UA researchers seek to better understand NHE8 protein’s role in GI disorders, colon cancer

About 1.6 million Americans suffer from inflammatory bowel disease (IBD), which encompasses several painful and complex disorders that include Crohn's disease and ulcerative colitis.

What's more, chronic inflammation in the intestinal tract, prevalent with IBD, has been linked to the development of colon cancer. Each year, nearly 142,000 people in the United States are diagnosed with colon cancer and about 50,000 die.

Although IBD can occur at any age, it's most often diagnosed in children and young adults.

Now, researchers at the University of Arizona Steele Children's Research Center will seek to better understand how a protein known as NHE8 may play a role in the development of these maladies and how it contributes to maintaining the stability of the gut microbiome - the community of bacteria that inhabits the intestines and influences the immune system.

Funded with a five-year, $1.9 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, the research will be led by Fayez K. Ghishan, MD, director of the Steele Children's Research Center and professor and head of the Department of Pediatrics, UA College of Medicine - Tucson, and Steele Center researcher Hua Xu, PhD, associate professor in the Department of Pediatrics.

NHE8 is a sodium/hydrogen exchanger protein that facilitates sodium absorption in the gut. Dr. Ghishan and his team have been at the forefront of research on NHE8 function and regulation for many years. They were the first to clone NHE8 from the intestines and characterize its function.

"Recently, our team discovered novel roles of NHE8, previously thought to be involved only in sodium absorption," Dr. Ghishan said. "It turns out that when we 'knock out' - that is, delete the function of NHE8 - you have 'goblet cell dysfunction,' changes in the microbiota, and the hyper-proliferation of epithelial cells, which leads to the development of colon cancer."

"This is a major grant with the potential to shed light on the mechanisms behind gastrointestinal diseases and colon cancer - diseases that not only affect quality of life for many Americans, but also can lead to death," said UA President Robert C. Robbins. "The foundational work for this research happened at the UA, and so it's fitting that the NIH is providing the investment needed so our researchers can take it even farther."

Over the next five years, Drs. Ghishan, Xu and their research team will examine the role of NHE8 in these areas:

• Goblet cell function. The researchers discovered that NHE8 not only is expressed in the intestinal epithelial lining but also in goblet cells, one of the major cells in the gastrointestinal tract that secrete mucus. "Mucus is very important because it separates bacteria in the GI tract from the lining of the GI tract," Dr. Ghishan explained. "When NHE8 was removed, goblet cells secreted less mucin, reducing the protective barrier of mucus, enabling the bacteria in the lumen (the space inside the intestines) to get closer to the intestinal lining. This produces inflammation and can cause diseases such as ulcerative colitis."
• Changes in the gut microbiome. When NHE8 is inhibited, it alters the microbiota in the gut, making it out of balance, or "dysbiotic." This microbial imbalance has been shown to cause IBD and other GI disorders.
• Hyperproliferation of epithelial cells and the development of colorectal cancer. The research team examined human tissue samples from colon cancer patients. "Normal tissue versus tissue with colon cancer shows marked expression that NHE8 is not present in colon cancer tissue samples. Clearly when you knock out NHE8 you develop polyps and colon cancer," Dr. Ghishan said.

"We believe this study will shed new light on colonic tumor development and potentially provide new ideas for early detection and provide better treatment options," Dr. Xu said.

"In addition to possibly discovering insights into a mechanism of colon cancer development, our findings about how NHE8 impacts goblet cell function and microbiota homeostasis may lead to novel treatments for IBD and other inflammation problems of the gut," Dr. Ghishan added.