Richard G. Petty, MD

How Does Fiber Help You?

Unless you’ve been living on Mars (!), you will doubtless have heard of the advantages of increasing the amount of fiber in your diet. A high-fiber diet reduces your risk of colon cancer, constipation, hemorrhoids hypercholesterolemia and insulin resistance syndrome.

We have always wanted to know how fiber does so many magical things at once, and now we may an answer. In a paper published in the open-access Public Library of Science Biology today, by a group from one our local institutions – the Medical College of Georgia in Augusta – collaborating with a researcher from Josai University, Sakado, Saitama in Japan.

The epithelial cells lining the intestine have a life span measured in 1-5 days. They spend their short life times working to process enormous amounts of food residue on its way past. It is this layer of cells that acts as the barrier between the body and items floating past on the inside of the intestine.

Long before it became the topic of some popular books are over-enthusiastic magazine articles, we became very interested in the idea of the “Leaky gut:” the concept that some illnesses are a result of breakdown of the normal integrity of this protective barrier. Over 20 years ago, a friend and colleague at Northwick Park Hospital – Ingvar Bjarnason – did some pioneering work on this important issue. Several recent studies have indicated that a breakdown of this barrier may be involved in several childhood illnesses including allergies and asthma. There is also some early information suggesting that “leaky gut” may be involved in some autoimmune processes involving the intestine. Both zinc supplementation and oats may prevent gut leakiness under certain very specific circumstances.

When the epithelial cells in the gut wall encounter indigestible fibrous foods, the outer covering of the cell ruptures, releasing a coating of cell-protecting mucus. In a matter of seconds, the cell begins to repair itself, in the process releasing yet more of the beneficial mucus. Not only does it lubricate, but also it may keep some carcinogens and allergens out of your system.

The constant buffeting of the cells causes mild damage that increases the level of lubricating mucus. Injury at the cellular level promotes the health of the gastrointestinal tract as a whole.

Here we see a basic principle of nature: many of the same things that apply in the cells of the body apply equally in the life of someone trying to achieve success. Without the buffeting, the cells of the intestine could not produce the mucus on which your life depends.

Without some occasional adversity, you will find it more difficult to grow as a human being.

“Storms make oaks take deeper root.”
— George Herbert (English Religious Poet, 1593-1633)

“He who knows no hardships will know no hardihood. He who faces no calamity will need no courage. Mysterious though it is, the characteristics in human nature which we love best grow in a soil with a strong mixture of troubles.”
–Harry Emerson Fosdick (American Clergyman, Writer and Broadcaster, 1878-1969)

Toxoplasmosis, Behavior and Mental Illness

This title may seem odd, but this item may actually turn out to have enormous implications for all of us.

A couple of years ago I read a fascinating book: Parasites and the Behavior of Animals, in which the author – Janice Moore from Colorado State University – cataloged some of the extraordinary ways in which parasites can impact the behaviors of a vast array of animals. As difficult as it is to interpret studies of parasites in humans, I kept coming back to some odd observations about an illness with which I’ve been involved for more than 30 years: schizophrenia. I kept wondering if some of the odd observations made over the years could be explained by the parasites?

What kind of odd observations?

  1. Reports of mental illness have been found throughout history, yet this strange illness that we now call schizophrenia seems to have been very rare until about 1750, when it increased dramatically throughout Western Europe. I have had the privilege of working at the Bethlem Royal Hospital from which got the word “bedlam.” I know of the incredible records kept there. Something began to change in some of the types of patients being admitted at that time. I have also had the opportunity to look at some of the records at the Philip’s Hospital in Southern Germany, which has been in existence since 1533. Again the records show the sudden appearance of many cases of something that had been quite rare until then. 1750 marked the early years of the industrial revolution in Europe and the mass migration of people from the countryside to the new and very crowded cities
  2. There has been recent evidence that being born and raised in a city increases your chance of developing schizophrenia.
  3. There is increasing evidence that acute episodes of psychosis, mania and depression are associated with increases in circulating inflammatory mediators. There is also intriguing new data that both psychosis and depression can be improved by giving people COX2 inhibitors.
  4. There has also been the strange observation that bipolar disorder may have been becoming more common in recent years, over and above our greater ability to recognize the illness.

Several years ago the well-known psychiatrist E. Fuller Torrey first suggested that a small protozoal parasite called Toxoplasma gondii might be responsible for all of these observations. Cats can carry it, which is why pregnant mothers are advised not to pet their cats during pregnancy.

