MAP and its Relationship to Crohn's Disease

I just read a really great paper ("Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn’s disease") that summarized recent literature on the role of Mycobacterium avium paratuberculosis (MAP) in Crohn's Disease. I've had several previous posts regarding MAP's potential role in Crohn's and IBD, but this paper was much more comprehensive and cited studies I had not heard of.

It's really worth reading the whole thing if you're looking for background on this topic. Here were the topics covered:

• Introduction
• MAP - description and background on the MAP bacterium
• Detection of Map in Crohn's Disease - intro of detection techniques
• MAP Culture - different methods of culturing MAP and results of studies related to Crohn's
• Detection of Insertion Sequence IS900 - methods of detecting the IS900 gene sequence (which is unique to MAP)
• Serologic Studies of MAP - looking for antibodies in the blood of Crohn's patients
• MAP and Genetic Susceptibility to Crohn's Disease - interaction between genetic susceptibility (via the NOD2/CARD15 Crohn's gene mutations) and MAP (e.g. overgrowth, etc.)
• Anti-Mycobacterial Antibiotics for Crohn's Disease - review of studies that tried (unsuccessfully) to cause long-term remission of Crohn's through use of antibiotics. MAP is very resilient and the interaction between antibiotics and immunosuppressive agents (which may also impact MAP function) leave room for doubt in the studies.
• Epidemiologic Evidence for MAP as a Cause of CD - lots of epidemiologic evidence for why MAP is likely not the cause of Crohn's, but some support of it being a cause.
• Conclusion (full excerpt below)

For reference, I'm including an excerpt of the conclusion of the paper:

MAP is the causative agent of Johne’s disease. It seems likely that chronic infection with MAP does occasionally occur in humans. MAP is widely present in our food chain and the DNA of this organism can be recovered from the intestine of CD patients. Studies have shown that a high percentage of subjects with CD are infected with MAP, though whether the association of this bacterium and CD is causal or coincidental is not known. Epidemiologists have gathered enough information to indicate an association between MAP and CD. Nonetheless, the role of MAP in CD etiology is not known, and may be determined from consistent results of studies using improved methods of isolation and detection of MAP bacilli and/or MAP-elicited immune responses in the host.

Bacteroides ovatus (B. ovatus) May Help IBD Suffers

Saw an article about some recent work regarding a bacteria called Bacteroides ovatus (B. ovatus) that helps repair the intestinal lining. Here's the excerpt:

The group focused on the bacterium Bacteroides ovatus (B. ovatus), which is one of an assortment of intestinal microflora in humans. B. ovatus thrives in the oxygen-free environment of the large intestine, where it breaks down xylan—a fiber found in plants—and other sugars for energy and growth.

The team created a strain of B. ovatus that used xylan to induce secretion of human keratinocyte growth factor, a protein that helps repair and restore the intestine’s delicate lining. This increased the ability of the intestine to repair IBD-inflicted damage.

The researchers found that IBD-affected mice treated with oral doses of xylan and the engineered strain of B. ovatus had intestinal tissues that healed more rapidly. This group of mice also lost less weight and had lower levels of rectal bleeding. In addition, dosing mice with B. ovatus provided protection from induced IBD and limited the development of subsequent intestinal inflammation.

Maybe this will end up as another probiotic supplement at some point in the future.

Probiotics May Help Prevent Crohn's Disease

Saw an interesting mention of a research report in a Wall Street Journal article. Here's the excerpt:

Crohn's Disease: Probiotics—live microorganisms that appear to improve gastrointestinal health—may prevent the onset of Crohn's disease, according to a study in the Proceedings of the National Academy of Sciences. The researchers fed young mice, who had been bred to develop a Crohn's-like inflammatory bowel disease, diets that included a high dose of eight probiotic bacteria strains. The disease, ileitis, was entirely prevented in five of those 11 mice, and markedly less severe in five of the remaining six. A lower dose of the bacteria, given to another set of mice, provided little beneficial effect. The researchers suggested, based on necropsies of the mice, that the probiotics guarded against ileitis by stimulating the immune system of the gut lining.

Caveat: It's not known whether probiotics would prevent actual Crohn's disease in humans, or what dose would be required. (Read the Report)

This kind of raises an interesting question around the Specific Carbohyrdrate Diet (which I'm using). How do you train or sensitize your immune system to handle different types of gut bacteria if you're on a diet that is targeted at eliminating many strains of bacteria in the gut? Perhaps you slowly introduce new bacteria (or foods that allow those other bacteria to develop). That way your body can slowly develop (or re-develop) it's sensitivity to these.

A Potential Stem Cell Treatment for IBD from Pfizer

Pfizer announced some news this week that could result in a stem cell treatment for inflammatory bowel disease (IBD), including Crohn's. On Monday, Pfizer struck a development and commercialization agreement with Athersys, Inc., a Cleveland biotech company. Pfizer plans to develop a therapy for IBD based on MultiStem, the Athersys adult stem cell product line.

From reading through the MultiStem website, the product seems to have great potential as a therapy. The really dumbed-down version of the therapy (I'm a dummy, so correct me if I'm wrong) would be to inject these cells into a sufferer of IBD and then the cells, based on the

local environment and specific type of inflammatory response, would produce molecules to help properly regulate the immune system. The stem cells would not be a permanent solution. Similar to other biologics (e.g. Cimzia), they would have a temporary impact on how the immune system functions and to continue to see benefits you would need to continue to take the drug. Here's an excerpt:

MultiStem consists of a special class of human stem cells that have the ability to express a range of therapeutically relevant proteins and other factors, as well as form multiple cell types. Factors expressed by MultiStem have the potential to deliver a therapeutic benefit in several ways, such as the reduction of inflammation, protection of damaged or injured tissue, and the formation of new blood vessels in regions of ischemic injury. These cells exhibit a drug-like profile in that they act primarily through the production of factors that regulate the immune system, protect damaged or injured cells, promote tissue repair and healing and most or all of the cells are cleared from the body over time.

