IBD Less Common in Sunny States

I've blogged about this before, but there was a recent study that revealed that people who live in sunnier regions of the United States are less likely to develop IBD. It confirms previous research conducted in Europe that generated the similar results. The study followed over 200k participants that began the study without symptoms of IBD.

The basic explanation for this is Vitamin D. There's a strong role for Vitamin D in the immune response and IBD patients (including myself) often have low Vitamin D levels. So stop postponing that vacation to Hawaii already!

Here's an excerpt:

"A leading explanation for this north-south gradient in the risk of ulcerative colitis and Crohn's disease may be differences in exposure to sunlight, or UVB radiation, which is generally greater in southern latitudes," wrote Dr. Hamed Khalili, of Massachusetts General Hospital in Boston, and colleagues.

"UV radiation is the greatest environmental determinant of plasma vitamin D, and there is substantial experimental data supporting a role for vitamin D in the innate immunity and regulation of inflammatory response," they noted.

Crohn's Disease, the Rise of Agriculture, and Gene Expression

Just read a really complicated article that went way over my head in Discover Magazine, but thought I'd share it as there are some interesting theories presented.

Here's an excerpt:

So what happened? The authors posit that the 503F allele was selectively favored at some point in the past, and flanking it were the Crohn’s disease risk elevating variants of IRF1 and IL5. All things equal it is best not to have a risk for this disease, but all things are not equal. If there was a strong enough selective pressure on the target, 503F, then the downsides of the fact that it came as a “total package” with some deleterious alleles would be irrelevant. Over a long enough evolutionary time the deleterious alleles would be purified through negative selection because recombination does break apart associations, but there’s a lot of reality which consists of being between beginnings and ends.

Basically, the idea is that agriculture put a selective pressure on the genome that brought along genes that increased risk of Crohn's disease. To put that in more plain words, the rapid change in environment caused by the rise of agriculture (e.g. living off of certain grains), put pressure on the natural selection of genes. Certain gene variants (mutations) were favored in the new environment and so flourished. Unfortunately, those positive gene variants (which helped humans deal with the benefits of agriculture) brought with them negative gene variants (which increased risk of disease).

Interesting theory. The writer that's critiquing the article doesn't completely agree with the conclusion, but definitely some interesting analysis.

Broccoli Fiber Combats Crohn's Disease

Saw this article in Life Extension magazine about broccoli:

An article published online on August 25, 2010 in the journal Gut reveals that fibers found in broccoli and plantain block a stage in the development of the Crohn's disease, an inflammatory bowel disease. The stage involves a process known as translocation, which is the invasion of microfold cells (M-cells) lining the colon by bacteria, particularly E. Coli, which tend to adhere to one another.

Crohn’s disease is uncommon in countries whose citizens regularly consume fibrous fruits and vegetables, while the incidence of the disease has increased in Japan with the rise of Westernized dietary habits. Additionally, some enteral feeds have been shown to result in clinical remission. “It is therefore a plausible hypothesis that dietary factors may have either harmful or protective roles in Crohn’s pathogenesis as a consequence of their effects on the interaction between the host epithelia and intestinal microbiota,” the authors write.

Dr Barry J. Campbell of the University of Liverpool and his associates tested the effects of soluble fiber from leeks, apples, broccoli and plantain in cultured human M-cells. Concentrations of 5 and 50 milligrams per milliliter plantain fiber, and broccoli fiber concentration of greater than 0.5 milligrams per milliliter helped inhibit E. Coli translocation. While apple and leek failed to show an inhibitory effect, translocation of E. Coli was enhanced by the fat emulsifier polysorbate 80, which is included in some enteral feed solutions administered to Crohn’s disease patients and is a common dietary additive. The results were confirmed in epithelial tissue samples derived from humans who underwent surgery for colon cancer or colonoscopy.

“These studies show that different dietary components may have powerful and contrasting effects on bacterial translocation across intestinal M-cells,” the authors conclude. “These effects may be relevant to the role of environmental factors in the pathogenesis of Crohn’s disease and suggest possible novel therapeutic approaches.”

This is related to an earlier post I had about broccoli. Eat your broccoli!