The idea that such a complex disease as schizophrenia might sometimes be caused by a parasite caught the media’s attention, but in recent years the story – but not the ongoing research – died down a bit.

There was an excellent and provocative blog item by Carl Zimmer about this almost three weeks ago, but I wanted to check everything out before responding. He gave a brief review of a new paper published in the Proceedings of the Royal Society, by Kevin Lafferty from the University of California in Santa Barbara. Lafferty has attempted to correlate the varying rates of Toxoplasma in different countries with predominant personality traits and therefore – since our societies are aggregates of all our personalities, cultural characteristics.

That may all sound far-fetched, but I don’t think that it is. And I don’t think that the Proceedings would have taken a completely half-baked proposition.

I have also found a report published in the journal the Proceedings of the Biological Society. Four eminent authors, including Torrey, revisited the while issue of Toxoplasmosis and mental illness. When the parasite gets into the nervous system it can alter behavior: Rats are normally programmed to avoid cats, but once infected they are attracted to cats. Over the last few days I’ve been plowing the world literature, and I’ve learned some very interesting things that support the idea that Toxoplasma may be playing a role in several different types of psychiatric illness.

There is strong evidence that schizophrenia, bipolar disorder and major depressive disorder lie on a spectrum. The illnesses are not the same, but people often switch from one type of clinical presentation to another. The precise type if illness would be determined by the interaction of genes, physical and Intrapsychic environment. Nobody would be sufficiently naïve to try and reduce the whole of psychiatric illness to a single bug. Mental illness is a great deal more than just a physical problem, and apart from anything else, the rates of Toxoplasma infections show remarkable variations around the globe, while the rates of major mental illness are much the same everywhere.

So what have I learned?

  1. There are a remarkable numbers of studies showing that many people with schizophrenia have antibodies to Toxoplasma, including people having their first attack of the illness
  2. Blood donors infected with Toxoplasma have decreased levels of novelty-seeking
  3. In women who become infected, there are some marked changes in personality.
  4. Toxoplasma affects the dopamine systems of the brain that we know are intimately involved in mood, cognition, movement and motivation.
  5. Some drugs used to treat psychosis (haloperidol) and mood disorder (valproic acid) inhibit the replication of Toxoplasma gondii. The valproic acid already does it at concentrations lower than we normally aim for when treating humans.
  6. There is some intriguing work going on into the use of antibiotics to kill Toxoplasma and reverse its behavioral effects.

In the last few years, so many illnesses have turned out to have infectious origins, from peptic ulcers to arteriosclerosis and some cancers. Perhaps some mental illnesses will be next.

Last year Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their pioneering work on Helicobacter. I have a strong sense that there are more prizes to come on the interaction between infectious agents, inflammation, genes, the psyche and the environment.

Perhaps the reason that some antipsychotics and mood stablizers can reverse some of the neurological damage associated with schizophrenia and bipolar disorder is becuase they are killing off the causative agents and allowing the brain to repair itself.

I shall keep you posted!

Blueberries

One of the principles of integrated medicine is that anything that’s good for you should have more than one benefit. So omega-3 fatty acids may help with cardiovascular health, mood, memory, attention deficit disorder, as well as the health of skin and bones.

Another one is the blueberry. I’ve been sufficiently impressed by the data on the health benefits of blueberries to have been a regular grower and consumer for years. They contain a number of potentially healthful compounds including polyphenols and anthocyanins, which can help modulate and balance the free radical systems of the body. Remember what I said recently about the value of keeping some free radicals in the body? The last thing that we want to do is to be rid of all of them!

There is reasonably good evidence that regularly eating blueberries can support cardiovascular health and there have been suggestions that they may reduce the risk and aggression of cancers of the prostate and colon.

There is also some evidence in animals that some of the components of blueberries may reduce inflammation and the effects of strokes – interruptions to the blood flow in the brain.

As a consumer, I’ve been carefully watching the growing evidence indicating that blueberries – or some of their constituents may have effects on animal cognition, brain aging and the normal neuroprotective mechanisms in the hippocampal region of the brain.

