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 =)