Nav: Home

Chemotherapy-induced diarrhea traced to immune cells

June 26, 2018

Some 50 to 80 percent of cancer patients taking powerful chemotherapy drugs develop diarrhea, which can be severe and in some cases life-threatening. Their problems occur when contractions in the smooth muscle lining the gastrointestinal (GI) tract go haywire as food is digested. The same issues can occur in people with irritable bowel syndrome and inflammatory bowel disease.

For decades, scientists have thought the contraction problems originated with nerve cells in the intestines. But new research in mice at Washington University School of Medicine in St. Louis indicates that specialized immune cells called macrophages also can trigger intestinal contractions, independent of the nervous system.

The new findings, published July 17 in the journal Immunity, provide a new target to help treat chemotherapy-induced diarrhea and, potentially, diarrhea linked to other GI problems. They also raise the possibility that drugs developed to treat diarrheal-related intestinal disorders may have targeted the wrong cells, which could help explain why treatments for these conditions often aren't very effective.

"Diarrhea is a common side effect of chemotherapy that, in severe cases, can lead to death or to patients having to stop lifesaving treatment because often there are no effective therapies to control the diarrhea," said co-senior investigator Hongzhen Hu, PhD. "This research provides a new avenue to explore in developing drugs to stop such diarrhea."

Macrophages are known for their role in fighting infections, cancer and inflammation. Although the largest population of macrophages in the body resides in the gut, scientists have not understood what some of those cells were doing to help keep the GI tract healthy.

The Washington University researchers focused on a receptor on macrophages called TRPV4. These receptors are important to contractions in the gut but had been assumed to be located on nerve cells.

"We found that the macrophages themselves trigger muscle contractions in the gut without any involvement from neurons," said Hu, an associate professor of anesthesiology. "The pathway works in an entirely different way from what we had expected."

And somewhat surprisingly, the role of macrophages in intestinal motility was identified by researchers who don't normally study intestinal function. Hu and co-senior investigator Brian S. Kim, MD, are faculty members at the Washington University Center for the Study of Itch.

"People think the Itch Center exists only to solve itch-related problems, but that's an oversimplification of what we do," said Kim, co-director of the center and an assistant professor of medicine in the Division of Dermatology. "We focus on problems involving sensory perception. Itch is a great paradigm for that, but we're also concerned about things like chronic cough, migraine headaches and bowel function."

Previously, Hu and Kim had identified a role for macrophages' TRPV4 receptors in chronic itching in the skin. Here, they focused on macrophages that reside in the gut's smooth muscle layer, demonstrating that the receptors sense heat, chemical changes and the movement of food through the intestine. All of those things can trigger muscle contractions, or motility, in the gut.

In experiments involving genetically modified mice, the researchers found that animals without TRPV4 receptors on gut macrophages had poor intestinal motility. They also found that by inhibiting the actions of these receptors, they could reverse diarrhea caused by chemotherapy drugs.

"Solving problems with bowel function in chemotherapy patients is important because at least half of those patients develop diarrhea, but we'd also like to see whether these receptors on macrophages can be targeted to treat irritable bowel syndrome, which often doesn't respond well to existing drugs," Kim said.
-end-
Luo J, et al. TRPV4 channel signaling in macrophages promotes gastrointestinal motility via direct effects on smooth muscle cells. Immunity (49) 1-13, July 17, 2018 (published online June 26, 2018). https://doi.org/10.1016/j.immuni.2018.04.021

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of General Medical Sciences of the National Institutes of Health (NIH). Grant numbers R01 GM 101218, R01 DK103901, P30 DK052574, K08 AR065577 and R01 AR070116.

Washington University School of Medicine's 1,300 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

Related Chemotherapy Articles:

Nanotechnology improves chemotherapy delivery
Michigan State University scientists have invented a new way to monitor chemotherapy concentrations, which is more effective in keeping patients' treatments within the crucial therapeutic window.
Novel anti-cancer nanomedicine for efficient chemotherapy
Researchers have developed a new anti-cancer nanomedicine for targeted cancer chemotherapy.
Ending needless chemotherapy for breast cancer
A diagnostic test developed at The University of Queensland might soon determine if a breast cancer patient requires chemotherapy or would receive no benefit from this gruelling treatment.
A homing beacon for chemotherapy drugs
Killing tumor cells while sparing their normal counterparts is a central challenge of cancer chemotherapy.
Chemotherapy or not?
Case Western Reserve University researchers and partners, including a collaborator at Cleveland Clinic, are pushing the boundaries of how 'smart' diagnostic-imaging machines identify cancers -- and uncovering clues outside the tumor to tell whether a patient will respond well to chemotherapy.
More Chemotherapy News and Chemotherapy Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...