From the New England Journal of Medicine

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pb4
Elite Member


Date Joined Feb 2004
Total Posts : 20577
   Posted 1/30/2008 6:56 PM (GMT -6)   
 
 
:)
My bum is broken....there's a big crack down the middle of it!  LOL  :)


pb4
Elite Member


Date Joined Feb 2004
Total Posts : 20577
   Posted 1/30/2008 8:34 PM (GMT -6)   
Here's the full article thanks to Sarita over at the CD/IBS forum...

Inflammatory bowel disease results from a dysregulated immunologic response to commensal microbial flora residing in the intestinal lumen. Although this response is probably due at least in part to a genetic predisposition, patients with inflammatory bowel disease have also been reported to house an abnormal intestinal microbiota.1 Whether this altered flora is the cause or result of the associated chronic inflammation remains unclear. Also unclear is the exent to which inflammatory bowel disease may be transmissible.

A recent study by Garrett et al.2 sheds new light on this issue and on whether specific microbes contribute to the development of this disease. The authors have identified a new role for the transcription factor T-bet, known to regulate adaptive and innate proinflammatory immune responses, in controlling the host–commensal interface. They engineered mice that were deficient in both T-bet and the adaptive immune response since they lacked Rag2, which encodes a protein that processes antibodies. Severe colitis, which resembled human ulcerative colitis, developed in these mice (called TRUC mice).

Garrett et al. observed an increase in colonic levels of tumor necrosis factor (TNF-) when the mice were 2 weeks old. The TNF- level was associated with enhanced intestinal permeability and the extent of colonocyte apoptosis, which preceded the onset of colitis. It turned out that colonic dendritic cells, which sample the intestinal microbial flora, were the source of TNF- owing to their loss of negative TNF- transcriptional regulation by T-bet. Treatment of the mice with TNF- antibodies cured the colitis, and colitis did not develop in mice that were triply deficient in T-bet, Rag-2, and TNF receptor 1, which showed that TNF- is the key driver of disease in TRUC mice. Reconstitution of T regulatory cells in the TRUC mice controlled the colitis; microscopic imaging suggests that these cells interact with and thus down-regulate the proinflammatory program of the T-bet–deficient dendritic cells.

A role for microbes in inflammatory bowel disease is supported by the fact that mouse models develop colitis only in the presence of intestinal bacteria, and several human studies have shown a response of patients with inflammatory bowel disease to antibiotic therapy. However, the study by Garrett et al. is particularly exciting, since it includes a description of the development of a colitogenic gut flora. Colitis in TRUC mice abated after treatment with metronidazole, suggesting a role for anaerobes. Colitis was transmitted to progeny of untreated mothers but not to progeny of treated mothers; the disease was transmitted even to T-bet–sufficient Rag2–/– or wild-type progeny cross-fostered from birth by TRUC mothers, as well as to adult T-bet–sufficient mice that were housed with adult TRUC mice. However, TNF- levels were not elevated in T-bet–sufficient animals with colitis, which suggests that the microbiota from TRUC mice induce colitis in T-bet–sufficient hosts through a mechanism independent of signaling induced by TNF-.

The data described by Garrett et al. support a model for the development of inflammatory bowel disease in which the intestinal microbiota activate immune cells, leading to dysregulated cytokine production and ensuing intestinal inflammation. However, the immunologic milieu in the TRUC model is novel in engendering a colitogenic flora. Although the mechanism and the identity of the culprit organisms remain obscure, the observation indicates that increased concentrations of cytokines may affect other luminal processes — that is, increased cytokine production may modulate the composition of the commensal flora or alter gene expression in specific bacterial subgroups that are then responsible for the continuation and even transmission of colitis. For example, Pseudomonas aeruginosa binds interferon through an outer membrane protein, porin OprF, leading to activation of the quorum-sensing machinery that regulates the expression of virulence genes by detecting bacterial density and phase of growth. This, in turn, leads to downstream expression of virulence genes, including an adhesin.3

The study by Garrett et al. raises the interesting possibility that the appropriate environment leads to a colitogenic gut flora whose behavior is then modulated under various immunologic circumstances. Cytokine effects on bacteria are observed only in fresh isolates and are lost when these isolates are cultured in the absence of cytokines,4 suggesting that T-bet–sufficient colitic mice with normal TNF- levels may not communicate disease. Cytokines, including TNF-, have been reported to increase the growth rate of specific bacteria and to enhance virulence attributes, including adherence and invasion. It therefore seems reasonable to propose that dysregulated TNF- expression by colonic dendritic cells caused by T-bet deficiency increases intestinal permeability and apoptosis, leading to ulceration of the intestinal epithelium (Figure 1). Epithelial discontinuities allow influx of bacteria but also expose the intestinal microbiota to TNF-, which either shifts the composition of the microbiota or enhances the virulence of specific bacterial subgroups, possibly rendering them communicable.
My bum is broken....there's a big crack down the middle of it!  LOL  :)


Sara14
Veteran Member


Date Joined Mar 2007
Total Posts : 4381
   Posted 1/30/2008 10:38 PM (GMT -6)   
That made my brain hurt. I'm going to have to read that another 2 or 3 times before I understand it. Thanks for posting.
24 years old
Diagnosed with UC March 2007; yet to go into remission
Asacol 4 tablets 3x/day
Rowasa (generic) - daily
Nature's Way Primadophilus Reuteri 1/day; Chewable multivitamin; Metamucil; Viactiv (Calcium and Vit. D); fish oil


relativelyquantum
Regular Member


Date Joined Sep 2007
Total Posts : 196
   Posted 1/31/2008 4:39 PM (GMT -6)   
LOL, Sara. Still digesting it myself. Think I got the gist of it. Looks as if the microbial factor is a good theory--though it might just be that the mice have one form of colitis. Still, it makes good sense of the data and what may be underlying IBD.
Pancolitis '04
Yet to ever go into remission, additional Flare-up since Aug 12th
Time off work since 10/17.  Returned to work on 1/11 and doing much better.
 
