Inflammatory bowel disease research, just like clothes and music, is subject to trends. To give you a good idea about where things are heading at the moment, I’ve composed a list of five hot topics in IBD research. The choices were based mainly on my own research experiences, the research prioritization report published by the Crohn’s and Colitis Foundation of America (CCFA), as well as ideas found on patient forums.
Microbiota, all of the microorganisms that colonize our bodies, takes the first spot. This topic went from obscurity to the research darling at the end of the 2000s. The first searches for the term, “gut microbiota” were in October, 2008 and were precipitated by the Human Microbiome project and the publication of a comprehensive review of human microbiota in Nature Review Microbiology. Since then, the interest has steadily risen, and in 2012, Nature even published a special on human microbiota.
Gut microbiota, without a doubt, play a role in the initiation and progress of IBD. Gut microbiota are so important to our healthy intestinal functioning that they are like an additional organ. They are important to the immunological development of our gastrointestinal tract and they regulate the development of certain types of immunity, including regulatory T cell and T helper 17 responses. Research has already shown that a number of microorganisms are able to protect from IBD, while a number of them also encourage it.
Fecal transplantation, the transplantation of healthy donor feces to IBD patients is already showing some promise for ulcerative colitis. There are also companies developing synthetic feces for transplantation. Furthermore, there is also great interest in using probiotics as treatments. Controlling microbiota in patients to optimize health will be a future step towards treating IBD.
2. Parasitic Worms
This topic is less mainstream than microbiota, however, it wins a spot due to patient interest. Joel Weinstock of the University of Iowa was the first to consider parasitic worms as being useful immunomodulators for IBD patients. In the 1990s, he realized that the loss of parasitic worms from our intestinal tracts was indirectly correlated with the rise of IBD. Even though early experiments with patients were promising, it’s only now that serious clinical trials are being performed with pig whipworms and human hookworms. Despite the slow advance of clinical studies, patients have not been deterred in seeking out parasitic worms for self-treatment. Though unregulated, providers exist that specialize in delivering worms to patients.
More research is needed to determine how they work. To make it more complicated, each type of parasitic worm has its own characteristics. In general, it is well known that parasitic worms induce T helper 2 responses, which can counteract T helper 1 and 17 responses found in IBD and increase wound repair. Some nematodes are also known to support regulatory T cell induction through secreted TGF-β mimics. Pig whipworm treatment also seems to increase the amounts of IL-22 producing T helper cells, which is known to help epithelial barrier function.
3. Innate Lymphoid Cells
Interest about these cells exploded in 2011 with the publication of an article in Nature Immunology about their involvement in the lung response during influenza infection. Until this point, they certainly were not a mainstream topic. But, it soon became apparent that they had an enormous potential to influence inflammatory responses in the gut. These cells are the primitive counter-parts to the well-known T helper subsets of the adaptive immune response. They do not possess T cell receptors or lineage markers for T cells. Instead, they are extremely sensitive to cytokine signals produced by surrounding immune cells and then secrete their own signature cytokines in return.
Studies of innate lymphoid cells in IBD patients show that their populations can be affected by disease status, and they appear to accumulate during chronic disease. This would suggest that small changes in the immunological status of patients could result in a quick response by these cells as they pump out their pro-inflammatory cytokines. Finding ways to rein in these cells could limit flaring.
4. The Brain-Gut Axis
The term “brain-gut axis” became well known in 2012, although it has been since the 80s. The concept brings to light the interconnectivity between the nerves of the gut and the functioning of the brain. In fact, many common neurological disorders like autism, Alzheimer’s disease and Parkinson’s disease are associated with intestinal issues, while IBD and IBS patients often suffer from depression and anxiety. Even more interesting is the realization that microbiota (see the first topic) appear to influence behaviour.
The pathways that connect the brain and the gut include the endocrine system with the chain of command between the hypothalamus, pituitary and adrenals as well as the neural pathway consisting of communication between the enteric nervous system with the central nervous system via the vagus nerve or sympathetic nerves. This field could deliver much needed information for prevention and treatment of IBD. It’s speculated that childhood stress and trauma could contribute to IBD susceptibility and that neurological problems may be apparent before disease onset. This concept could also lead to treatments in the form of drugs that support the anti-inflammatory actions of the nervous system.
5. Memory T cells
Learning about adaptive immune responses and memory are the mainstay of any immunology course. However, the popularity of studying memory T cells in the context of IBD isn’t all that popular. A pubmed search reveals only 149 articles with the terms “inflammatory bowel disease” and “memory T cells.” However, recent publications on this topic as well as the fact adaptive immunity is a CCFA research priority merit its inclusion on this list.
Memory T cells are created after naïve T cells are primed and expanded. They recognise antigens from the past and also remember how they should react to them. This means that they can act quickly to alert and recruit other immune cells even without the benefit of additional immune triggers like ambient cytokines or co-stimulation. In IBD, they could explain why flares can sometimes be initiated by something so simple as eating the wrong food or by other environmental changes. New findings show that bone marrow cell-derived IL-7 is able to sustain colitis-associated memory T cells and that blocking T cell traffic lowers the severity in colitis models. These findings should boost interest in this area of research.
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Broadhurst, M. J., Leung, J. M., Kashyap, V., McCune, J. M., Mahadevan, U., McKerrow, J. H., & Loke, P. (2010). IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient. Science translational medicine, 2(60), 60ra88–60ra88.
Cryan, J. F. J., & Dinan, T. G. T. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews: Neuroscience, 13(10), 701–712.
Denson, L. A., Long, M. D., Mcgovern, D. P. B., Kugathasan, S., Wu, G. D., Young, V. B., et al. (2013). Challenges in IBD Research. Inflammatory Bowel Diseases, 19(4), 677–682.
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Kamada, N., Seo, S.-U., Chen, G. Y., & Nuñez, G. (2013). Role of the gut microbiota in immunity and inflammatory disease. Nature Reviews Immunology, 13(5), 321–335.
Nemoto, Y., Kanai, T., Kameyama, K., Shinohara, T., Sakamoto, N., Totsuka, T., et al. (2009). Long-Lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis. The Journal of Immunology, 183(8), 5059–5068.
Walker, J. A., Barlow, J. L., & McKenzie, A. N. J. (2013). Innate lymphoid cells — how did we miss them? Nature Reviews Immunology, 13(2), 75–87.
Whelan, R. A. K., Hartmann, S., & Rausch, S. (2011). Nematode modulation of inflammatory bowel disease. Protoplasma, 249(4), 871–886.