Bacteria Identified That May Lead To IBD

[JLH]

Bacteria Identified That May Lead To Inflammatory Bowel Disease In Genetically Susceptible Individuals
17 Sep 2010

Certain bacteria that inhabit the intestine provide the environmental trigger that initiates and perpetuates chronic intestinal inflammation in individuals who are genetically susceptible to inflammatory bowel disease (IBD), a study led by Harvard School of Public Health researchers has found.

Inflammatory bowel disease results from a loss of homeostasis, or balance, between the immune system and the microbes that inhabit the intestine. "In this study, we identified two microbes that instigate gut inflammation that leads to inflammatory bowel disease in mice," said lead investigator Wendy Garrett , assistant professor of immunology and infectious diseases at HSPH. "We show using both metagenomic and conventional culture techniques that an individual's genetic background influences what bacteria reside within his or her intestine. Several studies are currently underway examining the intestinal microbial communities of patients with IBD and we are looking forward to exploring the role of the Enterobacteriaceae we have identified in patients with IBD."

The study appears in the September 16, 2010, edition of Cell Host & Microbe.

IBD is a chronic inflammatory disorder that afflicts 1.4 million persons in the US and the incidence is rising around the world. Not only is IBD a devastating and debilitating chronic illness, it is also one of the three highest risk factors for the development of colorectal cancer. There are two principal forms of IBD: Crohn's disease and ulcerative colitis. Approximately 30,000 new IBD cases are diagnosed each year in the U.S.

Whether IBD is caused by individual species of bacteria or disruptions of entire microbial communities remains controversial, said senior author Laurie Glimcher , Irene Heinz Given Professor of Immunology at HSPH. "Our findings suggest that answer bridges both hypotheses--specific species of bacteria (Klebsiella pneumoniae and Proteus mirabilis) appear to work in concert with the indigenous gut microbial community to cause IBD."

This work was supported by the National Institutes of Health, Danone Research and the Crohn's and Colitis Foundation of America, plus career development awards from the Burroughs Wellcome Fund and the NIH.

"Enterobacteriaceae Act in Concert with the Gut Microbiota to Induce Spontaneous and Maternally Transmitted Colitis," Wendy S. Garrett, Carey A. Gallini, Tanya Yatsunenko, Monia Michaud, Andrea DuBois, Mary L. Delaney, Shivesh Punit, Maria Karlsson, Lynn Bry, Jonathan N. Glickman, Jeffrey I. Gordon, Andrew B. Onderdonk, and Laurie H. Glimcher, Cell Host & Microbe 8, 292-300, September 16, 2010.

Source:
Harvard School of Public Health

[Polly]

Interesting, Joan.

Many here have long suspected an infectious cause. Maybe this explains why Cipro is so helpful to MCers.......Cipro is very effective against both Klebsiella pneumoniae and Proteus mirabilis!

Love,

Polly

[tex]

As Polly suggested, I'm not sure that those researchers have come up with any profound discoveries in that project, at this point. They appear to have verified that two distinct species of bacteria can cause IBD, (confirming most people's suspicions), but that's probably just scratching the surface. They almost surely artificially induced the conditions which caused the inflammation, rather than "discovering" it in a natural setting, so that still leaves open the question of whether that mechanism actually occurs in normal life, (from a technical viewpoint).

It's certainly a step in the right direction, though. Now if they'll just check out all the rest of those enterobacteriaceae, ( ), to see how many more of them are also guilty of disorderly conduct.

OK, this statement got me started thinking:

Approximately 30,000 new IBD cases are diagnosed each year in the U.S.

That's only about 10 per 100,000 in the general population.

