Creative Minds: New Piece in the Crohn’s Disease Puzzle?

Posted on June 9th, 2016 by Dr. Francis Collins

Back in the early 1930s, Burrill Crohn, a gastroenterologist in New York, decided to examine intestinal tissue biopsies from some of his patients who were suffering from severe bowel problems. It turns out that 14 showed signs of severe inflammation and structural damage in the lower part of the small intestine. As Crohn later wrote a medical colleague, “I have discovered, I believe, a new intestinal disease …” [1]

More than eight decades later, the precise cause of this disorder, which is now called Crohn’s disease, remains a mystery. Researchers have uncovered numerous genes, microbes, immunologic abnormalities, and other factors that likely contribute to the condition, estimated to affect hundreds of thousands of Americans and many more worldwide [2]. But none of these discoveries alone appears sufficient to trigger the uncontrolled inflammation and pathology of Crohn’s disease.

Other critical pieces of the Crohn’s puzzle remain to be found, and Gwendalyn Randolph thinks she might have her eyes on one of them. Randolph, an immunologist at Washington University, St. Louis, suspects that Crohn’s disease and other related conditions, collectively called inflammatory bowel disease (IBD), stems from changes in vessels that carry nutrients, immune cells, and possibly microbial components away from the intestinal wall. To pursue this promising lead, Rudolph has received a 2015 NIH Director’s Pioneer Award.

Randolph became interested in IBD several years ago while running her lab at Mt. Sinai Hospital, New York, which coincidentally is where Crohn made his initial discovery. But Randolph wasn’t treating patients—she and her lab members were interested in the basic biology of cardiovascular disease. Their studies led them to the lymphatic system, the body’s other circulatory system, which serves as a one-way conduit to transport tissue fluid and white blood cells to the lymph nodes.

Her group had generated some interesting data on how the immune system controls lymphatic transport in other organs, and a colleague put her in touch with French gastroenterologist Jean-Frederic Colombel, who shared an interest in the lymphatic system, especially its possible connection to IBD. A collaboration ensued, and the two groups decided to take a look inside the digestive tract and explore the crosstalk between immune cells and the lymphatic system. To do so, Randolph and her colleagues pulled off an impressive technological feat. They adapted 3D confocal microscopy to view in high resolution the lymphatic vessels in human intestinal tissue, adding methodology that allows them to scan large portions of the gut [2].

What Randolph saw surprised her. Not only was the lymphatic system altered in people with IBD, key blood vessels were often constricted. Research into cardiovascular disease has benefited tremendously from looking at the blood vessels of people with severe symptoms, such as heart attack or angina, and working backwards to find the causes of those symptoms, such as atherosclerosis. And Randolph thinks a similar approach might be helpful for finding clues to the root causes of IBD. If so, in much the same way that cholesterol tests, lifestyle changes, and cholesterol-lowering drugs are currently used to reduce the risk of cardiovascular disease, it might be possible to develop tests and interventions to lower the likelihood of developing IBD.

With her Pioneer Award, Randolph will study in a larger number of people how changes to the blood and lymphatic vasculature contribute to Crohn’s disease. Her work will largely involve mapping the flow of fats, immune cells, and other molecules through the blood and lymphatic vessels. In one study, Randolph and her colleagues plan to compare the flow of fat through the intestinal lymphatic vasculature in healthy people with that of people who have moderate or severe Crohn’s disease. The volunteers will eat regular food with fats tagged with non-radioactive isotopes, or fat-based positron emission tomography (PET) tracers, which will allow researchers to track the fats’ route through the digestive tract.

The idea that the vascular system may be involved in IBD isn’t exactly brand new—some physician-scientists suspected as much back in the 1930s [3]. But, as happens quite often in biomedical research, it can take years of advances in fundamental knowledge and the development of innovative technologies before a creative mind like Randolph finally has the tools that it takes to seek conclusive answers to a long-standing question.

References:

[1] Burrill B. Crohn (1884-1983): life and work. Janowitz HD. Falk Foundation, (2000), p. 5-22

[2] Lymphatic transport of high-density lipoproteins and chylomicrons. Randolph GJ, Miller NE.J Clin Invest. 2014 Mar;124(3):929-935.

[3] The forgotten role of lymphangitis in Crohn’s disease. Van Kruiningen HJ1, Colombel JF. Gut. 2008 Jan;57(1):1-4.

Links:

Crohn’s Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Gwendalyn Randolph (Washington University, St. Louis)

Randolph NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program (Common Fund)

NIH Support: Common Fund; National Institute of Diabetes and Digestive and Kidney Disorders