Part One: Endotoxemia, Dysbiosis and Cardiovascular Disease | Syontix

Part One: Endotoxemia, Dysbiosis and Cardiovascular Disease | Syontix

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Santa brought you what for Christmas?!?!?

As we are about to enter the festive 2012
holiday season, I thought it appropriate to blog about heart disease.
Many of you may not know this, but the holiday season sees more deaths
from heart attacks than any other time during the year. Merry Christmas
and Happy Hanukkah y’all! (1)
For those of you who have read this blog for a while, you know I consider disordered gut flora and resulting endotoxemia
as the best explanation for those diseases grouped under the heading of
metabolic syndrome. I’ve explored the role of gut dysbiosis and
endotoxemia in diabetes, alcoholic and non-alcoholic fatty liver disease, depression, anxiety and insomnia. As I detail below, the link is also strong between disordered gut microbiota and cardiovascular disease.
As you also know, I’m not pleased about the
way epidemiological studies are misused, especially when used to shape
eating behavior. These types of studies can never prove causality
because they are not designed to. Nonetheless, they are very useful for
generating hypotheses.
With that as warning, I want to bring to
your attention an Italian epidemiological study published in the
scientific literature in 1999. This study followed 516 middle-aged men
and women aged 50 to 79 for five years. The researchers measured the
levels of lipopolysaccharides (LPS) in the blood plasma of these study
participants. As you recall, LPS are a component part of the cell wall
membrane of gram-negative bacteria.
They were looking to see if the development
of atherosclerosis assessed by either ultrasound or an actual heart or
stroke event was increased in those with higher levels of LPS in their
blood. What they found was that those participants who had plasma LPS
levels over 50 pg/ml (picograms per millilitre) had a three-fold
increase in developing atherosclerosis during the five-year study
period. Both smokers and non-smokers with low endotoxin levels had a low
risk of developing vascular disease. However, smokers and ex-smokers
with elevated levels of plasma endotoxin had a 13-fold increase in heart
and stroke disease risk. (2)
In another study, individuals afflicted
with inflammatory bowel diseases were at a higher risk of developing
coronary artery disease even though they had lower traditional risk
factors (lower levels of cholesterol, blood pressure, obesity and
diabetes) than their age-matched controls. (3) Endotoxins and dysbiosis are universal findings in those suffering from bowel diseases.
In the Wandsworth Heart and Stroke Study
conducted in Britain across multiethnic groups, increases in LPS
correlated with higher cardiovascular disease risk. (4)
Unlike the U.S., the black population of Great Britain has the lowest
cardiovascular disease rates. The white British and European population
have higher rates. Topping the list are Indian Asians with a 40% greater
incidence of cardiovascular disease than whites. From the abstract we
learn that:
Age-adjusted endotoxin
levels were lower in women than in men (p=0.002) and were highest in
South Asians (13.3EU/mL[95% CI 12.0–14.7]) and lowest in individuals of
African origin (10.1 EU/mL [9.1–11.1]) than in whites (p for linear
trend <0.001). Endotoxin levels were positively associated with
waist, waist–hip ratio, total cholesterol, serum triglycerides and serum
insulin levels and negatively associated with serum HDL-cholesterol.
By the way, did you notice the bit about the expanded waists? I
promise to get around to gut dysbiosis, endotoxemia and weight gain at a
later date when your dear blogger isn’t so swamped with work.
Why would these studies show this
relationship? Well, we know that the presence of LPS in blood plasma
impacts the body in many negative ways.
  • provoke a robust systemic inflammatory response,
  • increase levels of inflammatory cytokines like tumor necrosis factor and interleukin 6,
  • increase white blood cell counts,
  • increase the level of growth hormone,
  • increase the levels of chemokines like
    MCP-1 and fractalkine. These substances are involved in recruiting
    T-cells and white blood cells to the site of injury and infection. MCP-1
    has been implicated in rheumatoid arthritis, lupus, kidney and heart
  • trigger the increased production of the stress hormone cortisol by their impact on the hypothalamic-pituitary-adrenal axis,
  • negatively impact thyroid function,
  • increase transient heart rate at high doses,
  • decrease levels of tryptophan,
  • alter levels of serotonin,
  • reduce melatonin,
  • increase levels of toxic metabolites that
    injure brain cells via increased production of 3-hydroxy-kynurenine and
    quinolinic acid,
  • increase the odds of developing an autoimmune disorder,
  • increase levels of C-reactive protein, a marker for inflammation,
  • increase the release of free fatty acids into the blood,
  • increase levels of resistin, a hormone that promotes insulin resistance,
  • increase hormone levels of leptin, a substance involved in long-term weight regulation,
  • decrease insulin sensitivity and chronically raise blood glucose levels,
  • increase fat-tissue inflammation and,
  • induce genetic changes in fat tissue in animals similar to those observed in the visceral fat of type 2 diabetics.
But wait folks, there’s more! When LPS
binds to the endothelial cells of arteries, it initiates the release of
proinflammatory cytokines leading to endothelial dysfunction, the
formation and rupture of plaque, oxidation of LDL cholesterol, and
accelerates the formation of blood clots.
LPS increases the generation of reactive
oxygen species or ROS. ROS are what are popularly known as oxidants and
the reason some of you take antioxidants or include antioxidant-rich
foods in your diet. While reactive oxygen species are a normal byproduct
of the cellular use of oxygen, too much ROS can cause lots of damage.
At higher levels in response to infection, reactive oxygen species
promote cell death as a defense mechanism to protect the body. (5) This then calls forth macrophages, a type of cell that eats and disposes dead cellular debris.
