh, and for those of you telling yourselves that you’ve never heard of this happening in rodent studies, the reason why is this:
“In human and nonhuman primates inflammatory stimuli as well as individual cytokines consistently cause hypocholesterolemia [low cholesterol], whereas the acute effect in rodents of inflammation and cytokines is either an increase or no change in cholesterol levels.” (11)
Translation: in humans cholesterol production in response to acute inflammation reacts differently to what happens in rodents making any results from these animal studies next to useless for learning how inflammation affects cholesterol levels in us. However, rodent studies are of immense value in keeping the saturated-fat and cholesterol-kills-you hypothesis alive and well.
So the solution to this puzzle comes down to this: chronic, low-level translocation of gut pathogens caused by disturbed gut flora and increased intestinal permeability raises both LDL and triglyceride levels but lowers HDL levels. Acute endotoxemia, however, lowers not only HDL levels, but LDL and total cholesterol levels. Neither is ideal but if you ask me, I’d rather have the former than the latter because at least I would still have a functioning immune system.
Confirmation for the cholesterol-lowering effects of acute infection is evident in septicemia or blood poisoning. (12) There is no better way to lower total cholesterol. Not even statins or “heart healthy” polyunsaturated vegetable oils are as effective. Blood poisoning will decrease total cholesterol, including HDL and LDL cholesterol while simultaneously increasing triglyceride levels.
Here we see the results of a study that tracked 54 patients who developed sepsis during their hospital stay. White dots represent those who survived their infection and black dots those who didn’t. In those that survived, total cholesterol levels increased, as did HDL, LDL (represented by elevations in apoprotein B) and albumin. They also experienced decreases in triglyceride levels. Those that died didn’t. Next time someone tries to convince you that cholesterol is evil, be sure to point this out to them lest you end up in a grave next to these unfortunate souls.
Similar results are seen in those afflicted with cancer (13) and persons who experience a heart attack (14). This latter effect should come as no surprise to those who have read this series from the beginning. Once the fibrous cap in the artery ruptures, it spills its load of bacterial toxins into the bloodstream lowering serum cholesterol levels as in sepsis. (15)
All of you out there reading this and feeling smug about how your cholesterol-lowering diet is protecting you from heart disease and stroke, may want to revisit your dietary choices and the state of your intestinal health. Otherwise, I wish you lots of luck, I really do.
Here’s a quote you won’t often hear from your doctor. It’s from the Honolulu Heart Program study that followed 3,572 Japanese American Men for 20 years:
“Our data accord with previous findings of increased mortality in elderly people with low serum cholesterol, and show that long-term persistence of low cholesterol concentration actually increases risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater the risk of death.” (16)
So is cholesterol testing worth the trouble?
Let’s follow two patients in their 60s who visit the same doctor. Patient A arrives complaining of gastrointestinal symptoms that include bloating, cramps and constipation with alternating diarrhea. This patient is clinically obese and testing reveals they are borderline diabetic.
After a series of tests that do not include screening for small intestinal bacterial overgrowth (a very common oversight in medical practice), the patient is told they have irritable bowel syndrome (IBS). Translation: “we don’t know what the hell is causing your problem but so as not to appear stupid, we’ll tell you you have IBS so you’ll have something to tell your friends and family“.
In addition to dysregulated glucose control, cholesterol tests show high LDL, triglycerides over 200 mg/dl and HDL hovering in the 20 to 30 mg/dL range. Faster than you can say Lipitor®, the doctor writes out a prescription for a statin, hands it to the patient, advises said patient to lose weight, cut back on their saturated-fat intake, increase their consumption of “healthy” whole-gluten-grains, and rushes out the examining-room door to see their next patient.
Later that day, patient B arrives also complaining of the same GI issues. But this patient is not obese. Test results come back, and once again our patient is diagnosed with IBS and told to watch their stress levels which is a polite way of implying that the problem is all in their head. Liver tests come back slightly elevated but nothing to concern our clinician. Thyroid function, however, is very low and the patient tells the good doc they feel cold all the time and have low energy. The physician schedules a referral to an endocrinologist.
