New Animal Model Sheds Light On Crohn's Disease

[Igor_Passau]

McMaster University investigators have opened up a new area of research in the study of Crohn's Disease, a chronic inflammatory bowel disease that afflicts over 100,000 Canadians, one of the highest rates worldwide.

Led by Brian Coombes, Associate Professor in the Department of Biochemistry and Biomedical Sciences and member of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR), his group has been studying a variant of E. coli called adherent-invasive E. coli (AIEC) that is associated with human Crohn's Disease. In their new work, Coombes' group developed a new mouse model that showed that Crohn's-associated E. coli could cause chronic infection in the mouse gut. Interestingly, after infection the mice developed chronic gut inflammation that resembled that seen in human Crohn's Disease. This new model will allow researchers to understand the effects of chronic colonization on the host immune system and how this might play a role in disease development.

"Up to now, animal models of Crohn's Disease often rely on the use of genetically-modified mice that are hard to obtain, or use chemicals that cause inflammation in the gut. Previous work infecting genetically modified mice with this E. coli in the presence of pro-inflammatory chemicals lead to an infection that was fatal over a one-week period," says Coombes "Obviously, this is not a desirable model if you are trying to understand a chronic human disease."

Coombes' goal was to develop a new animal model that would allow researchers to study the effects of chronic infection: "In other words," he says, "could we take our strain of Crohn's-associated E. coli and colonize mice for life so we could study the long-term consequences on an animal carrying this particular E. coli in their intestine. We achieved that and successfully developed a chronic colonization infection model in five conventional mouse lines, allowing us to understand the host response in greater detail."

Crohn's Disease belongs to a group of diseases called Inflammatory Bowel Disease (IBD), affecting one in every 160 Canadians. Even more common is Irritable Bowel Syndrome (IBS), which in some cases can put people at greater risk for IBD. An estimated five million Canadians suffer from IBS, or about one in seven people. "We're very interested in trying to understand if there is a microbial link to IBS as well."

Little is known about the definitive causes of Crohn's Disease. While links have been made to genetic predispositions, there are many who suffer from Crohn's who have no known hereditary link to the disease.

"There is an accepted microbiological link to Crohn's disease and there is good data from human clinical studies and also animal studies suggesting that the presence of bacteria is necessary for the expression of Crohn's disease symptoms," Coombes says.

"This work opens up a whole new area of research where we can start to understand the host response to a bacteria linked to Crohn's Disease," he says. "And because we have the genome sequence of the bacteria we can begin to ask questions like what are the genes present in this particular bacteria that make it invasive, how does it colonize for long periods of time, and why is it so pro-inflammatory?"

His ultimate goal is to apply these findings to the human condition, to see whether these bacteria might be the cause of the chronic inflammation seen in humans with Crohn's disease. "There's clearly lots of work to do, but we're excited about the direction it's heading in."
http://www.medicalnewstoday.com/releases/261854.php

 

[kiny]

I posted the nature study below. Can't believe it took people decades to consider this might simply be an infection. Dalziel already said it's likely an infection in 1913. You can't clear the infection and the inflammation persists, the exact same thing happen in people where intestinal TB isn't cleared, they have the same transmural type of inflammation, the exact same granuloma and the same wall thickening.

But instead they made all these ridiculous theories that the body is attacking the gut or the gut flora and random **** that doesn't even make sense.

There is no disease in history where the body attacks the indigenous gut flora, none, it always involves a particular pathogen.

People with intestinal TB can have intestinal inflammation for years, and never will the body decide to attack the gut flora.

 

[kiny]

I wonder also about all the cases of crohn's disease that happen during teenage and late teenage years, when the peyer's patches are most active, and the first clinical symptoms of crohn's disease involve lymphatics and inflammation surrounding peyer's patches. If it's AIEC, it wouldn't surprise me that AIEC is getting into tissue through the peyer's patches.

 

[my little penguin]

Kiny- what about very young children ( 5-10) year olds? or those under 5 any ideas?