The real unique thing about MultiStem versus other biologics is that it could actually have multiple methods of working (the beauty of stem cells). Here's an excerpt:

Though the cells have the potential to differentiate into a variety of cell types, in certain indications the primary mechanism of MultiStem appears to be the production of a physiologically relevant and complex set of therapeutic molecules in response to the local environment. In the initial indications Athersys is pursuing, the cells appear to minimize the inflammatory reaction that occurs in response to ischemic events (such as myocardial infarction or stroke) or the anti-host immune reaction seen in graft vs. host disease (GvHD), and promote healing and recovery. Unlike traditional pharmaceuticals, MultiStem cells are dynamically regulated, and have the potential to respond to signals of inflammation or tissue damage in multiple ways. Potential mechanisms of benefit include protection of damaged or injured cells, reduction of inflammation, stimulation of new blood vessels, and the recruitment of other cell types to promote tissue repair and healing.

Athersys claims that one of the benefits of the drug is that it can be scaled to be produced efficiently on a large scale. That could mean the drug could be made available to people on the same scale that traditional pharmaceuticals are. (Although I wouldn't expect the scale economies to translate into affordable prices).

Great news and looking forward to see what Pfizer brings to market. And in terms of bringing the product to market, here's a good excerpt from The Motley Fool ("Pfizer Swings for the Fences"):

MultiStem is being tested in several conditions, but Pfizer's license is specifically for the treatment of inflammatory bowel disease (IBD), a group of conditions that includes ulcerative colitis and Crohn's disease. The license is only costing Pfizer $6 million up front because the technology is still relatively unproven, having not entered clinical trials for IBD yet. Athersys can get milestones of up to $105 million and royalties as the drug passes through clinical trials and is commercialized.

Pfizer will pay for the phase 1 and 2 trials. Then, if it gets that far, Athersys will have the option of co-developing the drug -- sharing profits and losses -- or letting Pfizer proceed on its own and take the milestones and royalty payments.

Unlike traditional stem cell companies like Geron (Nasdaq: GERN) that are developing stem cells to regenerate tissue, MultiStem uses donated bone marrow cells to produce a product that promotes healing of the tissue through cell signaling. Essentially it has a more drug-like profile as the stem cells are cleared from the body.

So certainly a ways out.

Frankincense a Treatment for Crohn's?

Thought this article ("Frankincense and Myrrh: The Wise Men brought...healthcare?") was timely given it's the holiday season. Apparently frankincense has been studied as an anti-inflammatory and treatment for Crohn's disease. Here's an excerpt:

But frankincense (Boswellia serrata) is less commonly known as a traditional remedy. What does frankincense treat? It's been a remedy for children, and studied as an anti-tumor agent against bladder cancer. In terms of rigorous assessments, a British Medical Journal review of the data looked at all research results and found particularly notable "trials related to asthma, rheumatoid arthritis, Crohn's disease, osteoarthritis, and collagenous colitis. Results of all trials indicated that B. serrata extracts were clinically effective. Three studies were of good methodological quality. No serious safety issues were noted."

Maybe Santa will leave some in your stocking.

Autoimmune Disease Clusters and Crohn's

Happy Holidays! Saw this article (GWAS Meta-Analysis Supports Existence of Autoimmune Disease Clusters) today about a study conducted by Stanford University researchers. They were trying to see if there were any connections between different auto-immune diseases. Specifically, they looked at six autoimmune diseases - type 1 diabetes, rheumatoid arthritis, Crohn's disease, multiple sclerosis, autoimmune thyroid disease, and ankylosing spondylitis - and five non-autoimmune diseases to see if genetic factors related these diseases with each other.

The researchers did find that diseases go together. However, Crohn's is not related to any of these other diseases. Here's the excerpt:

Based on their analyses, the researchers suggest autoimmune diseases fall into at least two different groups: one containing rheumatoid arthritis and ankylosing spondylitis and another containing multiple sclerosis and autoimmune thyroid disease.

Meanwhile, they reported, type 1 diabetes resembled both of the groups to a certain extent, sharing characteristics with autoimmune thyroid disease but not multiple sclerosis. Crohn's disease, on the other hand, did not cluster with either group.

I suppose we're just in a category of our own =)

Crohn's blamed on lazy immune cells

Saw this article. Not necessarily anything new here.

It still wasn't clear, however, what caused the weakened immunity in the first place. So Segal's team focused on cells called macrophages, the immune system's whistle-blowers. In people with Crohn's disease, they found that macrophages secrete lower levels of cytokines, the chemicals that rally other immune cells to infection sites (Journal of Experimental Medicine, DOI: 10.1084/jem.20091683).

The team concluded that ineffectual rallying of immune cells in people with defective macrophages is what allows intestinal bacteria to run amok in the early stages of an infection, setting in motion the series of events that leads to Crohn's disease.

Johne's Disease (and MAP) in as Many as 70% of U.S. Herds

I saw an article today that shared some startling news about the spread of Johne's Disease. In the last 15 years (from 1996 to 2009), the prevalence of Johne's has increased from only 22% to as much as 70% of U.S. dairy herds. Johne's Disease is caused by the MAP bacteria (see previous blog posts), which many people have found links with to Crohn's Disease.

Here's an excerpt:

"Studies showed that in 1996, Johne's disease was in about 22 percent of the U.S. herds, but because of rapid expansion of herds across the country, producers unknowingly purchased young heifers and older cows which were infected with the disease and thus has raised the prevalence of Johne's to be present in nearly 70 percent of the herds," she said.