We do not yet have proof that these same effects occur in humans, and there are always three questions when we look at nutritional data:

  1. Can we extrapolate from the animal to humans? Mice are not men
  2. Are the amounts of blueberries or blueberry extracts even close to what humans could consume without spending all day eating, or getting a terribly upset intestine? There have been countless reports of the benefits of supplements that had to be taken in the most enormous doses to do any good. I’ve mentioned before the problem of L-arginine, which is sold as a “Natural Viagra.” Except that you need to take around nine grams for it to do much good, and most supplements contain less than a tenth of that. Regular readers will also remember my report concerning an article on coffee and sex. It was said that coffee would raise a woman’s libido. And indeed it does, if she drinks at least ten large cups of coffee at once. And coffee is a marvelous diuretic.
  3. When extracts are used, are we sure that we are getting the correct ingredient of the fruit? Many beneficial fruits contain just the right combination of nutrients to help us, so each can be taken in a small dosage or concentration. As with so much in integrated medicine, combinations are key. Take out one extract of a fruit, and you may lose the clinical effect that you wanted.

All that being said, the evidence is becoming progressively more interesting, and there is enough suggestive evidence for me to keep packing away the blueberries.

And just to show that I leave no stone unturned when checking the literature on your behalf, I rejoiced to learn that supplementing the diet of Arctic char with various supplements – including blueberries – improved the quality of his, ahem, semen. I do not know how this information will help any of us yet. Neither do I really know why a fish would want to eat blueberries or any of the other supplements that they were tried on. Though I’m sure that people have often asked similar off the wall questions about some of my research….

Chronic Widespread Pain, Fibromyalgia and Anti-inflammatory Proteins

Chronic widespread pain is a common and distressing medical condition that can be difficult to treat and is usually associated with fatigue, poor sleep and depression. One major subgroup is fibromyalgia. A connection between fibromyalgia and cytokines – small proteins that act as messengers between cells – has been suspected for some time, since some cancer patients treated with the cytokine interleukin -2 develop fibromyalgia-like symptoms. A new study from Wurzburg in Germany, published in the August 2006 issue of Arthritis and Rheumatism examined cytokine profiles in patients with chronic widespread pain and found that they had significantly lower levels of the anti-inflammatory cytokines IL-4 and IL-10.

This is an important finding: Previous research has shown that IL-10, administered as a protein or via gene transfer, reduces sensitivity to pain. Similarly, IL-4 has been shown to dull the pain response. There is also another piece to this: genetic variations in different cytokine genes are associated with distinct diseases, such as the association between IL-4 gene variations and asthma, Crohn’s disease, and chronic polyarthritis.

Although low levels of anti-inflammatory cytokines could be a consequence of chronic widespread pain and its treatment, it is much more likely that these proteins actually play a role in the causation of chronic widespread pain.

This new research raises all kinds of possibilities for the physical treatment of a particularly horrible set of illnesses.

Cranberries and the Inflammation Associated With Severe Gum Disease

There is an interesting study from a team of researchers from Quebec, Canada. The findings, published in the Journal of Antimicrobial Chemotherapy, reveal that natural compounds in cranberries may help ward off periodontitis, or severe gum disease, by serving as a powerful anti-inflammatory agent. This anti-inflammatory effect may be attributed to unique compounds in the fruit that prevent the bacterium P. gingivalis from adhering to the teeth below the gum line. Though it is early days, this new research offers promise for the estimated 67 million Americans affected by periodontitis, the primary cause of tooth loss in adults.

The reason for the study was that cranberries have what are known as "anti-adhesion" activity. This helps guard the body from certain harmful bacteria that cause urinary tract infections (UTIs), gastric ulcers and gum disease. This anti-adhesion activity is primarily due to molecules called proanthocyanidins (PACs) found naturally in cranberries and other foods. Cranberry PACs contain a unique A-type structure that is responsible for this anti-adhesion mechanism of action, while most other foods contain only the more-common B-type PACs.

Researchers discovered that cranberry compounds can reduce the growth of P. gingivalis and subsequent plaque development — the initial step in the development of periodontitis. Periodontitis occurs when inflammation or infection of the gums is left untreated or treatment is delayed. Infection and inflammation spreads from the gums to the ligaments and bones that support the teeth and eventually leads to tooth loss.

In a paper in the Journal of Dental Research the same researchers had previously shown that cells treated with cranberry juice showed significantly less inflammation than cells that were not treated.

Not only can cranberry compounds decrease the growth of P. gingivalis, they may also prevent certain oral bacteria from directly destroying gum tissue itself — another major factor contributing to periodontitis. This may have more widespread implications as recent studies have also linked severe gum disease with an increased likelihood for heart disease and stroke.

The study was part funded by the Ocean Spray agricultural cooperative that sells cranberry juice.

Brushing, flossing and regular professional cleaning reduces the risk of developing periodontitis by helping to prevent the onset of gingivitis, or gum infection. Cranberries may provide an interesting ingredient in the development of new therapeutic approaches for treatment of periodontitis.