Let's do some math. The research article cited above claims that the (annual) incidence of IBD is 30,000 in this country. CCFA says that the prevalence, (overall), of IBD in this country is 149 per 100,000. The Cleveland Clinic says:

The prevalence of ulcerative colitis and Crohn's disease ranges from 10 to 70 per 100,000 people, but some North American studies have shown a prevalence as high as 200 per 100,000 people.

http://www.clevelandclinicmeded.com/med ... ase/#s0015

That's based on two somewhat dated references. Anyway, why the CCFA arbitrarily selected 149 as the magic number, (rather than 150, for example), is beyond me, but if we use 150 per 100K people in the general population, then apparently, prevalence is related to incidence by a factor of 5. IOW, total prevalence is approximately 5 times the annual incidence of newly diagnosed cases. To me, that number seems low - it suggests that either patients only live for 5 years after diagnosis, or the diagnostic rate is rapidly increasing, with each passing year, (which is probably true, but I doubt that it's increasing that rapidly for Crohn's and UC). Whatever the case, I see no reason why that number cannot be used as a "ballpark figure" to relate prevalence to incidence for MC, as well.

I have no idea what an accurate estimate of the current incidence and prevalence numbers for MC might be, but outdated statistics, (from 15 to 20 years ago), show a prevalence of roughly 10 per 100K, for the combined statistics on the various forms of MC. Using a factor of 5, that would suggest an annual incidence of approximately 2 per 100K, or a total of approximately 6,000 new cases of MC per year, in the U. S.

Hmmmmmmmmm. That's 20% of the total incidence of Crohn's and UC in this country, which is certainly not an insignificant number, by any means, and that's based on obsolete numbers for MC. Considering the current rapidly escalating diagnostic rate for MC, there is little question that MC is far, far more prevalent that the out-of-date statistics would indicate. In fact, MC is probably closer to at least 10 times more prevalent than the obsolete numbers suggest. If that's reasonable, then there are probably at least 60,000 cases of MC being diagnosed in the U. S., annually, today. Well Doh! That would be twice as many cases as the combined diagnostic rates of Crohn's and UC.

So why do all the major support organizations, and major medical institutions, continue to pretend that MC is such a rare disease, that they don't even bother to include it in IBD statistics? As I pointed out in another post, obviously, a working knowledge of elementary mathematics is not a highly-esteemed asset of the mainstream medical community. Shame on them.

Or maybe they're just too lazy to redo all their statistics, and all their websites, in order to correct their obvious mistake.

Tex

[Zizzle]

I too have always suspected an infectious cause to MC. I certainly fit that profile. I also had short-term remission while on Keflex. Makes me wonder whether they might develop a highly specific antibiotic someday to treat the disease. Much like the folks with RA being treated with Minocycline with great results. Thousands of patients have reported successfully using antibiotics for conditions including rheumatoid arthritis, scleroderma, juvenile rheumatoid arthritis, lupus, dermatomyositis, ankylosing spondylitis, Lyme disease, Reiter's syndrome, mixed connective tissue disease, fibromyalgia and psoriatic arthritis.

I actually think most autoimmune diseases are a response to some stealth bacterium or virus in our system that our labs simply can't identify. Perhaps mycobacteria that lack cell walls.

[tex]

Perhaps mycobacteria that lack cell walls.

I believe you're thinking along productive lines. That would likely be mycobacterium avium subspecies paratuberculosis, (MAP). Am I right? Have you seen any of our previous discussions on MAP? If you haven't, you may find these to be interesting:

http://www.perskyfarms.com/phpBB2/viewt ... berculosis

http://www.perskyfarms.com/phpBB2/viewt ... berculosis

http://www.perskyfarms.com/phpBB2/viewt ... berculosis

There are other threads that can be found by searching the archives, but I believe that these three may be the most interesting.

We're always interested in seeing new information on this topic, if you happen to be aware of any.

Tex

[Joefnh]

Thanks for posting that Joan. I have read similar studies related to Crohns disease as well. The question would be if the bacteria was removed with antibiotics would the disease still be present? or is it once the genes are expressed they remain 'turned on'

--Joe

[Zizzle]

Tex,
Yes, I am a believer in the possibility of the MAP doomsday scenario. I think we are seeing it playing out, as evidenced by the explosion of autoimmune conditions, and the fact that many sufferers are getting relief from antibiotics.

