Northwestern Medicine investigators have identified a surprising culprit in the progression of inflammatory bowel disease: a naturally occurring metabolic compound in the gut, according to a study published in Nature Immunology.
Inflammatory bowel disease (IBD), a chronic condition that includes Crohn’s disease and ulcerative colitis, is characterized by persistent inflammation of the gastrointestinal tract. It affects millions worldwide and can lead to debilitating symptoms such as abdominal pain, diarrhea, fatigue and weight loss. While the exact causes of IBD remain unclear, it is widely believed to be influenced by a mix of genetic, environmental and immune factors.
The new study revealed that elevated levels of the metabolite succinate may actively contribute to the disease by disrupting the function of regulatory T-cells (Tregs), which are essential for maintaining immune balance and preventing runaway inflammation.
The findings shed light on a previously unknown mechanism that could open new avenues for treatment, said Deyu Fang, PhD, the Hosmer Allen Johnson Professor of Pathology, who was senior author of the study.
“Succinate is a normal metabolite we all have, but levels are increased in the blood, gut and stool of colitis patients and those with other inflammatory diseases,” Fang said. “We’ve known this for years. But how succinate causes inflammation, we don’t know much about.”
In the study, Fang and his collaborators observed mice that consumed succinate in their drinking water. They found that higher succinate levels were associated with more severe symptoms of colitis, according to the findings.
Next, investigators administered succinate to cultured Treg cells from mice. They found that succinate impairs the expression of FOXP3, a key protein essential for the suppressive function of Tregs. This disruption makes FOXP3 more vulnerable to degradation. As a result, Tregs lose their ability to control inflammation, leading to more severe colitis in mouse models.
Further experiments demonstrated that deleting the gene Dlst mimicked the effects of high succinate levels, resulting in reduced FOXP3 expression, impaired Treg function and increased gut inflammation. However, restoring FOXP3 levels in these cells reversed the damage, highlighting the central role of this protein in immune regulation.
The study also examined samples from people with IBD and found that their Treg cells had lower levels of FOXP3, which correlated with higher succinate levels and more severe inflammation.
“This gives us a better understanding of why people have colitis,” Fang said. “One of the reasons is that increased succinate impairs the Treg immunosuppressive function through a direct mechanism. That’s the clinical implication that will help us to understand the pathogenesis of the disease.”
The discovery could pave the way for new therapeutic strategies aimed at restoring Treg function or targeting succinate metabolism to treat IBD more effectively, Fang said.
Next, Fang and his colleagues will examine other immune cells in patients with IBD to understand how and why succinate levels are heightened in the disease, he said.
“The bacteria that make succinate are actually ‘good’ bacteria and probiotic in the gut microbiome, not the bad ones, so it’s really puzzling the field,” Fang said. “We don’t know exactly why succinate levels increase in active disease and return to normal in recovery, but this study may provide a clue for us to understand.”
Fang is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Center for Human Immunology.
Yingzi Con, PhD, the Stanley Gradowski Professor of Gastroenterology, and Parambir Singh Dulai, MD, associate professor of Medicine in the Division of Gastroenterology and Hepatology, were co-corresponding authors of the study.
The study was supported by National Institutes of Health grants R01DK126908, R01DK120330, R01CA257520, CA232347, RO1DK135193 and RO1DK124132. Additional funding was provided by the Digestive Health Foundation at Northwestern Medicine.