LPS’s ability to disrupt the vascular
system is a well-known effect of blood poisoning or septicemia. In this
severe form of infection, numerous proinflammatory responses occur
including increased production of molecules that clump cells together
(cell adhesion molecules), increased production of inflammatory
cytokines, increased levels of oxidation, reduced integrity of arteries
and veins, and increased rates of cell death or apoptosis along the
vascular wall. What’s true of septicemia is also true for low-grade
blood poisoning, aka metabolic endotoxemia as a result of gut dysbiosis.
The only difference is that in the latter case, it can take years or
decades before the damage manifests itself as heart disease or stroke.
I’m sure some of you have heard of foam
cells. These cells are composed of macrophages, smooth muscle cells and
oxidized LDL cholesterol and form the fatty streaks known as arterial
plaque. If the fibrous cap that keeps all this intact ruptures, a heart
attack or stroke can result if the clot seals off the artery further
down the line.
However, this isn’t all that’s found in
foam cells. Bacteria is also consistently present within these
structures and I believe they are the primary reason these cells are
formed. Chlamydia pneumoniae is a common cause of pneumonia
worldwide and is often found as a constituent of arterial plaque. I’m
sure most of you wouldn’t be shocked to find out that this particular
pathogen belongs to the gram-negative bacteria family. However, you may
be surprised to learn that a previous bout of pneumonia is a risk factor
for a heart attack. (6) Now you know why.
Another bacteria detected in arterial plaque is Streptococus mutans, the major pathogen responsible for dental plaque and a leading cause of tooth decay. (7)
There is a well-known, long-standing association between tooth and gum
disease, and cardiovascular disease risk, especially in men under 50. (8)
As an aside, I’m quite familiar with this
particular pathogen as I used to suffer from some serious dental plaque.
Flossing or using a Sonicare® toothbrush twice daily did nothing to
curb it. I had to get my teeth cleaned every four months or risk the ire
of my dental hygienist who allotted an hour and a half to chisel away
at the stuff. This problem is now gone since I gave up eating wheat.
Apparently, not only do gluten grains have a negative impact on gut
flora, they also have a negative impact on oral microbiota. Is it any
wonder legions of parents are shuttling their kids to the dentist and
orthodontist? I’m surprised these dental professionals don’t advertise
on bread wrappers.
Other bacteria found in arterial plaque include Klebsiella pneumoniae, Chryseomonas and Veillonella (9);
however, up to 50 different types of bacteria have been discovered in
foam cells. Symptoms of a heart attack also closely mimic an infection.
When the plaque ruptures, spilling its bacterial contents into the
arterial bloodstream, it is very common for those afflicted to
experience a fever resulting in chills and sweat.
Where does this bacteria come from? Well,
in the case of bacteria from the respiratory tract and mouth, some
enters the bloodstream directly through the gums. But I suspect a good
portion is swallowed in saliva. If it isn’t killed by stomach acid—a
very likely possibility in the age of binge drinking, antacids and
proton-pump inhibitors as I covered in this post
on gastric-barrier dysfunction—then it reaches the small intestine
where in the presence of depleted beneficial gut flora populations, it
takes up residence. Add in increased intestinal permeability caused by
diet, drugs, alcohol, chronic stress, and the gut dysbiosis itself, and
the stage is set for the inflammatory cascade that eventually results in
vascular disease.
This is the most likely reason cigarette
smoking and binge drinking are high-risk factors for heart disease.
Cigarette and alcohol are extremely disruptive to the upper respiratory
and oral microbiota which is why those who smoke and drink have 15 times
the risk of developing oral cancer. Oral cancer kills more people than
cancers of the cervix, ovary, testes, brain, liver, kidney, Hodgkin’s
lymphoma or malignant melanoma. Bottoms up Don Draper! Those who binge drink and smoke make up 80% of the people who get oral cancer. (10)
A number of studies have found elevated levels of bacterial pathogens in the mouths of smokers and heavy drinkers: Streptococci, Prevotella, Veillonella, Porphyromonas and Capnocytophaga.
If you think these bacteria don’t travel down the throat in saliva,
colonize the gut, and enter systemic circulation via a compromised gut
wall, I have a lovely brick bridge I’d like to sell you located in New
However, as many of you already know,
swallowing pathogens isn’t the only way to get small intestinal bacteria
overgrowth (SIBO). Migration of gram-negative bacteria from the colon
into the intestine due to impaired motility is the number-one reason
bacteria take up residence in the small bowel. Hence the reason
constipation, SIBO, IBS, IBD, Crohn’s, etc. should be of more than
passing interest when it comes to the risk of developing future
cardiovascular disease.
I’ll leave you with another epidemiological
study, this one quite large and famous, but again with the caveat that
association never equals causation. While one of its vegan co-authors
interpreted the facts to make it seem that animal protein and saturated
fat were the cause of heart disease, Denise Minger’s masterful review of
the original data revealed that of all dietary components studied,
wheat intake had the most statistically significant association with
heart disease even after adjusting for numerous confounding variables.
You can read all about that here.
Knowing what you now know about this particular food’s negative impact
on gut flora, it all makes perfect sense don’t you think?
All disease begins in the gut said
Hippocrates. While a bit of an exaggeration, it’s certainly true for
heart disease even if it did take medical research until recently to
figure out the mechanism.
In the next post I’ll explore the roles dietary fat and cholesterol plays in all this.