On Lialda (2/dy), Probiotics, Fish Oil, Folic Acid, Alpha Lipoic Acid, Borage Oil, Iron


pb4
Elite Member


Date Joined Feb 2004
Total Posts : 20577
   Posted 1/31/2008 8:52 PM (GMT -6)   
This is what Sarita over at the CD forum concluded....

---------------------------------------------------------------------------

"Hey guys, I put this off until now because I just finished up a horrendous exam this afternoon that I was cramming for for the past couple of days. Ugh.

Anyway, this is basically what this article is saying: these "transcription factors" they are talking about - T-bet - were deficient in some of these mice. Transcription factors regulate the production of gene products. Not having enough T-bet leads to an increase in tumor necrosis factor (TNF), which makes bacteria more virulent (or capable of causing disease). Their theory is that TNF leads to abnormally high rates of cell death in the intestine, causing ulcerations.

My interpretation of this (keep in mind, I am only a first-year med student and not a bacteriologist) is that they believe there is both a genetic and environmental component of IBD, which most scientists have believed for quite a while now. It may be that they are at least discovering one (of perhaps many) mechanisms that drives this process. I am not sure how ground-breaking the discovery is, but if it's in the New England Journal of Medicine (the most prestigious medical journal in the world), it must have some significance!

Keep in mind that research can be very tedious, very slow, but these baby steps are necessary. Hope this helped a little."

---------------------------------------------------------------------------
:)
My bum is broken....there's a big crack down the middle of it!  LOL  :)


relativelyquantum
Regular Member


Date Joined Sep 2007
Total Posts : 196
   Posted 1/31/2008 9:45 PM (GMT -6)   
Thanks.
Pancolitis '04
Yet to ever go into remission, additional Flare-up since Aug 12th
Time off work since 10/17.  Returned to work on 1/11 and doing much better.
 
On Lialda (2/dy), Probiotics, Fish Oil, Folic Acid, Alpha Lipoic Acid, Borage Oil, Iron


UCinNC
Veteran Member


Date Joined May 2007
Total Posts : 528
   Posted 2/1/2008 2:42 PM (GMT -6)   
for what it is worth, I had my fiance, who is a medical researcher (but not in IBD stuff) at Duke med center, look at the article. he said:

"I pulled the NEJM reference and read it. The gist is that IBD is caused by an over-reaction of the immune system to microbes in the intestines. This much you probably already knew. What's novel here is the level of detail about exactly which immune cell is over-reacting and exactly what microbe it's over-reacting to and what missing molecule is causing the over-reaction. It's all mouse level work so it probably doesn't have immediate ramifications for therapy. We can sit down together and go through it together tonight in a bit more detail if you like, that's just what I could glean from a first pass."
30/Female/NC
Pancolitis dx 3/07
9 Colazal a day (was on 12 Asacol/day, but suddenly got sick from it)
150mg Imuran/day (steroid dependent, reached this dose 9/07)
Various vitamins, bit of fish oil, a probiotic.


marty1976
Veteran Member


Date Joined Nov 2005
Total Posts : 2045
   Posted 2/1/2008 3:43 PM (GMT -6)   
Thanks for sharing
                                     keep the faith 

         asacol/proctifoam/Zoton (lansoprazole)/propranalol



        http://www.myspace.com/martybuzz1<FONT]


jayce
Regular Member


Date Joined Nov 2007
Total Posts : 390
   Posted 2/1/2008 7:53 PM (GMT -6)   
thanks for sharing! it is greatly appreciated !
Mom to 19 year old daughter diagnosed 11/07.
asacol 2 3x daily-discontinued
colazal 3 3x daily/switched to 4 4x daily
proctofoam 3x daily/1-2xdaily
mesalamine enema 1x daily
canasa suppostiories 3x daily /switched to court supp 1-2x daily
culturelle probiotic 1 daily
chewable vitamin
hydrocortisone enema at bed time 6mp50


doors12
Veteran Member


Date Joined Jul 2006
Total Posts : 698
   Posted 2/1/2008 9:21 PM (GMT -6)   
>Treatment of the mice with TNF- antibodies cured the colitis

I don't understand. TNF-alpha (I don't know if that's different than the above) is mentioned in a lot of these studies. Are they saying a simple antibody cured the mouse colitis?

I thought things like Remicade worked by some process regarding TNF-alpha


Oh well.
Diagnosed with Ulcerative Colitis 6/2006 at age 26 after sudden E.R. visit
~Pancolitis (Mild to Moderate)
 ~I had Mono in 2000
On Colazal 3x3/day; Folic Acid 1mg; Calcium/Magnesium/Zinc combo
In remission about 2-3 months after E.R. but not back to normal!
 
~Interested in finding a cure/making sense out of U.C. and philosophical and psychological aspects of UC and "Stress" and Personal Development issues with Chronic Illnesses. 

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