Could the recent rise in Crohn's Disease be linked to this rise in the spread of MAP?

Anti-TNF Drugs Don't Seem to Increase Cancer Risk

Good news for those that use TNF-blockers to manage their Crohn's disease. Long-term use of the drugs (at least for 6 years or less) does not appear to increase your risk of cancer. That's certainly a concern as TNF is part of the body's immune response in dealing with "tumor"-like cells. The study looked at both short and medium term use of these drugs for rheumatoid arthritis and didn't find any elevated risk of cancer.

UPDATE: (6/21/2010) - The FDA released a cancer warning for TNF-blockers back in August 2009. See this related post. Thanks to the anonymous person that commented!

Scientists Link Diet and Immune System

Saw this article about Australian scientists that found a "direct link" between diet and how the immune system functions. The scientists found that a specific short-chain fatty acid (created when bacteria breaks down dietary fiber) binds with an immune cell receptor to influence immune response. The article didn't provide many details on the exact findings, but they were hopeful that it could help explain how dietary changes could be a contributing factor in the rise of autoimmune disorders.

Here's an excerpt:

"When (immune cells) go bad they cause inflammatory diseases, so asthma, rheumatoid arthritis, inflammatory bowel disease ..." Prof Mackay said.

"We think one of the mechanisms for their normal control is short chain fatty acids binding to this receptor.

"And if we were to speculate on the real significance of this, we believe firmly that the best explanation for the increase in inflammatory diseases in western countries ... is our changes in diet."

A lack of dietary fibre could also be behind the rise in type 1 diabetes, Prof Mackay said.

The research suggests that having a healthy diet rich in fruits, vegetables, grains, nuts and seeds would reduce a person's risk of autoimmune disease.

Gut Bacteria Linked to Immune Response

Just read this article about a new finding of a bacteria linked to a specific immune response in mice. The bacteria induced higher Th17 response. The finding suggests additional bacteria to look at in the formation of autoimmune disease. Here's an excerpt:

If the effect is present in humans, it suggests a clinical use for the findings, Littman said. "So you can immediately see some practical application of this, if one can mimic the presence of these commensal bacteria to strengthen resistance to pathogenic microbes," he said.

On the other hand, the level of the microbes could also play a role in the development of autoimmune disease, he said. "You have to have the right balance," Littman said.

With hundreds of strains of bacteria, the "right balance" seems very difficult to find.

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!

Wildlife May Cause Livestock Infections of MAP

A study by Scottish researchers found a possible source of Mycobacterium avium paratuberculosis (MAP) infections in livestock -- wild animals. The transmission of infection may be from wild animals to livestock to humans.

DNA Test Results May Not Be As Reliable As They Appear

Just saw an article in the LA Times about how much you can trust new consumer DNA tests. The article highlights a recent experiment that compared the results of two of the leading vendors in this space, Navigenics and 23andMe. The experiment found that in some cases the two vendors conclusions about disease susceptibility was in agreement, but in others it was wildly different. The reason: each company uses different research studies to draw their conclusions. So, one might say that you have a 25% chance of developing Crohn's while the other says something higher. So although both companies do a great job of reading your DNA correctly, the determination of disease susceptibility is simply not a perfect science. In many cases, particularly those where definitive cause is unclear (like Crohn's), it's far from perfect and can generate very different results.

CD39 and Gene Variant Linked to Crohn's

Saw an article posted yesterday via WebMD about another potential genetic link found to Crohn's Disease. The gene variant, common in white people and those with European descent, causes a lower amount of the enzyme CD39 to be created in the gut. The enzyme dampens inflammation. Here's an excerpt:

All humans have a CD39 gene. But some have a version of the gene linked to lower CD39 levels. Friedman and colleagues identified a genetic marker for low CD39 production. They then looked for this marker in 1,748 patients with Crohn's disease and in 2,936 people without IBD.

They found that the genetic marker was significantly more common in people with Crohn's disease. Moreover, people without IBD were more likely to carry two copies of the high-CD39 gene, while those with Crohn's disease were more likely to carry two copies of the low-CD39 gene.

Genetics are not destiny. Not everyone with the low-CD39 gene has or will have IBD. Even having two copies of the gene only increases a person's risk of Crohn's disease by 27%.

But since about 40% of whites of European ancestry carry at least one copy of the gene, its effects across the entire population should be quite large.

It seems there may be many contributing factors to Crohn's. Perhaps that means it's an umbrella disorder with many possible causes (rather than one single cause).

Just Say No To Antibacterial Burgers

Read a good Washington Post article about the extreme use of antibiotics in our livestock and food supply. An astonishing 70% of antibiotics used in the US are used for the raising of livestock (primarily in disease prevention rather than treatment). That means were are steadily getting small doses of antibiotics through our food supply our entire lives. But those antibiotics lets us keep our food cheap and accessible for the masses, right? How could we eliminate it? I thought this excerpt was good:

There's also the argument that the pennies we're saving on each burger are being spent in our hospitals. A 2005 study out of Tufts University estimated that antibiotic-resistant infections add $50 billion to the annual cost of American health care. On the other side of the coin, a National Academy of Sciences study found that eliminating non-therapeutic antibiotics from animals would cost only about $5 to $10 per person per year. I'd pay that for a lower risk of super-staphylococcus.

That's very reasonable.

50% of Type 1 Diabetics Show Adverse Immune Response to Wheat

Saw this post on Celiac.com about a recent study in Ottawa that found that nearly half of people with Type 1 Diabetes showed an abnormal response to wheat proteins. Here's an excerpt:

Dr. Scott’s results offer the first suggestions that T cells

Small lymph cells created in the thymus which orchestrate the immune system\'s response to infected or malignant cells. Also known as T lymphocytes. T cells in the immune systems of type 1 diabetics are also more likely to have adverse immune reactions to wheat. His results also suggest that such over-reaction is tied to genes associated with type 1 diabetes.