Caltech Researchers Discover that Gut Bacteria Affect Multiple Sclerosis

I've had a couple blog posts about multiple sclerosis (MS), including links to both viral and bacterial infections. I just came across another study, this one from Caltech, that found that gut bacteria can affect the onset of MS. The researchers found that gut bacteria could influence the creation of Th17 cells (certain kinds of immune helper cells).

The bacteria aren't necessarily the entire cause of the disease, but they may represent the "environmental" component that when combined with genetic susceptibility causes the disease to kick into gear. Here's an excerpt:

Mazmanian and his colleagues don't, however, suggest that gut bacteria are the direct cause of multiple sclerosis, which is known to be genetically linked. Rather, the bacteria may be helping to shape the immune system's inflammatory response, thus creating conditions that could allow the disease to develop. Indeed, multiple sclerosis also has a strong environmental component; identical twins, who possess the same genome and share all of their genes, only have a 25 percent chance of sharing the disease. "We would like to suggest that gut bacteria may be the missing environmental component," he says.

It's amazing that inflammation of something as sterile as the central nervous system and brain could be impacted by what's going on in your gut. But there does indeed seem to be a connection. Hopefully they can find the bacteria (or type of bacteria) that triggers Crohn's Disease as well.

Virus Plus Gene Mutation Spurs Crohn's Disease in Mice

Saw an article about a new study that found a specific link between a gene mutation and virus that caused Crohn's Disease in mice. The study found that mice that had a gene variant linked to Crohn's Disease only developed Crohn's symptoms when they were infected by a specific, common norovirus called MNV.

Here's an excerpt:

Two years ago, the researchers at Washington University School of Medicine in St. Louis and others discovered that mice with an ATG16L1 gene variant associated with Crohn's disease in humans develop similar abnormalities in gut immune cells called Paneth cells. But the mutation alone wasn't enough to trigger Crohn's disease.

In a routine screening, the team later found that mice with the gene variant developed Crohn's disease symptoms within seven days after exposure to the MNV norovirus.

The study appears in the June 25 issue of the journal Cell.

It's been suspected that autoimmune and other diseases might be influenced by viral infections, but "this is the first really clear indication of a disease caused by a susceptibility gene and a specific virus," study co-leader Thaddeus Stappenback said in a journal news release.

That last statement is important. They found a specific viral infection that can trigger the disease for a specific genetic predisposition. Given there are many genetic markers for CD, there may be many possible viral infections (or bacterial infections) that can trigger the disease. So there is lots of research still to be done. But this is an important finding. As an aside, I had another recent post about a bacteria triggering arthritis in mice, so there are many angles on this research.

When Good Germs Go Bad - Friendly Bacteria Triggers Arthritis in Mice

Saw a really interesting article in Scientific American about a study regarding a link between a specific strain of bacteria and rheumatoid arthritis (RA) in mice. The study found that the introduction of a single type of bacteria could increase the amount of IL-17 (interleukin 17), a protein that signals the immune system to cause inflammation, in the mouse. The "friendly" bacteria that causes this accelerated the onset of arthritis in the mice. The mice were selected to already be genetically predisposed to having arthritis, so all mice in the study developed arthritis. But the mice that were given the bacteria developed RA much more quickly.

Why is this important? This could mean that exposure to even a single bacteria or virus could trigger an autoimmune reaction in genetically susceptible individuals. Here's an excerpt:

Mathis emphasized that one should not take away from these mouse studies "that mice or humans can 'catch' an autoimmune disease or arthritis," she says. She added that the better way to think about it is that individuals have varying degrees of genetic susceptibility, and when exposed to certain environmental factors may then go on to develop disease. "It's really an interaction between genetics and environment," Mathis says.

Crohn's Disease or Inflammatory Bowel Disease (IBD) may have a similar pattern to RA. It could also mean that there is a single bacteria or virus responsible for the disease. Or ... it could also mean that there are any number of bacteria or viruses that trigger the disease. Either way, it's a very study and reinforces previous theories and studies I've seen.