Joe,
I don't think antibiotics can cure the disease, because MAP is so stealthy. You can kill many, but you will never kill them all, so you stop taking the antibiotics and the bacteria repopulate. Same goes for probiotics and gut flora. You must continue taking them to maintain the proper balance of healthy bacteria. If you could eradicate the bug, and take the steps necessary to heal the damage caused by it, I think you could cure the disease. However, in our case, I think the food intolerances would persist forever, because the food proteins passed through the gut during the inflammatory "leaky gut" stage and activated the immune response against those proteins. I also think this is why so many here have growing lists of food intolerances. If your gut is inflamed and leaky, you are constantly presenting food proteins to the bloodstream and the immune system. Eventually we may all end up intolerant to rice and chicken!!

Given my previous short-term remission while on antibiotics, I plan to research this further and find out if anyone from the Roadback Foundation has had success using their protocol on IBDs.

www.roadback.org

[Zizzle]

I FOUND A SMOKING GUN!!!

Today on Medscape (you have to sign up to read the whole story). I've posted the intro, but here's my BASIC analysis:

"Patients receiving anti–tumor necrosis factor-α (anti–TNF-α) therapy are at increased risk for tuberculosis and other granulomatous diseases" BECAUSE...THEY ALREADY HAVE THE INFECTION!!! RA patients (or Crohn's) take an immune suppressing drug and eventually the non-detectable mycobacteria causing their rheumatic disease replicate in such huge numbers that they can finally be identified. Unfortunately, they are very sick by then. IMHO, these researchers totally missed the boat by calling this an opportunistic infection. The infection is already there!

In the discussion:
"Alternately, given the slow progression and insidious nature of pulmonary NTM disease, some of the patients in this series likely had existing but undiagnosed pulmonary NTM disease before starting their anti–TNF-α therapy. This likelihood raises the question whether patients should be screened for NTM disease before initiating anti–TNF-α therapy" Well, DUH!!



From Emerging Infectious Diseases
Nontuberculous Mycobacteria Infections and Anti–Tumor Necrosis Factor-α Therapy
Kevin L. Winthrop; Eric Chang; Shellie Yamashita; Michael F. Iademarco; Philip A. LoBue


Posted: 02/16/2010; Emerging Infectious Diseases. 2009;15(10) © 2009 Centers for Disease Control and Prevention (CDC)


Abstract
Patients receiving anti–tumor necrosis factor-α (anti–TNF-α) therapy are at increased risk for tuberculosis and other granulomatous diseases, but little is known about illness caused by nontuberculous mycobacteria (NTM) in this setting. We reviewed the US Food and Drug Administration MedWatch database for reports of NTM disease in patients receiving anti–TNF-α therapy. Of 239 reports collected, 105 (44%) met NTM disease criteria. Median age was 62 years; the majority of patients (66, 65%) were female, and most (73, 70%) had rheumatoid arthritis. NTM infections were associated with infliximab (n = 73), etanercept (n = 25), and adalimumab (n = 7); most patients were taking prednisone (n = 68, 65%) or methotrexate (n = 58, 55%) concurrently. Mycobacteria avium (n = 52, 50%) was most commonly implicated, and 9 patients (9%) had died at the time their infections were reported. A high rate of extrapulmonary manifestations (n = 46, 44%) was also reported.

Introduction
Nontuberculous mycobacteria (NTM) are a large, diverse group of environmental organisms ubiquitous in water and soil.[1] They cause a variety of diseases in humans, notably severe, protracted lung disease in patients with underlying lung disorders. Conditions such as bronchiectasis, emphysema, previous tuberculosis (TB) or other lung infections, cystic fibrosis, rheumatoid arthritis, and other chronic diseases with pulmonary manifestations can predispose a person to NTM pulmonary disease.[2] In addition to lung infections, NTM cause skin and soft tissue infections, lymphadenitis (predominantly in young children), and disseminated disease in HIV-infected patients or others with severely compromised immune systems. The immunologic mechanism and related dysfunction that predispose persons to NTM disease are largely unknown, although defects in interleukin-12 or interferon-γ production are known to increase the risk for disseminated NTM disease in humans.[3]

