Cholesterol, fat, and human metabolism: a microbiome-based paradigm shift

December 15th, 2017 by Amy Proal

At the age of 64, after a morning playing golf, president Dwight D Eisenhower had his first heart attack. As Pulitzer Prize winning author Gary Taubes describes in his book “Good Calories, Bad Calories” Eisenhower’s heart attack “constituted a learning experience on coronary artery disease (CAD).” After the event, his doctors, considered the top experts in the field, gave the public a “lucid and authoritative description of the disease itself”, followed by twice-daily press conferences held on the president’s condition. Soon, most of America, particularly middle-aged men, became intently aware of dogma promoted by these “experts”: the notion that CAD is caused by eating foods high in fat and cholesterol.

Like much of the rest of the nation, Eisenhower began to avidly lower his fat and cholesterol intake. Yet this plan of attack was counterintuitive for Eisenhower who, before his heart attack, had none of these supposed risk factors connected with CAD. His blood pressure was only seldom elevated, his weight throughout his life remained around 172 pounds (considered optimal for his height). His total cholesterol was below normal – his last measurement before the attack was 165 mg/dl, a level that heart disease specialists today consider safe. He had even quit smoking six years earlier in 1949.

President Eisenhower after his first heart attack.

After gaining four pounds, the ex-president reduced the amount of food he ate for breakfast, then eventually sacrificed lunch completely. His doctor was mystified at “how a man could eat so little, exercise regularly, and not lose weight.” Eisenhower then renounced butter, lard, and cream. But despite these additional dietary changes his cholesterol levels began to rise. “He’s fussing like the devil about cholesterol,” wrote his doctor. “He has eaten in the last week only one egg, one piece of cheese.” It got to the point where Eisenhower’s doctor started to lie about his cholesterol levels in order to keep the president calm. At one reading, Eisenhower was told his level was 217 when it was actually 223. On his final day in office, he was made to believe his cholesterol was 209 when in reality it had soared to 259. Finally, in 1969 at the age of 78, Eisenhower died of heart disease. By that time he’d had six other heart attacks.

We now know that the medical experts advising Eisenhower and the American public were wrong. In CAD, lipids, or fatty molecules, do accumulate in the arteries of patients with the disease. Indeed, CAD results from atherosclerosis: a gradual hardening and clogging of the arteries due to lipid accumulation. However, a growing body of research demonstrates that these lipids are not sourced from dietary fat and cholesterol. As Taubes describes it, the long held dogma about heart disease, in which cholesterol clogging the arteries and excess body fat are viewed as culprits, “as though the fat of a greasy hamburger were transported directly from the stomach to the artery lining” is no longer support by scientific evidence.

“Consensus thinking” led to incorrect CAD guidelines

It’s worth reading Taubes’ full book to better understand the scientific climate that, over the past decades, incorrectly linked to heart disease to dietary fat and cholesterol. For one thing, regulatory bodies were attracted to the simplicity of the “dietary fat/cholesterol clogs arteries” disease model. It was easy to communicate and implied that basic nutritional guidelines could prevent the illness. The model was also promoted at numerous “consensus” conferences: large meetings at which evidence to the contrary was often blatantly excluded.

For example, the largest diet-heart trial ever carried out in the United States was not included in medical or political debates about the best diet for the America public. Because the results opposed what was becoming the consensus view on diet and CAD, they went unpublished, (they were later published in a small cardiology journal that very few people read). The trial, which included 9,000 residents of various mental hospitals found that men on a low-fat diet had a slightly lower risk of heart attacks, although women did not. Overall, patients who had eaten a low-cholesterol diet were associated with a greater risk of heart disease.