According to Dr. Scott, the research suggests that "people with certain genes may be more likely to develop an over-reaction to wheat and possibly other foods in the gut and this may tip the balance with the immune system and make the body more likely to develop other immune problems, such as type 1 diabetes.”

Dr. Scott adds that the immune system has to find "the perfect balance to defend the body against foreign invaders without hurting itself or over-reacting to the environment and this can be particularly challenging in the gut, where there is an abundance of food and bacteria.”

In side comments that accompany the paper, diabetes expert Dr. Mikael Knip of Finland suggest that the team's results "add to the accumulating concept that the gut is an active player in the diabetes disease process.”

Nothing ultra-new here relative to previous studies that led to the SCD diet, but interesting to see this applied to Type 1 Diabetes.

Contamination of food products with Mycobacterium avium paratuberculosis: a systematic review

A study published back in March 2009 conducted a systematic review of previous studies of the potential threats to exposure to the MAP bacteria. Here's the abstract from the research:

Although a causal link between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease has not been proved, previous studies suggest that the potential routes of human exposure to MAP should be investigated. We conducted a systematic review of literature concerning the likelihood of contamination of food products with MAP and the likely changes in the quantity of MAP in dairy and meat products along their respective production chains. Relevant data were extracted from 65 research papers and synthesized qualitatively. Although estimates of the prevalence of Johne's disease are scarce, particularly for non-dairy herds, the available data suggest that the likelihood of contamination of raw milk with MAP in most studied regions is substantial. The presence of MAP in raw and pasteurized milk has been the subject of several studies which show that pasteurized milk is not always MAP-free and that the effectiveness of pasteurization in inactivating MAP depends on the initial concentration of the agent in raw milk. The most recent studies indicated that beef can be contaminated with MAP via dissemination of the pathogen in the tissues of infected animals. Currently available data suggests that the likelihood of dairy and meat products being contaminated with MAP on retail sale should not be ignored.

One of the tables that summarizes the rates of infection of MAP in livestock was pretty telling. In the US, rates of infection in herds ranged from 2% to 74%. Main take-away is that there is substantial risk to exposure to MAP in the US (and in most other countries - regardless of how developed they are).

Faces of Low Dose Naltrexone: New Book Explores Cutting-Edge Autoimmune Disease Treatment

I saw this blog post on About.com regarding an e-book that someone published summarizing many of the findings related to low-dose naltrexone (LDN). I haven't read through it yet, but just bookmarking it to review later.

This slide caught my eye while I was skimming through the document. It's a summary of the mechanism of how LDN works:

Urban Cluster of Crohn's Potentially Explained by MAP

I just came across a new research report published Sept 23, 2009 (Possible Transmission of Mycobacterium avium subspecies paratuberculosis through Potable Water: Lessons from an Urban Cluster of Crohn's Disease) that found a geographical cluster of people that developed Crohn's Disease.

Here's an excerpt that describes the clustering they found (only three people, but still warrants further research):

Despite the documented presence of MAP in tap water and its probable growth on tap water pipes, clusters of Crohn's disease have not previously been described in relationship to tap water pipes supplying patients' homes. This report describes three unrelated individuals who lived on the same block along a street in a midwestern American city and developed Crohn's disease within four years of each other in the 1960's. A common tap water pipe supplied their homes. This is the first reported cluster of Crohn's disease possibly linked to fully treated drinking water, and is consistent with previously reported clusters of Crohn's disease linked to an infectious microorganism in water.

The full article can be found here.

Foods For Healthy Weight Gain

Just read this post about how to gain weight when dealing with diseases like Crohn's. Obviously everything about eating pasta, rice, potatoes, and such won't quite work on the SCD diet. But I thought the calorie counts were very interesting. Here's the excerpt:

Plan to eat about 6 meals daily, and eat about 500 calories a day more than usual. Sugary products like milkshakes (which could be made with skim milk and low-fat ice cream), jellies, jams, cakes and cookies can accomplish that goal easily, short-term.

Eating a balanced diet and managing weight long-term should be done thoughtfully. You don’t want to only gain fat and no muscle. Any kind of SAFE dieting program suggests eating healthy foods while exercising, to keep the body at an ideal weight while building muscle.

Know your recommended weight for your height and body type. The average 165-pound man, between 19 to 24 years old, needs 3000 calories a day to maintain his weight. But, as we age, we need fewer calories, so that same man will only require 2700 calories daily from the age of 25 to 49. And even less beyond that.

An average woman, ages 19 to 24, will need 2100 calories daily to maintain a weight of 127 pounds. As she ages, up to 49, she will only need 1900 calories.

Good guidance. The article also mentions to work with a nutritionist along side your doctor. It's tough to get 3000 to 3500 calories a day on the SCD, but I suppose I'll have to find a way.

Is Soy Bad? Type 1 Diabetes and Leaky Gut

I came across a blog post about Type 1 Diabetes (again thanks to Google Alerts) where the author talks about why Soy is bad and how it may have contributed to the recent (i.e. last 30 - 40 years) growth in Type 1 Diabetes or other autoimmune disorders. I thought it was pretty interesting. The idea (regarding Type 1 Diabetes) is that soy damanges the gut mucosa, causing a leaky gut, thereby allowing large proteins (e.g. gluten) directly into the bloodstream where they cause an immune response around the body.

