The Hedgehog signaling pathway — named after a gene mutation that caused short, spiky protrusions on fruit fly larvae — received much attention in the past decade for its role in organ development and tumor growth. And now, Stanford researchers have found that manipulation of the Hedgehog pathway can have dramatic effects on mice with colitis.
The study was published in PNAS.
Ulcerative colitis, the inflammation of the colon, is a form of inflammatory bowel disease. Categorized by abdominal pain, bloody diarrhea, and weight loss, colitis is debilitating but not fully understood by researchers.
“The problem with colitis is that the causes are nebulous,” said lead author John Lee, MD, a visiting scholar at Stanford's Institute for Stem Cell Biology and Regenerative Medicine. “There are limited treatment options such as steroids or other anti-inflammatory drugs, and they work to some extent but nothing is very satisfactory.”
Lee and his team sought to understand how colitis develops and progresses at a molecular level by examining what would happen to the colitis-induced mice if they inactivated parts of the Hedgehog pathway. They found that by deleting a critical signaling protein in the pathway, colitis symptoms grew more severe. Mice with regularly functioning Hedgehog pathways had milder symptoms.
The researchers also explored enhancing the Hedgehog pathway and found that mice with highly functioning pathway had a decrease in colitis intensity.
They found that an anti-inflammatory molecule, called IL-10, is regulated by the Hedgehog pathway and appears to be involved in colitis. “The lining of the colon is continually being replaced throughout our lives and it is regulated by a very complicated set of molecules,” said Mike Rothenberg, MD, PhD, co-author of the study and an adjunct clinical assistant professor of medicine. "We are just starting to learn who those molecules are and what they do."
“The results of this study suggest a possible new approach for treating colitis that may be useful in the future,” Lee said. It could also help develop therapies for colon cancer, which is more likely to affect patients with colitis.
Previously: Can low-fiber diets' damage to our gut-microbial ecosystems get passed down over generations?, Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers and Stanford pediatric gastroenterologist answers your questions on inflammatory bowel diseases
Photo by Hey Paul Studios