Hidden Inflammation Drives High Colon Cancer Risk, Garvan Research Reveals

Garvan Institute Study Reveals Hidden Immune Activity in PSC-Associated Bowel Disease

Primary sclerosing cholangitis is a chronic liver disease affecting roughly 1,000 Australians that blocks bile ducts and scars the liver, according to the Garvan Institute. Approximately 70 percent of PSC patients also develop a form of inflammatory bowel disease (IBD) resembling ulcerative colitis. For years, researchers puzzled over a clinical contradiction: PSC patients experience less severe flare-ups yet face a colorectal cancer risk three times higher than individuals with ulcerative colitis alone.

To uncover the root cause, researchers at the Garvan Institute examined colonic biopsies from eight patients with PSC-associated IBD, 11 patients with ulcerative colitis alone, and 10 healthy volunteers. Utilizing single-cell sequencing, spatial mapping, and microbiome analysis, the team discovered that the guts of PSC-associated IBD patients harbor a distinct microbiome and elevated immune activity, even during periods without active inflammation or flare-ups.

“Chronic, low-level inflammation is a known contributor to cancer risk, and our findings may explain why these patients with a milder-looking disease have a much greater chance of developing colorectal cancer,” said Dr. Kylie James, lab head at the Garvan Institute and lead author of the study. Dr. James noted that understanding this baseline activity allows researchers to explore treatments targeting inflammation even when patients show no obvious symptoms.

Single-Cell Sequencing Detects Silent Cytotoxic Cells in Normal Tissue

Standard colonoscopy and microscopic examination by pathologists often classify tissue as free from inflammation during remission. However, the Garvan team’s advanced spatial mapping revealed a hidden accumulation of cytotoxic, or cell-killing, immune cells within areas of the colon that appeared normal under a standard microscope.

“In IBD, we’ve long known that sustained remission should mean quiet immune cells, not just quiet symptoms,” Dr. James explained. “What we’re finding here goes further – there’s immune activity happening in tissue that a pathologist would call quiet, and it’s in the very part of the colon where these patients face their highest cancer risk.”

Dr. Jacqueline Tearle, a postdoctoral researcher at the Garvan Institute and first author of the study, emphasized the clinical significance of these maps. “This is the first time this kind of immune activity has been mapped in these patients, and it tells us where to focus. If we can find ways to detect this activity in the clinic, there’s real potential to reduce the cancer risk that comes with it,” according to Dr. Tearle.

Mast Cells and Shared Immune Signals During Active Flares

When examining patients during active disease flare-ups, the Garvan researchers identified another key cellular feature: a surge of mast cells in the gut. Mast cells are fragile immune cells involved in inflammation and allergic responses that are typically destroyed during standard tissue-freezing procedures, which explains why previous studies frequently overlooked them.

By processing patient tissue immediately after collection, the Garvan team preserved these delicate cells. “We found quite a unique mast cell population, and its gene expression suggests it could contribute to cancer risk during periods of active inflammation or flare ups,” Dr. Tearle stated.

Associate Professor Simon Ghaly, a gastroenterologist at St Vincent’s Hospital Sydney who led patient recruitment for the study, highlighted the clinical gap the research addresses. “For patients living with PSC-related bowel disease, the risk of colorectal cancer is a real concern, and current tools don’t always capture what’s actually happening in the gut,” Professor Ghaly said. These discoveries provide a rationale for exploring targeted treatments matched to biological drivers rather than shared symptoms.

Broader Mechanisms Connecting Gut Inflammation to Cancer Risk

The link between chronic gut inflammation and heightened colorectal cancer risk is a major focus of international research teams. A study published by researchers at Weill Cornell Medicine in Immunity identified a separate immune pathway involving TL1A, an inflammatory signaling protein linked to both IBD and colorectal cancer. According to that study, TL1A activates gut-resident cells known as ILC3s, which then stimulate the rapid production of neutrophils in the bone marrow—a process called emergency granulopoiesis—that travel to the gut and promote tumor development.

Meanwhile, research funded by the National Institutes of Health (NIH) and conducted by scientists at the Broad Institute of MIT and Harvard investigated how chronic colitis leaves long-lasting effects on colonic stem cells. Published as part of the Cancer Grand Challenges initiative, that research demonstrated that repeated cycles of gut injury alter the epigenome, increasing the activity of AP-1 transcription factors. This epigenetic memory persisted in cells for over 100 days after inflammation ceased, accelerating tumor growth when cancer-triggering genes were introduced.

Study / Institution	Key Focus	Primary Mechanism Identified
Garvan Institute of Medical Research	PSC-Associated IBD	Hidden cytotoxic immune cells and unique mast cell populations driving cancer risk.
Weill Cornell Medicine	Inflammatory Bowel Disease (IBD)	TL1A signaling recruits neutrophils from bone marrow via ILC3 activation.
Broad Institute of MIT and Harvard	Colitis and Epigenetic Memory	Persistent AP-1 transcription factor activity in colonic stem cells following injury.

Frequently Asked Questions

What is primary sclerosing cholangitis (PSC)?

Primary sclerosing cholangitis is a chronic liver disease that blocks bile ducts and causes scarring of the liver, affecting around 1,000 Australians according to the Garvan Institute.

Why do PSC patients face a higher risk of colon cancer?

Recent research from the Garvan Institute shows that patients with PSC-associated IBD harbor hidden, low-level cytotoxic immune activity and unique mast cell populations in the colon, even during clinical remission when tissue appears normal.

How do researchers study hidden gut inflammation?

Scientists use advanced methods such as single-cell sequencing, spatial mapping, and immediate tissue processing to preserve fragile cells like mast cells and detect immune activity undetectable by standard microscopic examinations.

What are the next steps for PSC and IBD treatment?

Researchers are currently examining changes in cells lining the colon using patient-derived gut models to better understand how underlying biological mechanisms translate into cancer risk and to guide targeted treatments.