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Brushing Your Teeth is Good for Your Heart

This was the title of an article in Time magazine and something that I’ve been meaning to discuss for a while now.

We have known for some years now that there can be a link between periodontal bacteria and heart disease, but a new study from the Department of Health Sciences in Kristianstad University, in Sweden and published in the Journal of Periodontology.

The researchers found the presence of specific bacteria in periodontal pockets, which are those areas of tissue surrounding teeth, that might be an explanation for the relationship between periodontal disease and acute coronary syndrome (ACS). ACS is the term used to describe insufficient blood supply to the heart muscle that results in heart disease.

The investigators compared 161 subjects diagnosed with ACS with a control group of people who did not have cardiovascular disease. They found that the bacterial burden – the amount of oral bacteria –was twice as high in the ACS group for the combination for the bacteria streptococci, and three less common bacteria: P. gingivalis, T. forsythia and T. denticola. These findings suggest that this combination of bacteria is the link between periodontitis and ACS.

The periodontal bacteria cause an inflammatory response that elevates the white blood cell count and increases one of the key inflammatory markers: high sensitivity C-reactive protein levels in the blood, a factor which has been linked in past studies to heart disease.

Alveolar bone loss—atrophy of the bones that support your teeth—was also found to be significantly greater among subjects with ACS. The extent of bone loss was more severe in the ACS group than in the non-ACS group with 77%of the participants in the ACS group afflicted with periodontitis versus 42% in the control group.

The study highlights the importance of routine periodontal examinations and at-home dental care, particularly if you have a personal or family history of heart disease.

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How Many Angels Can Dance on the Head of a Needle? Moving Beyond the Metabolic Syndrome

I have written a great deal both on this blog and in scholarly articles, about insulin resistance and the insulin resistance and metabolic syndromes.

You will have noticed that I’ve always used the term insulin resistance syndrome.

This is not a matter of semantics. For years now I’ve been worried about the splitting that’s been going on in the field: we currently have six sets of definitions of the metabolic syndrome. And apart from the fun of going to all those conferences in exotic parts of the world, you have to ask what’s been achieved by these ever more divisive attempts to “define” the medical consequences of insulin resistance.

The American Diabetes Association has begun to promote the concept of “cardiometabolic risk.” The Association has established a national Cardiometabolic Risk Initiative (CMRI) to stress the association between diabetes, heart disease and stroke. The idea of introducing this umbrella term is to help people better understand and manage all diabetes and cardiovascular risk factors, and to side-step some of the controversy surrounding the definition of insulin resistance or metabolic syndrome and which cluster of variables are in and out.

A new Cardiometabolic Risk (CMR) Calculator to help us evaluate an individual’s risk of diabetes or vascular disease should be available by the end of the year.
The formula already includes factors such as:
1.    Body mass index
2.    Waist circumference ratio
3.    Fasting plasma glucose
4.    HDL-cholesterol
5.    LDL-cholesterol
6.    Triglycerides
7.    Apolipoprotein B
8.    Blood pressure
9.    C-reactive protein
10.  Age
11.  Sex
12.  Race/ethnic origin
13.  Family history
14.  Tobacco use

Part of the reason for this new initiative is the discovery that pre-diabetes, or impaired fasting glucose, where plasma glucose levels are 100-125 mg/dl, is associated with a high prevalence of cardiovascular disease risk factors such as obesity, hypertension and dyslipidemias.

The person who first proposed the insulin resistance syndrome, a.k.a. syndrome X, a.k.a. metabolic syndrome, is Gerald Reaven who first recognized the syndrome in a landmark paper in 1988. He recently gave a lecture entitled; “Insulin Resistance Versus Metabolic Syndrome: Different Names, Different Concepts, Different Goals.” I am in complete agreement with his basic proposition, which is that insulin resistance explains the clustering of all of the components that make up the metabolic syndrome. So Gerry’s position is that there’s no point in trying to make a diagnosis of metabolic syndrome: everything is due to insulin resistance.

So instead of wasting time and resources in trying to diagnose metabolic syndrome, it is much better to understand the pathophysiology: what is going on at the molecular level, how these processes produce risk factors, and whether we can predict others. We should identify and treat each of the underlying processes and the complications of insulin resistance. If we are going to have a syndrome, it should be called insulin resistance syndrome.

And let’s stop these academic debates and get on with the job at hand: there is a 600% variation in peoples’ ability to have insulin transport glucose into cells. More than half the US population is destined to develop at least some degree of insulin resistance, so we need to look for better ways to identify people who have it, and to apply the principles of integrated medicine to keeping them healthy.