Cholesterol results, however, are stellar, the doctor exclaims with obvious glee! Total levels are well below 200 and some of the lowest they have seen. The patient, still miserable about their unresolved IBS, nonetheless perks up when hearing this bit of “good” news and shares with the doctor how they credit their “heart-healthy” low-saturated fat, high-polyunsaturated omega-6 and whole-gluten-grain diet for these “fantastic” results. The doctor grins from ear to ear congratulating our patient on how well they are doing and encourages him or her to keep up the excellent work! As our physician rushes from the examining room clutching their shiny new iPad provided by the HMO they work for, he or she thinks to him or herself how nice it is to finally see a patient who “gets it”.
Two patients, both with raging gut dysbiosis and translocation of gut pathogens to the liver and systemic circulation, but entirely different cholesterol readings. If doctors were trained to interpret low cholesterol results with equal alarm, I would say cholesterol testing is a valuable part of the diagnostic arsenal when complemented with routine testing for inflammatory cytokines and other indicators of endotoxemia. But we all know that’s not how these tests are actually used.
A week later our good physician finds out that patient B suffered a heart attack and was admitted to the local hospital where the patient is also battling a severe case of pneumonia. The doctor, a bit perplexed, chalks this up as another example of the cholesterol “paradox”. Nonetheless, our upholder of the Hippocratic oath has no time for reflection because he or she needs to pack their bags to attend an all-expenses-paid medical conference in Hawaii sponsored, coincidentally enough, by a manufacturer of statin drugs.
I started this series with a picture of a man clutching his chest and noting that the holiday season is the most heart-attack prone time of the year. The reason for that should be clear. This season is hardest on beneficial gut flora populations and the integrity of the gut wall.
Excess alcohol, gluten, refined fructose, polyunsaturated omega 6 vegetable oils—all of these dietary agents are drunk or eaten to excess over the holiday season. There isn’t a commercially made fast- or processed-food “delight” that isn’t loaded with industrial omega-6 fats, gluten and refined fructose—the unholy trinity if you will. Wash it all down with copious quantities of alcohol, add a pinch or two of stress along with a simmering case of small intestinal bacterial and yeast overgrowth, and your gut wall hasn’t got a snow ball’s chance in hell.
The next stop for translocating gut pathogens is the liver, and it’s only as healthy as the gut. If it’s simultaneously battling a case of viral hepatitis or fat accumulation or fending off a long-standing case of gut dysbiosis, don’t be shocked to discover it’s as incapable of handling what you’re throwing at it as your gut flora and intestinal wall.
If you’re “lucky”, your gut dysbiosis will “only” cause you to gain some stubborn-to-lose weight, screw with your sleep, increase anxiety or depression or mood swings, exacerbate an existing autoimmune disorder, depress your defenses against catching the cold or flu, and make your intestines spasm to the rhythm of Jingle Bells. If you’re unlucky, you may not live to see the new year.
Ho, Ho, Ho!
None of the studies I’ve brought to your attention during this series are difficult to find. It’s a welcome relief to see the increasing attention being paid in the scientific literature to the gut’s effect on overall health, including the cardiovascular system. It’s long overdue. Unfortunately, this new explanation threatens an entrenched hypothesis of cardiovascular disease that supports some very powerful economic interests. I’ll leave it to your imagination to figure out who or what those interests might be.
As a blogger with only a few hundred hits a day, I have no illusion that anything I write here will change this. I’m not even a David fighting Goliath, more like a speck on David’s face. However, I hope my efforts, humble as they are, contribute to a much-needed paradigm shift in how we view this devastating disease.
And that, dear reader, is that…
Enig, M. G. (2000). Know Your Fats : The Complete Primer for Understanding the Nutrition of Fats, Oils and Cholesterol. Silver Spring: Bethesda Press.
Lipoprotein Metabolism and Disease, 1996-2012, themedicalbiochemistrypage.org.