Although the epidemiology of NTM disease is not well described, the belief that these infections are increasing in prevalence, particularly among women, is widespread.[2] Assessment of the epidemiology of these infections may be increasingly useful because newer forms of biologic, immunosuppressive therapies have become widely used for treating patients with rheumatoid arthritis, Crohn disease, and other autoimmune inflammatory conditions. Many of these conditions are associated with lung manifestations known to be associated with NTM pulmonary infections.[2]

To date, TB and NTM infections and concurrent biologic therapies that inhibit tumor necrosis factor-α (TNF-α) have been reported. These therapies include infliximab (Remicade; Centocor, Malvern, PA, USA), etanercept (Enbrel; Immunex, Seattle, WA, USA), and adalimumab (Humira; Abbott Biotechnology, Abbott Park, IL, USA), which have been approved in the United States and elsewhere to treat patients with rheumatoid arthritis and selected other autoimmune inflammatory diseases.[4] Because TNF-α is integral to granuloma generation and maintenance,[5,6] patients using these agents are at increased risk for granulomatous infections, including activation of latent TB infection.[7,8]

The US Food and Drug Administration (FDA) postmarketing surveillance system (MedWatch) (www.fda.gov/medwatch) collects voluntary reports of adverse drug events from physicians. The most recent review of this system in 2004 for reports of granulomatous infections that occurred during TNF-α blockade found that mycobacteria disease was more common than other granulomatous diseases; TB was reported 5–10× more frequently than NTM, dimorphic fungi, and other intracellular infections in this setting.[7] (Although this program does not specifically target participation outside the United States, it also includes nondomestic case reports.) Subsequently, much attention has been focused on prevention of TB in patients who are using anti–TNF-α agents. To date, little is known regarding the types and relative frequencies of NTM infections that occur in such patients.

We recently conducted a survey among infectious disease physicians within the Emerging Infections Network of the Infectious Diseases Society of America (IDSA). This survey suggested that cases of NTM disease associated with anti–TNF-α therapy occur twice as frequently as cases of TB associated with anti–TNF-α therapy in the United States.[9] NTM infections are likely underreported to the FDA, relative to TB, for a variety of reasons.[10] NTM disease is generally insidious, sometimes difficult to diagnose, and is not reportable to health authorities. Accordingly, we reviewed the MedWatch database for NTM reports through January 1, 2007, to evaluate whether these case reports met clinical case criteria, to describe their clinical spectrum and outcome, and to evaluate the relative reporting frequency of cases among the different anti–TNF-α agents now in widespread use.

http://www.medscape.com/viewarticle/715794_4

[tex]

Zizzle,

I think you're right. They're slow to change, normally, and difficult to detect.

Good work,
Tex

[hoosier1]

So would a GI focused drug like Rifaximin, given for travelers diarrhea and sometimes to people with IBS, be indicated for MC? I know that Chron's patients get it on occasion.

Years ago, in my days of "IBS", I was given some extended doses of Rifaximin. I don't recall it helping then. But with "evolved" symptoms, I wonder...

[tex]

Rich,

When you read the specs on Rifaximin, it looks promising, but a few members have tried it, (one or two have tried it more than once), and it never seems to produce results. No one knows why. Of course, those members who have tried Rifaximin, insisted that they were not gluten-sensitive, and were not on the diet, to the best of my memory, (which could be wrong, obviously).

Probiotics seem to be in the same boat. Theoretically, they should be very helpful for someone with an IBD, and even Dr. Fine recommends them. The problem is, very, very few members of this board have ever been successful in deriving any benefits from them. In fact, some of us have had severe reactions against them. Again, no one knows why. I can think if only two members who were successful, but maybe I'm overlooking someone. The last I heard, Dr. Fine has never been successful in finding a probiotic that works for him, personally, either, even though he believes that in theory, probiotics should be beneficial for someone with MC.

Maybe this is suggesting that MC is not just an autoimmune reaction involving gut bacteria, after all, but something more, such as a MAP infection.

Tex