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Oxidative Stress and Insulin Resistance

As we have discussed before, insulin resistance is a cardinal feature of type 2 diabetes, and is an important factor in many other illnesses. Last year saw the publication of a study from Albert Einstein College of Medicine in New York, showing that high levels of blood glucose induced an inflammatory response in fat cells, and reactive oxygen species was a key player in the process.

Now, a very interesting paper in the journal Nature indicates that fat storage cells exposed to chemicals (dexamethasone and tumor necrosis factor-α) raise the levels of reactive oxygen species and these raise insulin resistance. If the cells are then treated to suppress this production, insulin resistance falls. We have been interested in balancing the oxidant and antioxidant systems to reduce the risk of the complications of diabetes, but now it looks as if antioxidants may also help the underlying disease process itself.

In a future blog I’m going to explain why free radicals and oxidative stress are not all bad: they are key cancer killers!

And in one of the programs coming out later this year, I shall explain how to modulate oxidative stress to keep your systems in constant dynamic balance.

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Another Controller of Appetite and Weight

We recently discussed the role of cytokines in modulating appetite and energy balance. Now a study in mice has shown that animals deficient in interleukin-18 (IL-18) develop a voracious appetite, very marked obesity and insulin resistance. The insulin resistance is secondary to the obesity that was induced by increased food intake and occurred in the liver as well as muscle and fat.

When the little creatures were given recombinant IL-18 their food intake returned toward normal.

Only recently discovered, IL-18 is an important regulator of innate and acquired immune responses. The fact that a modulator or immunity and inflammation has a key role in feeding and in energy metabolism shows us once again just how closely all these systems are tied together. You lose weight when you are sick or depressed because the body is battling the illness. As you recover, the body needs to replace everything that was lost and re-establish your resilience. These systems don’t just exist in humans, they are found in all mammals and even some birds and fish. So they have evolved over millions of years and we need to be very careful about tinkering with these complex systems. Or of allowing stress or environmental toxins to compromise these protective mechanisms.

This finding may well pave the way not just for new pharmacological approaches to weight management, but also to some non-pharmacological approaches.

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Cytokines and Weight

Anyone who has ever had a sick child knows that one of the surest signs that he or she is recovering is a return of appetite. From a biological perspective, this is an attempt by the body to make up for any losses that took place during the illness. The major mediator of this effect is one set of a group of chemicals known as cytokines.

Cytokines are glycoproteins that behave like hormones and neurotransmitters, serving as chemical messengers between cells. There are many families of cytokines, including leptin, that we have met before. In recent years most of the attention of researchers has been directed not at the cytokines themselves, but at their receptors, whose activity is far more subtle.

Cytokine receptors are involved in the regulation of cell growth and repair and have important roles in immune responses. Apart from their role in feeding behavior, cytokines have roles in fatigue, fever, sleep, pain and stress. Some key cytokines: interleukin (IL)-1,  IL-6 and IL-8 are dysregulated in fibromyalgia.

At a meeting of the 6th International Congress of Neuroendocrinology in Pittsburgh last month, researchers from the Centre National de la Recherche Scientifique (CNRS) at the Pasteur Institute and the University of Lille, France, presented evidence that The cytokine interleukin-7 (IL-7) is not only involved in immune function, but also prevents obesity-prone mice from getting fat. This is the converse of those cytokines that cause weight gain. IL-7 interacts with the regions of the hypothalamus involved in appetite control. This is yet another piece of evidence indicating that the immune and neuroendocrine systems are closely inter-linked.

This is not really a surprise. One of the big problems I people with many chronic illness, particularly cancer, is that they tend to lose appetite and weight. Sometimes they lose a great deal of weight even while maintaining a decent diet. The anorexia of cancer is caused by many factors working on the signaling pathways in the hypothalamus that modulate energy homeostasis. Research has shown that cytokines are major mediators of weight and appetite loss in cancer patients, by working on two systems known as melanocortin and neuropeptide-Y. It also seems likely that the weight loss that happens with stress, depression and chronic inflammation are all mediated by specific cytokines. These same cytokines increase the risk of developing heart disease. A recent study from Ireland has shown that treatment with an SSRI antidepressant reduces measures of systemic inflammation.

It may be that this new insight into the relationship between inflammation and weight will offer up some more solutions for the problems of obesity, but we are going to need to be alert to the possibility that anything that modulates cytokines may increase the risk of vascular disease.

The more that we learn, the more that we understand about the miraculous checks and balances that keep us healthy.

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