Interesting article-IBD in dogs confirms our human and mouse models.

Sometime last year a research team noticed that German Shepherds have a high incidence of IBD. Affected and non-affected dogs were screened for SNPs (single nucleotide polymorphisms, a change to a single base pair of DNA) and found the affected dogs had mutations in Toll-like receptors 4 (i think, i'm a bit fuzzy on this one) and 5. Toll like receptors are molecules that respond to patterns found on many pathogens, such as flagellin or double stranded RNA. TLR 4 and 5 respond to bacterial products.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030117

They transfected the TLR5 (TLR5 reponds to bacterial flagellin) molecule from high risk dogs and low risk dogs into stable cell lines and stimulated them with bacterial products. Dogs with the high risk mutation had a higher NFkB activation and TNFa production, which are both very important in inducing an immune response.

I think the work this group is doing is really interesting and I can't wait to see what future studies bring!

Well, its the interaction, but that's not how the experiment worked exactly. They used a cell culture expressing the TLRs from the dogs with the mutation and the normal dogs. You can make cells express different things by having them uptake the DNA. The TLRs set off signaling events which in a healthy individual would create a normal immune response. The cell lines with the mutant TLRs where more sensitive-they produced more inflammatory chemicals than cell lines with the normal TLRs. Normal cell lines produced those chemicals too-they are supposed to-but the mutants produced them in much higher amounts. I hope that answers your question.

Basically, our models right now show that IBD is probably the result of a combination of genetic mutations and interaction with gut bacteria. The bacteria are directly stimulating the inflammation, but people with normal genes don't wont get inflammation even with the bacteria present. Also it looks like some bacteria have a protective effect-some bacteria have evolved ways to not trip up pattern recognition receptors (think of them as tripwires for your immune system) or produce things that suppress the immune system.

Doubtful-the mutation would have to arise in multiple cells simultaneously. The mutations would be germline (in sex cells). However, we think at this point that there is a triggering event which sets the gut immune system off balance (something like an infection or other type of inflammation). Normal people can recover from this, however in people with IBD the mutations make it hard for them to regain tolerance to the bacteria.

Interesting theories Malkavian...but you know I always wondered why this was a disease of young adults primarily. Meaning, I am sure we all have had GI infections as kids, but for the most part the disease onset is primarily of people in their 20's. Just curious if you had read anything or seen a possible explanation for this?

Yes, it's strange isn't it...cats and dogs can get IBD or even IBS (my mom's cat had IBS) and of course there's Johne's disease primarily found in cows which is caused by a bacterial infection (MAP)....and they know that bacteria plays a role in IBD as well.

The age thing is interesting too...pediatric IBD is on the rise and has been for at least the last 10 yrs if I remember correctly....Inflammatory bowel disease usually begins before the age of 30. But, it can occur at any age, and some people may not develop the disease until their 50s or 60s. My mom was in her mid 60's when she got sick with UC....I already had my crohn's and was in my early/mid 20's. Oddly enough, I got sick with my IBD before my mom got sick with hers.

I am heartened by this research because it goes beyond specific components of the immune system to look at he gene expression and gene variations that are linked to immune dysregulation. The potential for a genetic therapy which would constitute a cure instead of management seems high. Not today, or next year, but maybe in less than 10 years.