Virus infection may trigger unusual immune cells to attack the brain and spinal cord in multiple sclerosis

I came across a really interesting article regarding a possible causative mechanism for multiple sclerosis (MS). As you most likely know, MS is an autoimmune disease (similar to IBD and Crohn's) where immune cells misguidedly attack the body's own cells. In the case of MS, the body is attacking the protective sheath around major nerves. In the case of IBD, the body is attacking your intestinal tissue.

The above mentioned article found that a viral infection could incite certain rare immune cells to be released in the body that attack both the virus and (in the case of MS) nerve cells. The rare immune cells do this because they have receptors for both the virus' proteins and proteins present in nerve tissue (myelin). I found this research interesting given the recent talk from Amy Proal that I blogged about regarding the viral and bacterial metagenome and the recent study (similar to the MS one) that found a possible link between errant T-cells and diabetes.

The study about MS suggests that there's not necessarily a single virus that causes the disease, but instead a combination of factors that generate the errant T-cells:

The authors explained that it's possible that multiple viruses could influence susceptibility to multiple sclerosis. The ability of any particular virus to contribute to the disease could depend on an individual's own repertoire of other predisposing genes, exposure to other predisposing environmental factors, and the random chance that T cells had been generated that recognize a myelin protein and a pathogen.

Receptors on T cells are randomly generated during their development. This observation helps explain why multiple sclerosis is partly a matter of chance. Some people with a genetic predisposition and environmental exposure develop the disease, while others with similar genetic predisposition and environmental exposure do not.

This suggests some really interesting (and challenging) directions for future research. Many current studies are focusing on finding a single bacteria or virus (e.g. MAP) that someone is infected with or a single genetic mutation (e.g. NOD2) that cause IBD. This is a potentially flawed approach, though. This study suggests that even after the infection is cleared, the errant T-cells that cause the autoimmune reaction may persist (i.e. there's no smoking gun). It certainly makes finding the root-cause difficult! But it suggests a different direction to take research.

Antibiotics in Infancy Potentially Linked to IBD Risk

A small study showed that there might be an increased risk of IBD for infants that are given antibiotics in their 1st year of life. The study compared 36 children with IBD with 360 children that did not have IBD. 60% of the group with IBD had been given antibiotics compared to only 40% for the non-IBD group. The difference was even more pronounced for boys than girls. The study suggests a possible root cause or causative agent in the development of the disease. But again, this was a very small study, so this just suggests areas for additional research.

Discovery Prompts New Theory on Cause of Autoimmune Diseases

Saw an article in ScienceDaily about a new theory on the cause of autoimmune diseases, including Crohn's Disease. Researchers discovered a protein (or peptide) fragment that's capable of causing diabetes in mice. The basic hypothesis is that the unusual introduction of these peptides allows errant T-cells to escape the thymus and make there way to other parts of the body where they initiate immune responses associated with autoimmune diseases. These errant T-cells that are autoreactive (or that react to your body's own cells) are normally deleted by the immune system. However, the introduction of these rare peptides causes the deletion procedure to not work properly.

Here's an excerpt:

In the April 23, 2010, issue ofImmunity, Drs. Brian Stadinski, John Kappler and George Eisenbarth propose that the unusual and rare presentation of protein fragments (peptides) to the immune system allows autoreactive T cells to escape the thymus and trigger autoimmune disease. The findings could lead to a new strategy for preventing type 1 diabetes.

"The immune system normally deletes dangerous, autoreactive T cells that recognize 'self' peptides, which are a normal part of the organism," said Dr. Kappler, Professor of Immunology at National Jewish Health. "We believe autoreactive T cells in diabetes and other autoimmune diseases escape destruction in the thymus because they never see these poorly presented peptides there. But the T cells do encounter those peptides elsewhere in the body and trigger an autoimmune attack."

Pretty fascinating if the theory is correct. It could also suggest very new areas of research for treatment options.

Stress Aggravates IBD

Saw this article commenting on an upcoming study that will be published in the American Journal of Gasteroenterology. The study found that stress was linked to a more than twofold increase in the risk of symptom flare ups in IBD sufferers. Here's an excerpt:

Stress had long been among the main environmental factors linked to the flare-up of symptoms in some individuals. This theory, however, had never been clinically proven.

