The protein MCL1 was found to be critical for maintaining intestinal homeostasis in a study performed on MCL1 knockout mice. The mice lacked the ability to make the protein and developed irreparable damage to the intestine and eventually developed intestinal tumors. The team determined that the intestinal changes seen in the mice are similar to those in people with chronic intestinal disorders and inflammation, raising the possibility of a link between dysfunctional MCL1 and poor intestinal health. The research, led by a team at the University of Zurich, was published in a paper in Gastroenterology.
MCL1 is known to have an indispensable role in maintaining liver homeostasis, prompting the researchers to study its function in the intestinal tract. In this study, the team used MCL1-deficient mice and healthy control mice. Both were fed a normal diet, though some were given antibiotics in their drinking water, and were kept in germ-free housing.
Endoscopy was performed on the animals looking for disruptions to the intestinal epithelial barrier. Intestinal tissues were further analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces.
MCL1 knockout mice spontaneously developed several signs of intestinal dysregulations: apoptotic enterocolopathy, characterized by increased intestinal epithelial cell apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Further, loss of MCL1 prevented the differentiation of intestinal stem cells. Over time, the intestinal stem cells in these mice showed accumulated DNA damage such that by one year of age, more than 80 percent of the MCL1 deficient micedeveloped intestinal tumors within the small intestine and/or colon. Those tumors had with morphologic and genetic features of human adenomas and carcinomas.
The researchers noted that the mice lived in germ-free housing, protecting them from potentially infectious agents known to induce intestinal inflammation. While the MCL1-deficient mice had lower markers for intestinal inflammation they were not protected against tumor development.
“These findings, in particular the microbiota-independency of MCL1 deficiency-associated tumorigenesis, clearly demonstrate an essential role for MCL1 in preserving intestinal homeostasis,” the authors say. “These results may have important implications for understanding the pathogenesis of apoptotic enterocolopathy, inflammatory bowel disease, and colorectal carcinoma development.”
Unexpectedly, the researchers noted that some tumors expressed excess MCL1, rather than a deficiency. The team speculates that the tumors overexpress MCL1 in an attempt to improve survival. And for that reason, a number of new therapies are currently being tested to interfere with and reduce MCL1 function.
With this new research, understanding the yin and yang of MCL1 regulation for intestinal health is of increased importance.
“The regulation of this protein is like walking a tightrope,” warns Marc Healy, first author of the study. “Our study therefore urges an element of caution when it comes to using MCL1 inhibition in cancer therapy.”