From the New England Journal of Medicine

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pb4
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   Posted 1/30/2008 4:55 PM (GMT -7)   
 
 
:)
My bum is broken....there's a big crack down the middle of it!  LOL  :)


nikki0294
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   Posted 1/30/2008 5:07 PM (GMT -7)   
PB4-
I wanted to read the article but do not want to sign up for nejm. Do you have the full text of the article??

Thanks
Christine

Maverick747
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   Posted 1/30/2008 5:14 PM (GMT -7)   
Yeah could you copy and paste or post it somewhere. I too am very interested but dont want to have to sign up. Thanks for bringing this to our attention!

pb4
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   Posted 1/30/2008 5:33 PM (GMT -7)   
LOL, I'm not a registered member either, but I was kinda hoping someone here might be and they could get the whole article...I wonder if googling the heading might take you to the full text?

I'll try it later, I'm hungry and going to eat supper right now.

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


Sarita
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   Posted 1/30/2008 6:08 PM (GMT -7)   
Well, of course your very own medical student would have NEJM access! Here you go...

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.
Co-moderator - IBS Forum


pb4
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Date Joined Feb 2004
Total Posts : 20576
   Posted 1/30/2008 6:33 PM (GMT -7)   
Thanks so much Sarita...Now I can copy and paste your reply over at the UC forum as well!!

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


gumby44
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Date Joined Nov 2007
Total Posts : 4095
   Posted 1/30/2008 6:57 PM (GMT -7)   
Hey Sarita...translation please:)
49 yr. old female, diagnosed with Crohn's in small intestine and terminal ileum Sept-Oct. 2007
currently taking Pentasa 2750 mg- 9pills/day and on and off Prednisone for flares


EMom
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Date Joined Aug 2007
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   Posted 1/30/2008 9:04 PM (GMT -7)   
omg... confused
EMom
Mother to 15 year old boy diagnosed in June, 2007.
Currently taking Asacol, omega 3s, digestive enzymes, probiotics, iron, vit. C, calcium w/D3 and a good multivitamin.
Started The Maker's Diet in early September.


pb4
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Date Joined Feb 2004
Total Posts : 20576
   Posted 1/30/2008 9:07 PM (GMT -7)   
What's the matter EMom? This is a good thing, it means they can find a way(s) to deal with it and help us crohnies, don't worry.

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


Sarita
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   Posted 1/31/2008 5:42 PM (GMT -7)   
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.
Co-moderator - IBS Forum


Roni
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   Posted 1/31/2008 7:29 PM (GMT -7)   
This is why I always sterilize my toilets before guests sit on them. I worry that if my relatives also have the genetic predisposition, that they may somehow end up ingesting crohn's causing bacteria by not washing their hands properly.

I also ALWAYS make sure my son washes his hands with soap after sitting on the toilet.

I know the bacteria theory isn't proven, but I'm not taking chances.

broomhilda
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   Posted 1/31/2008 9:00 PM (GMT -7)   
Hmmm, if it were truly transmittable....wouldn't you see more cases of CD in marital spouses with no genetic connections? After all, a spouse would have the most intimate contact, would they not?

Outside of the aforementioned theory....EVERYONE should ALWAYS wash their hands after using the restroom (in a perfect world of course)!
Dx'd Jan'06, 1st Resection 7/06, Predinsone, Humira, Imuran, B12 injections, Nexium. Secondary conditions: Psorasis, Acne, Fatigue, Joint Pain, Lactose Intolerant, gallstones, fibroid cysts, peri-menopausal.


FitzyK23
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   Posted 1/31/2008 10:17 PM (GMT -7)   
Roni - I pray it isn't communicable but I have to admit ... it seems like every where I go people I know are getting IBS, IBD, Celiacs, stomach bugs. They all laugh and say they got it from me but don't really believe it. Yet my track record is getting up there. And Broom, my hubby, his roommate from college, and my roommate from college are among them. Yikes.  OH! And one of my partners from when I worked corrections and then my other partners fiance who also worked with us just in a different unit.


26 Year old married female.  Diagnosed w/ CD 3 years ago, IBS for over 10 years before that, which was probably the CD.  Currently on Pentasa 4 pills/4x day, hysociamine prn, nexium, and ortho evra.  Good times!!!
 
 


pb4
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   Posted 1/31/2008 11:26 PM (GMT -7)   
If there's even any evidence of it being communicable I say one still has to be predisposed (genetics) in order for them to "catch" it....and so far there's nothing saying that my theory isn't a possibility....but for it to be communicable to those who are not predisposed to it then I have a really hard time accepting that.

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


Sarita
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   Posted 2/1/2008 12:08 AM (GMT -7)   
I don't think this article was saying it's communicable, necessarily, like a stomach virus would be. Just that there may be an environmental component that triggers an already genetically-susceptible person to develop disease activity. Which has been the theory for quite some time.
Co-moderator - IBS Forum


TraciZ
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Date Joined Aug 2007
Total Posts : 255
   Posted 2/1/2008 9:32 AM (GMT -7)   
It sounds to me like this article is stating that the bacteria in the intestines of individuals with a susceptibility to IBD's is more capable of causing ulcerations. That individuals with a genetic predisposition to IBD and who expereince an environmental trigger (the diathesis-stress model) are prone to IBD. I'm not convinced that there's any mention (or evidence) of transmitting to otherwise healthy people. I've never heard anything of IBD's being contagious.

To go on- maybe this is groundbreaking research, because it identifies the T-bet deficiency. Maybe one day, humans will be able to increase their T-bet with a supplement or something and eliminate the disease???

Does this make sense to you, Sarita?

EMom
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Date Joined Aug 2007
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   Posted 2/1/2008 10:20 AM (GMT -7)   
pb4 said...
What's the matter EMom? This is a good thing, it means they can find a way(s) to deal with it and help us crohnies, don't worry.


I was saying "omg" because of the technical language. Like gumby, I felt I needed a translation!

You're right, though, this is good. I feel like they're getting closer and closer to understanding Crohn's.
EMom
Mother to 15 year old boy diagnosed in June, 2007.
Currently taking Asacol, omega 3s, digestive enzymes, probiotics, iron, vit. C, calcium w/D3 and a good multivitamin.
Started The Maker's Diet in early September.


pb4
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Date Joined Feb 2004
Total Posts : 20576
   Posted 2/1/2008 12:40 PM (GMT -7)   
Oh, LOL, I didn't realize that.  :)
EMom said...
pb4 said...
What's the matter EMom? This is a good thing, it means they can find a way(s) to deal with it and help us crohnies, don't worry.


I was saying "omg" because of the technical language. Like gumby, I felt I needed a translation!

You're right, though, this is good. I feel like they're getting closer and closer to understanding Crohn's.


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


UCinNC
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Date Joined May 2007
Total Posts : 528
   Posted 2/1/2008 12:42 PM (GMT -7)   
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.


EMom
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Date Joined Aug 2007
Total Posts : 990
   Posted 2/1/2008 2:56 PM (GMT -7)   
UCinNC, please tell your fiance that was VERY helpful! Thanks for posting it!
EMom
Mother to 15 year old boy diagnosed in June, 2007.
Currently taking Asacol, omega 3s, digestive enzymes, probiotics, iron, vit. C, calcium w/D3 and a good multivitamin.
Started The Maker's Diet in early September.

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