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Guest Commentary: Nobel Prize reflects possible breakthroughs in IBD
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In this guest commentary, Peter D. Higgins, MD, associate professor of internal medicine at University of Michigan Health System, discusses the work of cell biologist Yoshinori Ohsumi, PhD — who was awarded the 2016 Nobel Prize in Physiology or Medicine for his discoveries of the mechanisms underlying autophagy — and its significance in understanding the development of inflammatory bowel disease.
Autophagy is a fundamental process of all cells, which was little known or understood until Yoshinori Ohsumi decided to study it in yeast, where he found it is critical in recycling protein aggregates and damaged organelles. This recycling process is very important as a response to stress or cell damage. Cells that can’t do this accumulate many damaged proteins or organelles that can contribute to diseases such as Alzheimer’s or Parkinson’s.
How autophagy is relevant to Crohn’s is a little bit different. Basically, this pathway has been adapted to fight bacteria or mycobacteria that can invade a cell and get inside the organelles. Somewhere in evolution, cells developed a way to use this pathway that is normally used for recycling to actually kill these invasive bacteria that have evading normal cell defenses.
It turns out that many people have a variant in one of these genes so they do not perform autophagy as well. If you put in these variants in mouse cells, they can’t fight off these invasive bacteria. Normally, cells would fuse the captured organelles with lysosomes and destroy the invading bacteria, but they fail to do that. The bacteria can then replicate inside this protected region of the cell. The cell is able to sense their presence, and responds by secreting more pro-inflammatory cytokines.
This secretion is basically a signal for help, an inflammation signal, which is effectively stuck in the on position because the cells cannot kill the bacteria. The problem is that this generates chronic inflammation, particularly in the intestine where you’re constantly exposed to bacteria.
IBD association
Two different genes associated with autophagy — ATG16L1 and IGRM — are also associated with an increased risk for Crohn’s disease. We now know that people who have mutated versions of these genes that aren’t quite as good at bacterial killing inside the cell are also about twice as likely to develop Crohn’s disease.
That’s not a very powerful association, and there are a lot of people with these genes who will never develop Crohn’s, but it seems to be a primer for the development of Crohn’s disease. If these people are in the right environment, under the right stress, or exposed to the right infection, these events may activate Crohn’s disease. While this mostly impacts our understanding of how Crohn’s disease develops, it will possibly impact treatment in the future.
For the subset of people who have this particular pathway activated — which is not all people with Crohn’s — this pathway suggests more effective treatments. Perhaps antibiotics aimed at killing these intracellular bacteria or mechanisms that could activate the autophagy and drive the autophagy process could reduce the chronic inflammation. It’s a subset of patients, but for that particular group, we may be able to target therapies to boost this autophagy pathway.
We are gradually understanding there are a lot of subgroups of Crohn’s disease and subgroups of ulcerative colitis who may need very targeted and customized therapy. We normally think of ulcerative colitis and Crohn’s as only two diseases, but we are now approaching nearly 200 different genes that have been associated with IBD. While many of them are related to bacterial killing or bacterial defenses, there are a lot of different variations and, in effect, there are a lot of different kinds of Crohn’s disease and ulcerative colitis. We may find eventually that we need to identify which kind of IBD someone has to really target the right pathways for them and provide them with the right medication for the pathways involved in their IBD.
Disclosures: Higgins reports no relevant financial disclosures.