According to the study published in the American Journal of Gastroenterology, stress is associated with a more than twofold increase in the risk of symptom flare ups in sufferers.

Such a link was not seen in other factors suspected of triggering IBD symptoms such as the use of antibiotics or non-steroidal anti-inflammatory painkillers, and infections including colds, pneumonia and urinary tract infections.

"This is among the first evidence to show that the perception of stress had a direct association with disease course," said lead researcher Charles N. Bernstein, stressing that learning better stress management methods could help treat the condition more effectively.

Here's an excerpt from another article on the same topic suggesting a possible reason for the connection:

There are biological reasons to believe that a person's response to stress would trigger or worsen IBD symptoms, Bernstein and his colleagues note.

The sympathetic nervous system, which jumps into action during times of stress, acts on the lining of the colon, and might exacerbate existing inflammation. There is also evidence that stress hormones may help harmful bacteria take up residence in the intestines, which might, in turn, affect symptoms.

Italian researchers discover a possible onset mechanism for Multiple Sclerosis

I just read an interesting article on how bacterium might be a trigger for the onset of Multiple Sclerosis. One theory regarding the cause of MS is that it is an autoimmune triggered. A recent study in mice found that a harmless bacterium made to look like a nerve cell allows T-cells to modify to the point where they can repeatedly break into the central nervous system. Normally, T-cells can not do this. However, in mice where this modified bacterium has been introduced, the T-cells modify in the inflammatory response. These modified T-cells persist well after the bacterium has been killed and continue to cause inflammation in the central nervous system.

I think it's interesting to see how other immune disorders operate as there may be analogs in Crohn's.

Here's an excerpt:

This is the hypothesis that the researchers coming from the Institutes of General Pathology, Microbiology and Anatomy of the Catholic University of Rome have been testing with their two-year long work. To demonstrate the viability of this idea, scientists have fooled the mouse immune system, modifying subtly a bacterium of the common family of mycobacteria (the same family to which also the bacterium causing tuberculosis belongs) to make it look like to myelin, the protein coating nerve cells. This modified mycobacterium is completely innocuous. As all external agents, though, it is capable to trigger the reaction of the T-cells of the immune systems. They intervene to destroy it. Since they are innocuous bacteria, although very common in the environment, and since they induce an immune reaction, they are the ideal bacteria scientists can use to study the environmental factor contributing, together with the genetic factor, to cause multiple sclerosis.

"Normally, T-cells cannot penetrate into the Central Nervous System", adds Rea, "because the hematoencephalic barrier prevents them from doing so. But the bacterium modifies the characteristics of the T-cells and allows them to overcome the barrier. In 15 days the bacterium disappears completely from the body".

Yet these T-cells can now enter into the brain. This way, they begin to attack the myelin of the nerve cells, and here is how the immune disease breaks out.

"We basically demonstrate – explains Rea – that in an animal model it is possible to be infected with something not carrying any disease, and later on develop a purely autoimmune disease".

Pretty interesting.

Distinct demographic profiles between Crohn's disease and ulcerative colitis

Just read a short article on the demographic differences between UC and CD sufferers in the UK. Additional support for environmental differences being a contributing factor. Interesting that CD was more common among "deprived social groups". Perhaps a different diet in that group? Here's an excerpt:

They found that hospitalization for severe CD was more common among women than men and it peaked among younger people aged 16󈞉 years. UC was similar among men and women and was more common among older people. There was no link between social deprivation and UC, but CD was more common among more deprived social groups.

The differing demographic profiles between CD and UC, suggest that environmental factors play a more significant role in the etiology of CD. The findings of this large population-based study on the prevalence and mortality of IBD are also important for service planning and provision.

Vitamin D may help fight Crohn's Disease

More evidence regarding the benefits of Vitamin D for Crohn's in this recent article. See my post from Sept 2009 for additional evidence - "Vitamin D and Why Immunosuppressants May Be Counterproductive".

Excerpt from the recent article:

“Our data suggests, for the first time, that Vitamin D deficiency can contribute to Crohn’s disease,” says Dr. White, a professor in McGill’s Department of Physiology, noting that people from northern countries, which receive less sunlight that is necessary for the fabrication of Vitamin D by the human body, are particularly vulnerable to Crohn’s disease.

