Why does IBD continue to get worse? Scientists have found a clue in the intestinal lining: ScienceAlert

For people with inflammatory bowel disease, feeling better thanks to treatment does not always mean permanent improvement: the disease may come back.

One study suggests part of the explanation may lie in intestinal cells that remain fragile even when symptoms such as abdominal pain and diarrhea are controlled.

Crohn’s disease and ulcerative colitis are the main forms of inflammatory bowel disease (IBD). Both involve chronic inflammation of the digestive tract.

Treatment can bring IBD into remission, a period in which its activity decreases, but another flare-up may follow.

Researchers found signs of abnormal cell death in intestinal tissues, even in patients whose disease was under control.

“The gut may still have a vulnerability that is not apparent from symptoms alone,” gastroenterologist Britt Christensen, head of the inflammatory bowel disease unit at the Royal Melbourne Hospital, told ScienceAlert.

The study, published in Scienceexamined more than 900 intestinal biopsies, small tissue samples, from 80 people with and without IBD. Most IBD patients had inactive or mildly active disease.

Led by researchers from Australia’s Walter and Eliza Hall Institute, the team studied the intestinal lining: a protective layer that is constantly rebuilding itself.

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Normally, controlled cell death eliminates unwanted or damaged cells, while stem cells produce replacement cells.

Researchers found that inflammation could change the behavior of intestinal cells, making them more vulnerable to abnormal death signals.

Some signals were detectable even in tissue without obvious inflammation, suggesting that problems could persist beneath a seemingly healthy surface.

“This suggests that clinical remission does not always mean that the underlying biology has returned to normal,” Christensen explained.

To further their research, the researchers grew miniature intestinal tissues from human samples. These laboratory models, called organoids, allow scientists to examine how cells respond to inflammation. Other researchers have used human cells to recreate the characteristics of IBD on a chip.

The experiments revealed an unexpected link between two ways cells die. The patient’s tissues showed signals associated with necroptosis, a process that can rupture cells and release contents that promote inflammation.

But when the organoids were exposed to inflammatory signals, their cells died primarily through apoptosis, a more orderly process of cellular dismantling.

Blocking necroptosis did not prevent cell death under the conditions tested. Thus, drugs targeting a signal observed in diseased tissues may not be sufficient on their own to protect cells.

In the laboratory, deleting specific genes protected particular cell types. Further research is needed to determine whether these mechanisms can be safely targeted in patients.

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The team examined whether tissue outcomes were associated with subsequent flares.

Of 52 IBD patients, 30 had follow-up information covering two to three years. Sixteen experienced a flare requiring treatment intensification or change, while 14 remained stable. Twenty-two were lost to follow-up.

Those who relapsed later had elevated levels of a cell death signaling marker compared to people without IBD. However, this comparison does not establish whether the marker can tell who will relapse and who will not.

Patients who relapsed also initially had greater microscopic inflammation. Larger studies could potentially determine whether the signals provide useful information beyond existing measures of inflammation.

“The monitoring results are promising but preliminary,” Christensen warned.

For now, the findings may help explain why the disease keeps coming back, although they are not a test that doctors can use to predict a flare-up.

“Protecting the mucosa and its ability to regenerate itself could therefore complement treatments that control inflammation,” Christensen said.

But cell death pathways also serve essential functions, including eliminating damaged or potentially cancerous cells.

“We have not demonstrated that blocking these mechanisms safely prevents flares in patients,” Christensen said.

The longer-term goal is what she calls “molecular healing”: solving cellular problems that persist beneath apparent healing. Whether this can keep patients healthy longer remains to be seen.

The research was published in Science.