Ancel Keys on the 1961 cover of Time Magazine. There, he advanced the idea that dietary fat “clogs the arteries”

A scientist named Ancel Keys played a central role in perpetuating the belief that dietary fat/cholesterol clog the arteries. He famously linked dietary fat to heart disease after studying seven distinct populations around the world who ate diets relatively low in fat and also seemed to have a lower incidence of CAD. However, researchers at the University of California, Berkeley later found that Keys had chosen only six countries for his comparison though data was available from 22 countries. When all twenty-two were included in the analysis, the link between fat and heart disease vanished.

In fact, Keys theory implicating diet as the cause of heart disease appeared on the cover of Time Magazine in 1961 despite the fact that at the time, only two studies had directly tested the connection. One of these studies actually proved Keys wrong. It was a British trial, in which the fat content of the meals of a group of men who had previously suffered from heart attacks was reduced to 1/3 of its previous level. A control group continued to eat a normal diet. After three years the average cholesterol levels dropped from 260 to 235, but the recurrence of heart disease in the control and experimental groups was essentially identical. “A low-fat diet has no place in the treatment of myocardial infarction,” the authors concluded in 1965 in the Lancet medical journal.

Recent studies continue to disprove the “dietary fat/cholesterol” model  

Lipids are “fatty molecules”

Despite studies like that described above, the “dietary fat/cholesterol clog arteries” model for CAD became so popular that debate on the topic continues in 2017. Many physicians and policy makers still issue “heart-healthy guidelines” urging Americans to lower dietary cholesterol/fat despite ever-increasing evidence to the contrary.

For example, a 2016 study by researchers in Finland found that a relatively high intake of dietary cholesterol was not associated with an elevated risk of coronary heart disease. Another meta-analysis found no association between consumption of saturated fats and either coronary heart disease, ischemic stroke, type 2 diabetes, death from heart disease or early death in healthy adults. A different study even demonstrated an inverse association between saturated fat and stroke (i.e. those who ate more saturated fat had a lower risk of stroke).

The authors of the first meta-analysis conclude their paper by stating: “Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong.”

In 2014 Time Magazine reversed its position on dietary fat and CAD

In 2014, even Time Magazine published a cover story reversing its position on Ancel Key’s earlier claims. The article was titled: “Eat butter. Scientists labelled fat the enemy. Why they were wrong.”

So where do the lipids (fatty molecules) driving CAD come from?

This begs the million dollar question: if lipid accumulation in CAD is not sourced from dietary fat and cholesterol, then where do the lipids in arterial plaque come from!? The results of a seminal study by researchers at the University of Connecticut provide a novel “answer” to at least part of this question. Indeed, the team’s findings are so important that they are positioned to change the future of heart disease research.

The team, led by Frank Nichols, found that two important forms of lipid detected in diseased artery walls are created by bacterial members of the human microbiome. More specifically, both lipids (Lipid 430 and Lipid 654) are made by bacteria from the phylum Bacteriodetes: a family of bacteria so common to the human body that they represent 1/3 of bacteria currently able to be cultured from the human intestine.

The team arrived at their results by analyzing lipids in atheroma collected from patients at Hartford Hospital in Connecticut. They identified bacterial Lipids 430 and 654 in the samples, and distinguished them from human lipids by analyzing their chemical structure. Both Lipid 430 and Lipid 654 contain fatty acids with branched chains and odd numbers of carbons (a structure not typically associated with human/mammalian lipids).

In a press release about the study, Nichols stated the following about Bacteriodes bacteria: ”I always call them greasy bugs because they make so much lipid. They are constantly shedding tiny blebs of lipids. Looks like bunches of grapes.”

Recovery of Lipid 430 and Lipid 654 in common Bacteroidetes bacteria.

Interestingly, both Lipids 430/654 were shown to activate TLR2 – a protein at the heart of the immune system’s response towards foreign/infectious threats. This suggests that the human immune system recognizes Lipids 430/654 as foreign, and mounts a sustained inflammatory response to their presence. These results “jive” with the fact that atherosclerosis is now understood to be a serious chronic inflammatory disease.

