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 of 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 dysbiosis 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. White British and European populations 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 disease.
- 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,
- decrease 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 of 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 leading to the heart.
However, this isn’t all that’s found in foam cells. Bacteria is also consistently found 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 dentists 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—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 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. 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 in Brooklyn.
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.
In the next post I’ll explore the roles dietary fat and cholesterol plays in all this.
Díez J.J., Hernanz A., Medina S., Bayón C., Iglesias P. (2002). Serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function. Clinical Endocrinology, 57(4):515-21.
Dinan T. G. and Cryan J. F. (2012). Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37: 1369-1378.
Mehta N. N., McGillicuddy F. C., Anderson P. D., Hinkle C. C., Shah R., Pruscino L., Tabita-Martinez J., Sellers K. F., Rickles M. R., Reilly M. P. (2010) Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans, Diabetes, 59: 172-181.
Mehta N.N., Heffron S.P., Patel P.N., et al. (2012) A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial. Journal of Translational Medicine, 10: 124.
Manco M., Putignani L. and Bottazzo G. G. (2010) Gut Microbiota, Lipopolysaccharides, and Innate Immunity in the Pathogenesis of Obesity and Cardiovascular Risk. Endocrine Reviews, 31(6): 817-844.
Stoll L.L., Denning G. M., Weintraub N. L. (2004). Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis. Journal of the American Heart Association, 24: 2227-2236.
Wichers M. C. and Maes M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. Journal of Psychiatry and Neuroscience, 29(1):11-7.