Why a gluten-free diet fails in some coeliac patients

A research team led by the Garvan Institute of Medical Research and UNSW Sydney has discovered why some people with coeliac disease continue to suffer debilitating symptoms despite avoiding gluten.

The team’s study, published in the journal Science Translational Medicine, used cutting-edge single-cell sequencing techniques to reveal that certain immune cells in the gut of these patients carry genetic mutations. Their findings suggest these abnormal immune cells are driving ongoing intestinal inflammation that causes symptoms like diarrhoea, pain and malnutrition — and point to a new way to diagnose and potentially treat the most severe form of coeliac disease.

Coeliac disease is a chronic autoimmune condition where the body mistakenly attacks the small intestine in response to gluten — a protein found in wheat, barley and rye. While most people with the condition experience relief when they remove gluten from their diet, around 1% develop refractory coeliac disease (RCD), which is where symptoms persist despite strict dietary control. RCD is classified into two types: type 2 is caused by abnormal immune cells that can rapidly develop into an aggressive lymphoma, but the cause of type 1 has remained a mystery until now.

For this study, the researchers tested biopsies taken from the small intestine of 10 individuals with RCD1 and compared them with biopsies from four people with newly diagnosed coeliac disease on a gluten-containing diet, two individuals with RCD2 and seven people without active coeliac disease. They found the mutated immune cells present in seven of the 10 people with RCD1, and in one of four people with newly diagnosed coeliac disease.

“We discovered that some patients with refractory disease have an accumulation of immune cells with genetic mutations,” said Dr Manu Singh, first author of the study and a Senior Research Officer at Garvan. “These may develop during periods of chronic inflammation, such as earlier gluten exposure.

“These mutations share similarities with those we see in certain lymphomas, appearing to give the cells a growth and survival advantage. This is a potential explanation for why they persist even after a patient eliminates gluten from their diet.

“Until recently, these abnormal immune cells were undetectable using traditional methods, but new single-cell sequencing techniques have made it possible to analyse thousands of individual cells from intestinal biopsies.”

This discovery could lead to new ways to identify at-risk patients earlier and more targeted, precise treatments. Currently, the only treatment for RCD is broad immunosuppression, which dampens the immune system but does not specifically target the mutated cells.

“If we can confirm that these mutated immune cells are driving the disease, then we may be able to target them with existing drugs,” said co-senior author Professor Fabio Luciani, Visiting Scientist at Garvan and Professor in Systems Immunology at UNSW Sydney.

“For example, we found that many of these aberrant cells have mutations in the JAK-STAT pathway, which is already targeted by approved drugs known as JAK inhibitors. With more investigation, this could lead to a personalised medicine approach where we treat patients based on their specific immune cell mutations.”

The research thus highlights the power of advanced genetic technologies in understanding numerous autoimmune diseases — not just coeliac disease — with Luciani noting that it will accelerate our ability to develop personalised therapies for patients battling these chronic disorders.

Image credit: iStock.com/Jelena Stanojkovic