Now, I don't have Type 1 Diabetes so that's only partially interesting for me. But the process described in the post raises some interesting questions. One of the things mentioned was that there are diabetes related genes that have been found (and that have been present for decades), but recent environmental (or in this case diet) changes are making those genes get expressed more than they previously were. Could something similar be happening in Crohn's? I need to research leaky gut syndrome some more and perhaps it makes sense to continue broadening my research beyond Crohn's to other auto-immune disorders.

Fecal Bacteriotherapy

In reading through a recent report on the autoimmune disease treatment options (mostly from a market sizing perspective), I came across a therapy called fecal bacteriotherapy. The treatment is a last resort option for patients with pseudomembranous colitis or ulcerative colitis. The therapy is based on the premise that these diseases are caused by imbalances of bacteria in the colon or small intestine and so by transplanting fecal bacteria from a healthy individual (i.e. microflora from someone that doesn't have any GI issues) to an afflicted patient you restore the balance of bacteria in the gut. By introducing a "healthy" mix of bacteria, you can replace whatever pathogenic bacteria is there (e.g. Clostridium difficile in the case of pseudomembranous colitis) with healthy, probiotic bacteria. It's not unlike other probiotic therapies, but this one literally uses all the bacteria from a healthy person rather than just a subset.

I found this interesting for two reasons. One is that it's interesting to see a related disorder where they have pinpointed the bacterial agent that causes the disease. And second, it might be another last resort option for people for Crohn's or UC.

SCD Website - "No More Crohn's For Me"

Came across this website sharing best practices (recipes, etc.) for he Specific Carbohydrate Diet.

Vitamin D and Why Immunosuppressants May Be Counterproductive

I just saw a post from the Napa County Science News Examiner (thank Google Alerts for that) commenting on an upcoming research paper that will be published in the September issue of "Annals of the New York Academy of Sciences" regarding Vitamin D's role in auto-immune diseases. The post talks about a recent research paper that discusses why Vitamin D may be even more important for women than in men (and could also explain higher rates of auto-immune diseases in women). The paper found that women have a higher number of Vitamin D receptors in their body, in particular in the endometrial cells (lining of the uterus). When Vitamin D binds with these receptors, many genes are expressed that help kick-up the immune system.

Here's an excerpt:

The key to how vitamin D plays its part is to understand what the VDR does. When the correct form of vitamin D (a form known as 1,25-D or calcitriol) binds to VDR, VDR then directly causes the expression of over 900 genes to occur. Two of the genes that are turned on produce proteins that are directly responsible for kicking the immune response into active mode. The reason for VDR in the endometrium is that it provides protection against infection for the developing fetus.

Another key to the puzzle has been the growing evidence that bacteria may play a role in the development of autoimmune disease. If so, why wouldn’t women, who have more VDRs, be better off than men? The problem is that bacteria of various kinds can interfere with VDRs and prevent vitamin D from binding. If vitamin is unable to bind, then the immune response is disrupted. Not only is the immune system affected, but thyroid hormone problems can result too.

There are many clear links that have been established between Crohn's and bacteria. However, this finding could point to why immunosuppressants could be hurting rather than helping the problem. Here's another excerpt:

Although these results do not provide a clear path to treatment, “the potential role of persistent pathogens in autoimmune disease mandates reconsideration of the use of corticosteroids as a first-line treatment for many autoimmune diseases. Corticosteroids effectively reduce the ability of the immune system to respond to pathogens, including persistent microbiota, which is counterproductive to recovery.”

This would suggest that Vitamin D supplementation, particularly in women, is important in recovery. Plus, it really calls into question usage of corticosteroids as a treatment for Crohn's.

With all that said, though, you don't want too much Vitamin D apparently. Another study (from 2004) conducted at UCLA found that people with Crohn's had very high levels of Vitamin D in their blood. The high Vitamin D level (contrary to what you would think) actually causes loss of bone density, which could lead to osteoperosis. Here's the excerpt:

ISLAMABAD: Contrary to expectations, people with the inflammatory bowel condition Crohn’s disease are likely to have excessive levels of the active form of vitamin D in their blood, researchers have found. This is associated with low bone mineral density, they report.

Dr. Maria T. Abreu from the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center in Los Angeles led the study. She told Reuters Health, "Most doctors think that Crohn’s patients automatically have decreased vitamin D levels and encourage supplementation with vitamin D. We would like to urge doctors to check vitamin D levels before making that recommendation."

As Abreu’s team explains in the medical journal Gut, under certain circumstances too much active vitamin D can actually contribute to the breakdown of bone, leading to osteoporosis. The researchers found "inappropriately high" blood levels of the active form of vitamin D in 42 percent of the 138 people they studied with Crohn’s disease. This was true of only 7 percent of 29 patients with ulcerative colitis, another type of inflammatory bowel disease.

Also, the higher the blood levels of active vitamin D in Crohn’s patients, the lower was their bone density -- regardless of whether they were treated with steroids -- the investigators found. "We believe that high vitamin D levels are most likely a manifestation of the underlying gut inflammation," Abreu said. A high vitamin D level is "an additional risk factor predisposing to development of osteoporosis" for some Crohn’s disease patients, the team concludes. Treatment of the underlying inflammation, "may improve metabolic bone disease."

I suppose it's a mixed verdict then. But at the very least it's worth getting your Vitamin D level checked to see where you are and then only supplement if necessary.

Rifaximin (Xifaxan) Antibiotic Used to Treat Crohn's

Rifaximin

I came across a drug called Rifaximin (Xifaxan) via a post about IBD drugs in the pipeline in the About.com IBD blog.

The drug has been around and used for over 20 years to treat travelers' diarrhea. The drug is an antibiotic that works exclusively in the GI tract and does not enter the bloodstream. Here's the excerpt from the About.com blog that comments on its efficacy:

Rifaximin (Xifaxan) is currently being studied for use in treating severe Crohn’s disease. This drug, manufactured by Salix Pharmaceuticals, is an antibiotic currently approved for use in traveler’s diarrhea. Rifaximin is not absorbed into the bloodstream like other antibiotics, but instead affects the digestive tract directly. The theory is that intestinal bacteria may have a connection to the inflammation in Crohn’s disease, and an antibiotic may be effective if it kills these bacteria.