 

[kiny]

http://www.ncbi.nlm.nih.gov/pubmed/21994005

study about AIEC in CD kids

if you believe a bacteria is the primary cause there aren't that many candidate bacteria we know of, if you go by genetic defects you end up looking at intracellular bacteria, since NOD2 and ATG16L1 are involved in autophagy, so you end up with a few candidates, MAP (which is really hard to isolate), AIEC (which is increasingly isolate from patients in much higher numbers than MAP). Then you have listeria and yersinia, which make a lot of sense since crohn's disease increased around the time they started using refridgerators (sp?), but they're not commenly isolated for people with CD. Salmonella and some others that make less sense, and would have shown up in high numbers by now. TB of course too, intracellular like all mycobacteria, but that ends up in intestinal TB, not crohn's disease.

Dalziel in 1913 knew the people he looked at didn't have intestinal TB, that was his first assumption, intestinal TB looks a lot like CD.

I don't know what UC is, but it has nothing to do with CD, I don't think it's related to AIEC in any way either. It's a shame the term IBD even exists, there is no relationship between UC and CD, they couldn't be farther apart.

V. Kruiningen has done a lot of studies trying to find the holy grail bactera, if you just look by his name, or want a list of all studies trying to isolate bacteria I have posted many.

The idea that it's just an infection makes a ton of sense, it also sounds incredibly simple, you have a pathogen, that invades someone with immunodeficiency, they can't kill it, as long as it's not killed you have inflammation.


Now if AIEC is the holy grail, I don't know, but it sure is causing a lot of inflammation in people they find it in, and they sure are starting to find it in a lot of people with ileal crohn's disease.

There are also many pieces that fall into place with AIEC, AIEC actually takes advantage of autophagy deficiencies and macrophage deficiencies, AIEC stimulates TNF-alpha, and they see it raised Th17 in people. T helper responses were thought to be unbalanced because of the hygience hypothesis, acquired, but I don't think it's acquired, it's just being caused by a pathogen. Anyway, I'm rambling, I just think AIEC is very interesting.

 

[kiny]

Let's say you don't believe in the holy grail infection theory.

Well, let's look at what's left:

Autoimmune disease.....a number of problems with that:

*you'd have inflammation all over the intestine, you don't in CD
*you'd have found a self-antigen by now like in UC, it's not found in CD
*NOD2 and ATGL16L1 point to bacterial involvement

Loss of tolerance to indigenous gut flora.....a number of problems with that:

*why is the disease in the ileum, why not in the colon where the concentration of gut flora is much higher?
*why isn't the inflammation all over the intestine?
*why is the inflammation transmural, if it's a reaction against gut flora? CD is transmural, that's why people get fistula
*this would be the only disease in history where the body turns against the gut flora? it would just one day have lost tolerance ... for some reason .. sounds pretty damn far fetched
*people with intestinal TB can have inflammation for years, they have ulcers and granuloma, never once does the body decide to attack gut lumen content
*the disease that looks most like CD is intestinal TB, and that's an infectious disease

 

[kiny]

Just the mere fact that some people get better on quinolones and macrophage penetrating antibiotics.

If it was actually the indigenous lumen content, you'd put people on broad spectrum and they would get better, you'd see a lot of improvement after amoxillin and medication that modulates gut flora, you don't, the only thing those broad spectrum antibiotics do for people with CD is give them C diff. But the macrophage penetrating types help, the ones that get into tissue help, the quinolones and some of the macrolydes helped people. It doesn't cure them, they likely run into resistance, but enough studies have shown that broad spectrum lumen antibiotics do didly squat, and macrophage-penetrating ones do, that doesn't look good for the gut flora theory.

Maybe they can prove people wrong by curing everyone with a fecal transplant....but if the indigenous flora isn't the issue, if it's a bacteria that has entered tissue, you're going to make a lot of people a lot sicker than they already are.

It would be like giving people with intestinal TB a fecal transplant, I wouldn't want to be the doctor responsible for doing that.