Nichols and team contend that Lipids 430/654 are created by Bacterioides bacteria in the gut/mouth. Under such conditions, lipids produced by these microbes would travel to the arteries via the bloodstream. However, additional research is needed to confirm that bacteria capable of living directly in the arteries don’t additionally contribute to lipid creation. For example, one study found that periodontal bacteria in the mouth can directly invade human arterial skin cells in culture.

In addition, Stanford researcher Stephen Quake recently reported the presence of thousands of previously undetected microbes in human tissue/blood. Many of these “new” microbes may also produce lipids capable of collecting in the arteries. It’s also worth noting that dead white blood cells (macrophages) are often found near lipids in arterial plaque. Since many intracellular pathogens directly infect macrophages, these dead cells may represent those parasitized by infectious agents.

Bacterial lipids may disrupt human metabolic feedback pathways

The accumulation of bacterial lipids in human arteries helps account for the “plaque” and chronic inflammation characteristic of atherosclerosis. However, bacterial lipids may also promote various forms of disease by interfering with human metabolism.

An extremely important paper by Tony Lam and team at the University of Toronto details feedback pathways that control hormonal signaling between the human gut and the human brain. These pathways help the body regulate appetite control, energy expenditure, and other important mediators of human metabolism. Lam’s paper shows that, in conditions like diabetes, glucose levels are regulated by a complex network of these pathways – many of which sense hormone/nutrient production in the gut and relay this information to the brain via the nervous system.

Gut peptide hormones and regulatory signals are released along the length of the gastrointestinal tract. (Lam et al)

Most of the pathways described in Lam’s paper are too complex to detail here, but the CCK pathway provides a good example of their general function. CCK is a gut hormone released following a meal. It acts on local gut receptors to help the body regulate glucose levels. CCK is secreted in the small intestine in response to fatty acids or lipids. It conveys information about these lipids (amount, composition, structure) to the brain. The brain integrates this information with signals arriving from related pathways and signals back to the gut to adjust glucose levels accordingly.

Under conditions of health, the CCK pathway is tightly controlled by the human body. It is governed by a series of “checks and balances” that help keep glucose and other hormones/nutrients in a normal range. This begs yet another important question: what might happen to the CCK pathway (and related pathways) if foreign, bacterial lipids accumulate in the body?

While there are differences between human and bacterial lipids, the fatty molecules created by both species also share many common chemical structures (molecular mimicry). For example, the Nichols study found that Lipids 430/654 are similar enough in structure to human lipids that they can be “broken down” by the same human enzyme (PLA2).

This means that human signaling molecules may be able to “sense” the presence of bacterial lipids. In the case of the CCK pathway (in which CCK is created in response to lipid concentration) this could significantly change the information the hormone conveys to the brain: in simple terms, the brain would begin to adjust glucose levels based off a sum total of human lipids AND bacterial lipids.

Many of the Bacteriodes bacteria that create lipids are major human pathogens – eg. members of the genera Prevotella, Tannerella, Capnocytophaga and Porphyromonas (a driver of to tooth decay). If the human brain integrates lipids created by these pathogens into the input it uses to adjust glucose levels and other aspects of human metabolism, serious illness may result.

In summary, there are three main ways bacterial lipids can drive human heart/metabolic disease:

  1. Bacterial lipids are created (or travel) to human arteries where they may contribute to formation of arterial “plaque.”
  2. The human immune system reacts to these foreign bacterial lipids, which results in sustained, chronic inflammation.
  3. Human feedback pathways may incorrectly “sense” foreign bacterial lipids, and factor them into signals controlling human glucose levels and other aspects of human metabolism. This would “throw off” or “mess with” these human pathways in a manner that promotes disease.

Imagine the satisfaction of going back in time to tell President Eisenhower about the Nichols and team findings. While preliminary, they suggest that he could probably relax, eat a second egg, and feel a little less crazy. The same goes for millions of patients around the globe, who must “re-learn” basic heart disease guidelines – but in the context of research that may better address the “root cause” of their symptoms.

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