In a 16-week study of rifaximin, 78 percent of the patients with Crohn’s disease experienced an improvement in their disease, and 59 percent went into remission.

This drug is also being studied for use in treating pouchitis, a complication that can occur after j-pouch surgery. In one study, 11 patients for whom other therapies had failed received either 400 mg of rifaximin twice a day or 200 mg three times a day -- both groups showed improvement.

I investigated the efficacy of this drug a bit more in terms of its use for Crohn's. I came across a website where folks post their experiences with drugs. There were two pages that were relevant, one for primary treatment of Crohn's and the other (with more responses) regarding maintenance of Crohn's.

From reading through the reviews, it appears that the drug provides quick relief of symptoms, but that relief appears to be temporary if you stop taking the drug (and even if you continue taking it). One person, for instance, went on a regimen combining Xifaxan, probiotics, and Boswellia serrata. Here's an excerpt from that person's experience I thought was worth capturing:

Xifaxan for Crohn's I take this med for Crohn's disease, my doc is trying it although it isn't a "recognized" Crohn's drug yet. I take 2-200mg pills twice a day. It is very easy to take, coated tablets do not taste bad although they are on the larger side. I do not feel nauseous on them or anything, no side effects at all. Can be taken with or without food. After 24 hrs on this (two doses) I had my first solid "BM" in a very long time, it worked like a charm. It continued to work for 4-5 days when I started getting BMs more frequently and less solid. I realized that this is probably killing off the good bacteria so I started supplementing with a several-strain probiotic which has helped (I take the probiotics between the doses of Xifaxan, not at the same time which would be useless).

One huge drawback of this medicine is the cost. My insurance has told me they won't cover it, so I am in the process of appealing that and hopefully they will cover it because a one month's supply costs $1100.00. Nope I'm not kidding. There is no generic.

Overall I think it has done me some good and hopefully my results will continue to be positive. Looking forward to reading about other people's experiences with this drug.

**Update 6/26/05

I have continued taking this drug along with Boswellia serrata capsules, probiotics, and a multivitamin and as of 2 days ago I was officially in remission! I am very pleased with the results and would encourage others to try it. Please read my rating on boswellia too because I truly believe that boswellia had a big impact on my remission as well as this antibiotic. Also, my insurance did eventually cover the entire cost of this medicine but my dr had to send a letter before they would do it.

Another person combined use of the Xifaxan with the Specific Carbohydrate Diet and probiotics and seemed to have positive results as well:

I was diagnosed with Crohn's disease in 2002. Since then I have tried just about everything to cure myself of this disease. Through my journey I have discovered that the Specific Carb Diet combined with a course of Xifaxan and high quality six strain probiotics (powder form) from customprobiotics.com has put me very close to remission. The first few days in Xifaxan caused severe painful bloating (die off of the bad bacteria) and then I was ok. You must stay way from bad carbs (ie. sugar, bread, cereal) and dairy if you want to get well.

The drug, combined with other regimens, certainly appears to have promising results and hence warrants further investigation. However, the use of antibiotics long-term is rather disconcerting to me. My assumption is that you need more than just a few strains of probiotics in your intestines to be really healthy (e.g. creation of Vitamin K). Can you really live your entire life taking antibiotics?

A Link Between Food Poisoning and Crohn's

Another one I saw off of the About.com IBD blog (post). A recent study conducted in Denmark found a connection between certain types of food poisoning and increased rates of IBD.

Here is the excerpt:

Increased Risk of Inflammatory Bowel Disease After Salmonella or Campylobacter Gastroenteritis: A Population-Based Study (Abstract #80)

Researchers in Denmark have discovered a link between inflammatory bowel disease (IBD) and an initial bacterial infection with either salmonella or campylobacter gastroenteritis, an important step in understanding the development of IBD that may help explain the increasing incidence of IBD over the past decade.

Denmark’s system of tracking its citizens with individual identification numbers allowed researchers to examine patient interaction with the health-care system over a 15 year period. Investigators examined how many patients in a control group would develop IBD and compared them with those who have been exposed to bacteria in the past. They found that over 15 years, three times as many patients who had been exposed to bacteria later developed IBD as those who had not been exposed.

“This is the first time we are able to make such a clear association with an initial exposure to bacteria and subsequent development of IBD in the long term,” said Nielsen Henrik, MD, professor of infectious diseases at Aalborg Hospital in Denmark. “Our research has important implications for food safety and disease prevention. If we can reduce and prevent the spread of food bacteria and infections, we may reduce or even largely eliminate IBD in the long term.”

Dr. Nielsen is hopeful that further research will go beyond the association between bacteria exposure and IBD established in his study and attempt to prove causality by studying in detail the biology of individual patients.

I find this very interesting as I was recently thinking about several severe bouts of food poisoning I had about 5 years before being diagnosed with Crohn's. Such episodes would no doubt have some impact on the microflora in your gut.

A possible link here could be that those severe bacterial infections caused dysbiosis or some other imbalance of bacteria in the gut - perhaps killing off some good bacteria that helped to regulate the immune response in the gut. Over time, the problem that was introduced at that point compounded (or at least makes you susceptible) to other bacteria or pathogens that cause of the problem.

Cases of Crohn's Rising in Scotland, Canada (Ontario), and Northern France

I read three posts in the About.com IBD blog about recent epidemiology studies pointing to rising cases of Crohn's in Scotland and Ontario, Canada. Also came across a study that showed rising cases in youth (0 - 19 yrs) in Northern France.

