Fat Metabolism Plays an Unexpected Role in IBS

Irritable bowel syndrome (IBS) affects roughly 10 percent of the population. The condition causes long-term gastric pain, bloating, and constipation or diarrhea. There’s evidence that miscommunication between the gut and the brain helps drive IBS. Previous genetic studies have suggested links between IBS and nerve signaling as well as conditions such as anxiety and other mood disorders.¹

But many of the mechanisms behind IBS have remained unclear, frustrating researchers and patients who need help with their chronic symptoms.

Biological Conversations Involved in IBS Risk

In a new study, an international group of researchers suggests that the metabolism of fats in the blood called triglycerides may play a previously unheralded role in IBS.² The team carried out the most thorough examination of the genetics of IBS yet. The study, published in the journal Gut, brought together data from nearly 2.8 million people with and without IBS, split across nearly two dozen biobanks worldwide.

“We have long known that IBS involves a complex dialogue between the gut and the brain, but these results show that the conversation includes the body's metabolic system too,” said Mauro D’Amato, a medical geneticist at CIC bioGUNE and a study coauthor, in a statement.

The researchers found that 35 regions of the human genome were linked to IBS risk. Some of these signals confirmed what was previously known about IBS: There were strong links to the enteric nervous system, a nexus of nerves that links the brain to the gut. But there was a powerful link between disease risk and cardiometabolic traits as well. “The genetic link to triglyceride regulation and liver function gives us a completely new framework for understanding the condition,” said D’Amato. The genetic risks identified were consistent across different definitions of IBS.

The team undertook further computational analysis, which suggested a possible causal link between higher levels of triglycerides and the risk of IBS. One of the most robust links centered on a gene called glucokinase regulator (GCKR), a powerful regulator of sugar and fat metabolism in the liver. A mutation in GCKR identified in the study is known to increase fat accumulation in the liver.³

Translational Drug Development for IBS

The researchers went further than just identifying disease risks. They also identified compounds that may be able to alter molecular signatures associated with IBS. These included drugs used to treat cardiovascular disease and that alter fats in the body. The authors are hopeful that some of these drugs could be repurposed for IBS. They also proposed that the study’s findings may help divide people with IBS into different subgroups for specialized treatment depending on whether their disease has a metabolic component.

“Our findings support a more integrated view of IBS that extends beyond the traditional gut-brain axis,” added D'Amato. “The specific pathways we highlighted may contribute to mechanism-based patient stratifications and the identification of new or existing drugs to be tested in patients who do not respond to current therapies.”