Perhaps an argument to finally take that vacation to Hawaii.

The Hunt for an Autism Drug

Just read an interesting article in Business Week ("The Hunt for an Autism Drug") about how many companies are seeking drugs to treat autism. Apparently, 1 in 110 8-year old children in the US falls someone on the autism scale. That's a pretty staggering statistic when you think about it. Obviously autism is a very different disease from Crohn's, so why am I mentioning this? When I was reading the book Breaking the Vicious Cycle, they mentioned how the Specific Carbohydrate Diet showed improvement in children with autism. One start-up drug maker is looking at this link:

One of the most promising treatments in this category is a drug called CM-AT made by a startup called Curemark. Dr. Joan Fallon, the company's founder and CEO, observed that many autistics show a strong preference for foods high in carbohydrates and low in protein. A diagnostic test revealed that some autistic children lack enzymes that digest protein. As a result, these children produce fewer of the essential amino acids that are the building blocks for brain development and neuroreception. Fallon believes this deficiency is linked to the most severe symptoms of autism, and she says an early observational study of CM-AT, an orally ingested powder that delivers protein-digesting protease, showed "significant improvements." Curemark is enrolling patients in phase III clinical trials at 10 to 12 sites—the largest autism trial to date.

Seemed related and interesting so thought I would mention it.

The other thing I found interesting was the mention of epigenetics, which I think I'm going to do some further research on. The basic premise is that the environment can influence gene expression. So many diseases may be a combination of both genetics and environmental influences (pollution, viruses, diet, etc.). Perhaps that's why it is so hard to pin down a single cause for Crohn's, autism, and many other diseases.

I'll Take a Parasite Please: Helminthic Therapy and the Hygiene Hypothesis

I've been wanting to post on this topic for a while, but never got around to it. I just saw this article in ABCNews titled "Allergy Desperation: I'll Take a Parasite, Please" (linked to from this blog post). It includes a story of a guy named Jasper Lawrence who in desperation from long-term allergy problems decided to infect himself with hookworms. The result was that his symptoms were dramatically diminished (if not cured). Why?

Here's a good excerpt from the article that sums it up:

The hypothesis goes that until recently, humans were fighting off some sort of parasite or another for millions of years, ever since humans evolved into humans. That co-existence eventually led humans to evolving an immune system that worked with parasites.

"When you're born you have an immune system, but your immune system is a blank slate," said Weinstock.

Weinstock explained that just as humans create a functioning digestive system by populating their digestive system with bacteria, humans historically developed an immune designed to account for parasites in the body.

But in the last 150 years, the industrialized world's clean food supply and plumbing suddenly removed parasites from people's bodies. In response, researchers now widely think that people's immune systems stopped developing properly.

Weinstock said most people still have a powerful "attack" function of their immune system, but that many believe the immune system does not develop to regulate properly in the absence of helminthes (parasitic worms).

"People who are not exposed to helminthes have sloppy regulation," said Weinstock. As a result some people's immune systems go off kilter and misfire against their own bodies creating autoimmune disorders such as allergies, asthma, or inflammatory bowel disease.

There has been a lot of research into this area and the general "hypothesis" mentioned has been around since the 1980's. The theory is called the hygiene hypothesis. Basically, our overly hygienic lifestyles in developed nations (particularly in the northeast) means that our immune systems have not been properly balanced and exposed to regulating agents. The lack of this exposure causes all sorts of downstream effects when your body encounters mostly innocuous allergens -- basically it over-reacts. The type of therapy described in the article, helminthic therapy, is meant to correct this problem (albeit later in life than probably should have been the case).

In helminthic therapy, you purposely expose the body to parasites such as hookworms. This exposure forces the immune system to develop the proper regulation systems and as a result it no longer over-reacts.

Sounds great! Pass the bowl of hookworms over so I can load up. Perhaps not so fast. Immune development is really complex and many of these parasites can have serious side effects (... they are parasites after all ...), so it's likely wise to wait for many of the clinical trials underway to be completed. You never know, within a few years you may find hookworms in the same category as probiotics!