Here's the post about Scotland:

Scotland Has High Incidence of Pediatric IBD

Monday July 13, 2009

Researchers in Scotland are puzzled by the dramatic increase of pediatric cases of inflammatory bowel disease (IBD) in recent years. IBD is increasing all over Europe, but the 4-fold increase in Crohn's disease in Scotland has been the most dramatic. Scottish researchers are currently recruiting for a new study to determine what may be causing the rise in IBD cases. The research will focus on the role bacteria may play in the onset of IBD. The BISCUIT (Bacteria in Inflammatory bowel disease in Scottish Children Undergoing Investigation before Treatment) Study is underway at the Royal Aberdeen Children's Hospital, with plans to expand to hospitals in Dundee, Edinburgh, and Glasgow.

And here's the post about Ontario:

Increased Rate of IBD in Ontario Children

Monday August 10, 2009

A new population-based study has shown that the rate of inflammatory bowel disease (IBD) in children in Ontario, Canada is increasing. The rate of IBD in children under the age of 18 increased from 42.1 per 100,000 in 1994 to 56.3 per 100,000 in 2005. The most striking increases occurred in preschool and school-aged children. The rates in pre-teens and teenagers showed no significant change. The authors stress that even at the increased rate, IBD is still considered rare in children.

It's already known that Canada has a very high rate of IBD, and especially pediatric IBD. The authors of this study indicate that the high immigration rates from south Asia to Ontario may be partly responsible. Research has shown that Asian immigrants to Ontario have a higher risk of developing IBD. The theory is that being exposed to the Western environment increases the likelihood of developing IBD.

And a much earlier post about Canada in general:

O Canada! Why So Much IBD?

Monday November 20, 2006

Inflammatory bowel disease (IBD) is known to be a “western” disease. In other words, it largely affects people who live in western societies. Canada appears to be a hotbed for IBD. Crohn’s disease appears to be particularly prevalent, with 13.4 per 100,000 people in Canada having the disease. In the United States, about 10 people per 100,000 have IBD. An estimated 0.5% of all Canadians have one of the two major forms of IBD. What can explain this?

The theory is that it’s the cold. The cold temperatures create a “sterile” environment which is inhospitable to bacteria. It is thought that when children are raised in an environment where they are exposed to too few bacteria, the risk of IBD is higher. Low exposure to bacteria can also occur in “too hygienic” conditions as well as cold climates.

The authors of the study published in American Journal of Gastroenterology that reported these findings indicate that hygiene and other factors may influence the development of IBD. They stress, however, that the exact cause(s) of IBD are not yet clear.

I thought the second (highlighted) paragraph in the last post was interesting. I have read elsewhere that rates of IBD are higher in northeastern areas. That's an interesting explanation for why it might be the case. Also, it could also be interesting to test dairy products in those regions to see if there is an increased presence of MAP.

Here's the text of the final study about children in Northern France:

The Changing Pattern of Crohn’s Disease Incidence According to Age in Northern France: A Constant Increase in the 0-19 Years Age Group (Abstract #114)

A population-based study of residents in northern France finds that the incidence of Crohn’s disease (CD) is on the rise, most dramatically among young people less than 19 years of age. The findings raise a number of questions about the likely causes of the increase, which the investigators say could be related to environmental factors.

Investigators from the EPIMAD registry in France tracked rates of CD among nearly six million patients in northern France between 1988 and 2005. They found that the incidence of CD among all patients increased 20.7 percent but that rates had stabilized 10 years into the study. Among young people less than 19 years of age however, the incidence of CD increased linearly by 48.5 percent.

The cause of the increased incidence of CD among young people is unknown, but investigators say aggravating factors like environmental pollution and changes in diet or smoking habits could be culprits.

“Since we now know that CD disproportionately affects young people, future studies to uncover its cause should focus on this age group,” said Guillaume Savoye, MD, EPIMAD registry and department of gastroenterology, University Hospital, Rouen, France.

All very interesting (and yet troubling) trends.

Additional Genes Linked to Crohn's - IL23R and 30 Others

Saw two posts on an About.com IBD blog (post one, post two) about new studies that found several genes that could be linked to Crohn's Disease. The first study pointed to the IL23R gene. The second study pointed to over 30 possible genes. It's seems to be unclear at this point how these genes are expressed in the body to contribute to the disease, but I assume that's the next step.

Microbial Symbiosis (e.g. B. fragilis) May Prevent Intestinal Inflammatory Disease

As discussed in previous posts (see Reduced Diversity of Faecal Microbiota in Crohn's Disease, Localized Dysbiosis of lactobacilli and the Clostridium leptum Subgroup May Be Related to UC, Lack of Faecalibacterium prausnitzii Bacteria May Contribute to Crohn's), imbalances or reduced numbers of certain types of bacteria in the gut have been linked to Crohn's disease.

A further example of this was demonstrated by researchers in regard to the Bacteroides fragilis bacteria. When the bacteria was not present in the gut and a pathogenic bacteria, in this case Helicobacter hepaticus, was introduced, intestinal inflammation was induced. The B. fragilis bacteria produces Polysaccharide A (PSA), which suppresses the inflammatory response of the immune system (by suppressing IL-17 production).

With hundreds of bacteria in the gut, it's unclear which ones are needed to have a "normal" balance. And it's also unclear what is "normal" based on genetic pre-disposition. Nonetheless, it does highlight the need for further investigation into how all of these bacteria interact and how exposure, diet, and other factors can influence the balance of those interactions.

