Given that Crohn's disease research was mentioned earlier this afternoon on NPR's Science Friday, I thought I would track down the first article mentioned in the interview with Dr. Russell Cohen, Co-Director of the Inflammatory Bowel Disease Center at the University of Chicago. This article was a study (sort of) involving the use of probiotics for Crohn's disease and colitis therapy, though not in a purely straightforward sense. Given my previous focus on probitics, I wanted to continue to follow this field. In a later post, I will also discuss the second article mentioned in today's interview... a Nature article on genes for Crohn's.
Crohn's disease research is getting some recognition... this is good! Go here to listen to the SciFri interview.
Today's featured article:
Motta et al. 2012. Food-grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis. Science Translational Medicine 4:158ra144.
The one-sentence synopsis
Basically, Motta and colleagues expressed the protein, Elafin, in lactic acid bacteria and found that this bacteria could then reduce intestinal inflammation when fed to mice with colitis.
Elafin... the protein that I couldn't figure out how to spell from the SciFri broadcast
Elafin is a protein that serves as a protease inhibitor... literally, an inhibitor of proteases... which basically means that Elafin is a molecule that prevents other proteins from getting degraded ("chewed up and digested", if you will) by enzymes called proteases. Elafin exists normally in cells of the human intestinal mucosa (lining) and has been previously demonstrated to possess anti-inflammatory properties. This research group found that Elafin levels were reduced in patients with inflammatory bowel disease (IBD), so they wanted to see if giving back more Elafin could be helpful to reduce intestinal damage or inflammation.
Elafin levels are reduced in IBD
Before they did anything with bacteria, Motta and colleagues actually studied the expression levels (i.e. amount) of Elafin in the gut. To do this, they took colonic biopsy tissues from normal control individuals and IBD patients with Crohn's disease or ulcerative colitis. When they compared the amount of Elafin between IBD patients and normal control individuals, they found the amount of Elafin to be greatly reduced in the colonic specimens from IBD patients. With that, they also found that the activity of proteases was higher in the IBD patient colon specimens, presumably because there is not enough Elafin around to inhibit the proteases.
Tinkering with genes in bacteria
In order to get more Elafin into the gut, Motta and colleagues engineered (which is sort of just a fancy way to say that they tinkered with or changed) two different strains of food-grade (can be eaten) lactic acid bacteria. The specific bacteria strains they used were Lactococcus lactis and Lactobacillus casei. As for L. casei, I currently have some Greek yogurt in my fridge that contains this bug as one of its active cultures. I don't think there is an L. lactis in any of my yogurt, but that's probably because (according to wikipedia) it is used for the production of buttermilk and cheese. For their genetic engineering of these bacteria, they introduced the gene for Elafin protein.
Bacteria for the therapetic delivery of Elafin
To test whether bacterial delivery of Elafin could improve gut inflammation, Motta and colleagues used a mouse model of IBD, in which colitis was induced by a chemical. The authors fed the engineered L. lactis and L. casei to the mice with colitis, and they found that the protease activity and inflammation could be dramatically reduced in the colon of these animals. They compared this result with feeding the IBD mice normal (i.e. with no Elafin gene) L. lactis, and the normal L. lactis had no effect on the gut inflammation... meaning it is the Elafin here that is helping the inflammation, not just the bacteria itself.
So would this work for chronic disease or in an actual IBD patient?
Well, maybe. To strengthen their above results, the investigators also tested their Elafin-engineered L. lactis in a mouse model of chronic colitis and found that inflammatory gut damage could be reduced in this model. In addition, Motta and colleagues continued with studies of the effects of their engineered bacteria in human intestinal epithelial cell monolayers (human gut cells, but grown in a dish). These cells in a dish were made to have "inflammation" by exposing them to TNF-alpha, the same inflammatory molecule that tends to be in too high of levels in Crohn's disease. However, I have put "inflammation" in quotations here intentionally. The GI inflammation in Crohn's disease is certainly not just due to TNF-alpha, but is largely due to damage from inflammatory cells, which would not be in the dish. Regardless, the investigators did see improvements in some of the inflammatory markers in the TNF-alpha-exposed human cells in a dish.
Why this is cool research (btw "cool research" is not an oxymoron)
Gene therapy has been on the horizon for a while now, but has thus far been largely unsuccessful in humans. The idea with gene therapy is to basically replace a missing or defective gene in a cell that needs it... e.g. replace the gene for the defective chloride transporter in cystic fibrosis. For those of you that don't know, genes basically tell your cells how to make proteins (although this is not the only thing written in your DNA). So when a gene is bad, the protein can be bad too... either missing all together or just dysfunctional. However, if we could somehow put in the correct gene through gene therapy, then the cell could make the correct protein, potentially curing the disease. One of the major problems with gene therapy (and why it has been unsuccessful or even, perhaps, dangerous) is because scientists haven't completely figured out a good way to deliver the correct genes into the cells that need them.
This is one situation in which it could actually be beneficial for treatment purposes that IBD impacts the intestinal tract. Because the gut interfaces with the environment through whatever you eat or drink, scientists can essentially do gene therapy on the GI system without necessarily putting the genes directly into gut cells. Instead, the scientists put the gene into bacteria (a much easier feat than putting them into a human), the bacteria make the protein, and we eat the bacteria with the protein... cool stuff. Thus, a whole new field of therapeutics is potentially evolving with the bacteria we can eat.
So, you may or may not be wondering why we can't just eat the protein... the simple reason is that it would get digested before it could ever reach the parts of the intestine where it could provide some benefit. Some of the bacteria would be destroyed by the stomach too, but enough can sneak by to the lower intestine, where they will thrive and multiply. Thus, the bacteria can make something that would otherwise be hard to get into the human body and could serve as therapeutic vessels.
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