The IBD Microbiota: New Therapeutic Target?

microbiota timelineThe latest publication of Nature Immunology focuses on microbiota. With four excellent reviews, they cover a wide-range of microbiota-related topics from pattern-recognition receptors in the fruit-fly to the microbiota-nutrition-immune triangle. Does this new field of study offer any hope for inflammatory bowel disease (IBD)?

It’s important to realize that the microbiota inside one’s gut isn’t just bacteria. In actuality, it also has representatives from the Archaea (ancient bacteria) and Eukarya domains. Examples of Eukarya are fungi and parasites. Together, this thriving community is called the “microbiome,” and it is highly diverse containing between 1000-36,000 species of bacteria. Most scientists are currently focusing on the bacterial inhabitants.

Using high-throughput 16S small-subunit ribosomal sequencing to identify bacterial species, scientists can now identify changes in the microbiome of IBD patients. In 2007, one of the first studies was published in PNAS using this technique on surgically isolated gut wall bacteria. It revealed that in IBD many bacteria from the phyla Firmicutes and Bacteroidetes were depleted while a variety of Actinobacteria and Proteobacteria were more abundant. The study also revealed that abnormal microbiotas were also significantly correlated with abscesses in Crohn’s disease (CD).

These studies fail to tell us, however, if these changes are cause or consequence. This explains why studies with probiotics, fecal transplantation and diet are now so popular. From these studies, it appears that modulating the IBD microbiota can influence the disease, especially in ulcerative colitis (UC) patients. The probiotic formulation VSL#3 is now recognized as a treatment in ulcerative colitis. Fecal transplantation, where feces from healthy donors are transferred via an enema to patients, has also shown success. Some UC patients have maintained remission up to 13 years with fecal transplantation alone. And, finally, diet is highly impactful on the intestinal flora, and it is well known that enteral nutrition can induce remission in IBD.

Interestingly, all of these manipulations of IBD microbiota need to be maintained. Probiotics need to be taken daily, fecal transplants repeated, and diets followed to prevent relapses. This would suggest that there is still something about the IBD patient’s intestinal microenvironment that’s still promoting disease. The fecal transplantation study particularly supports this idea seeing that the patients are more or less sterile before getting their new donor microbiota.

Genome wide association scans suggest a reason. The major mutations associated with IBD are in pathways that are involved with dealing with bacteria. One of the most well known genes found to be mutated in IBD is NOD2. NOD2 recognizes muramyl dipeptide, a bacterial-associated molecule and activates the pro-inflammatory transcription factor, NF-κB. In mice, loss of Nod2 reduces the expression of anti-microbial peptides in the terminal ileum. One could imagine that in patients with this mutation, there would be defects in regulating the microbiota.

In my last post, I described research using a stress-induced model of intestinal inflammation. There they showed that stress could induce changes in the immune system, which then led to changes in the microbiota and intestinal inflammation. Interestingly, changes could happen in the other direction. Co-housed, healthy mice were given the same disease (and immunological changes) just by eating the stressed mice’s feces. This study highlights that there is a bi-directional relationship between our microbiota and us. Could this mean that the best treatments are also the one’s that target both our flora and our immune systems?

Please tell me what you think? Leave a comment down below!

References:

Albenberg, L. G., Lewis, J. D., & Wu, G. D. (2012). Food and the gut microbiota in inflammatory bowel diseases. Current opinion in gastroenterology, 28(4), 314–320.

Aroniadis, O. C., & Brandt, L. J. (2013). Fecal microbiota transplantation. Current opinion in gastroenterology, 29(1), 79–84.

Brown, E. M., Sadarangani, M., & Finlay, B. B. (2013). The role of the immune system in governing host-microbe interactions in the intestine. Nature immunology, 14(7), 660–667.

Frank, D. N. D., Amand, A. L. A. S., Feldman, R. A. R., Boedeker, E. C. E., Harpaz, N. N., & Pace, N. R. N. (2007). Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. PNAS, 104(34), 13780–13785.

VSL#3®, The Living Shield™ – Why VSL#3®?, accessed June 28, 2013

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