Myoconda (Anti-Biotic) Kills MAP as a Treatment for Crohn's

A follow-up to my last post about the body of evidence pointing towards MAP as a contributing cause to Crohn's, I came across a commercial anti-biotic being used in the treatment of the disease. The drug, Myoconda, is a combination of three already used and registered anti-biotics. More from the manufacturer's website (Giaconda Ltd):

Myoconda®, the Company’s therapy for the treatment of Crohn’s Disease is a combination of three registered antibiotics - rifabutin, clarithromycin and clofazimine. These three drugs are widely marketed world-wide for the treatment of mycobacterial and other infections. Myoconda® presents these three compounds in a specific patented combination.

Myoconda® is based on the proposition that Crohn’s Disease is caused by infection. Prof. Borody has long been at the forefront of this approach, which is gaining increasing acceptance among gastrointestinal specialists worldwide. Prof. Borody has published significant data demonstrating that patients treated with Myoconda®’s antibiotic combination experience long-term remission of clinical symptoms and inflammation, some for up to nine years.

The results of a Phase II clinical trial of Myoconda®, conducted at the Centre for Digestive Diseases (CDD), were published in 2002. This was followed up with a full retrospective analysis of all CDD Crohn’s patients treated for at least six months with anti-MAP therapy. This analysis of 52 patients demonstrated a remission rate of 65% with a clinical response of almost 95%. These results exceed those of any Crohn’s therapy on the market by major margins.

Myoconda's Investigational New Drug (IND) application was approved by the US FDA in April 2007, allowing it to proceed with Phase 2/3 trials of the drug. It doesn't quite seem to be the silver bullet yet, but certainly is a very promising start.

Link Between Mycobacterium avium paratuberculosis (MAP) Bacteria and Crohn's

Someone on one of the HealingWell.com message boards was pretty passionate about a strong link between a bacteria called Mycobacterium avium paratuberculosis (MAP) and Crohn's Disease. The bacteria is found in milk and beef from cows and is known to cause a very similar disease (in terms of symptoms) in cows called Johne's Disease.

Here's an excerpt about Johne's Disease and how people may get exposed to MAP:

The microorganism, mycobacterium avium subspecies paratuberculosis, has been established in the veterinary literature to be the cause for Johne's disease, a disease causing colitis in cattle, sheep, and subhuman primate species. This disease resembles, clinically, Crohn’s disease in humans and acts very much the same. Studies in England and in Wales have shown the presence of mycobacterium paratuberculosis in milk and water supplies. It is known that infected cows secrete this bacteria in milk and hence, milk borne infection appears to be theoretically possible.

Here's an excerpt from a Science Daily article (Dec 2007):

It is thought that the Mycobacteria make their way into the body’s system via cows’ milk and other dairy products. In cattle it can cause an illness called Johne's disease - a wasting, diarrhoeal condition. Until now, however, it has been unclear how this bacterium could trigger intestinal inflammation in humans.

Professor Jon Rhodes, from the University’s School of Clinical Sciences, explains: “Mycobacterium paratuberculosis has been found within Crohn’s disease tissue but there has been much controversy concerning its role in the disease. We have now shown that these Mycobacteria release a complex molecule containing a sugar, called mannose. This molecule prevents a type of white blood cells, called macrophages, from killing internalised E.Coli.”

Scientists have previously shown that people with Crohn’s disease have increased numbers of a ‘sticky’ type of E.coli and weakened ability to fight off intestinal bacteria. The suppressive effect of the Mycobacterial molecule on this type of white blood cell suggests it is a likely mechanism for weakening the body’s defence against the bacteria.

Professor Rhodes added: "We also found that this bacterium is a likely trigger for a circulating antibody protein (ASCA) that is found in about two thirds of patients with Crohn's disease, suggesting that these people may have been infected by the Mycobacterium."

MAP could release mannose (a sugar that acts as an immune inhibitor), which could then allow other bacteria to get overgrown (e.g. E. Coli).

Given today's milk processing, you might think that the pasteurization process would kill all bacteria in retail sold milk, including MAP. So how could someone ever be exposed to this type of bacteria in the first place? You'd be wrong, though. An excerpt from a Canada.com article commenting on milk in the U.S. and the possible link between MAP and Crohn's mentions how 3% of US retail milk has live MAP bacteria:

As part of his research, Dr. Rioux is focusing on the MAP bacteria. He believes it's plausible the bacteria may be a trigger for Crohn's disease. A recent study showed it was present in the intestines of some Crohn's patients.

"It found there was a significant association, finding this mycobacterium in Crohn's patients versus those who do not have Crohn's disease...we can see the footprints of this organism associated with Crohn's disease, but we can't really prove it's at the scene of the crime so to speak," adds Dr. Rioux.

The Dairy Farmers of Canada says a Guelph, Ontario study in 2002 found the bacteria in Ontario milk, though it wasn't alive. Yet a 2005 study in the United States did find live bacteria in almost 3% of retail milk sampled.

"It can survive pasteurization in a limited number of samples, and only in low numbers, so that would not explain the high numbers of Crohn's disease patients we have in the developed world at all," says Barkema.

The Food Directorate of Health Canada calls MAP an "emerging organism of concern." At a recent meeting in Ottawa, it called for more research and testing of food products, to see just how often MAP is found in the products we consume.

Other theories about milk actually go even further, suggesting that any bacteria presence, dead or alive, can contribute to Crohn's disease. Even the bacteria that are killed during the pasteurization process still cause problems. Apparently, although the bacteria are dead, the cell walls and remnants of the bacteria are still present in the milk. These fragments would most certainly be present throughout your GI tract as well as around the body due to leakage through the intestinal wall and circulation around the body via the blood-stream. For example, the fragments could get lodged in your joints in your hands, leading to an immune response there, which would cause arthritis.

There do appear to be some trials being conducted to use antibiotic mixes to kill the MAP infection. Worth looking into more.