Genetic research reveals surprising metabolic pathway for irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common condition that affects more than 10% of the general population, causing recurrent abdominal pain, bloating, constipation and diarrhea. IBS is considered a disorder of gut-brain interaction, and previous research, including genetic research, has established links to nerve signaling, the nervous system and other conditions including anxiety and mood disorders. The exact biological mechanisms have however, remained frustratingly difficult to pin down, leaving many patients without effective, targeted treatments.

Now, a major new study published in Gut suggests that metabolism, specifically the regulation of blood fats known as triglycerides, may be a missing piece of the puzzle.

An international team led by Mauro D'Amato, Professor of Medical Genetics at LUM University and Ikerbasque Research Professor at CIC bioGUNE, member of BRTA, conducted the most comprehensive assessment of IBS genetics to date. They analysed genetic and health data from 2,775,539 individuals across 22 biobanks worldwide, comparing people with and without IBS to find DNA differences associated with the condition.

The analysis identified 35 regions of the human genome linked to IBS risk. While several of these genetic signals pointed to the brain and enteric nervous system (the network of nerves controlling the gut), researchers also found a strong, unexpected overlap with cardiometabolic traits.

Using advanced computational methods, the team demonstrated a likely causal link between genetic liability for IBS and elevated levels of triglycerides, a type of fat found in the blood. The strongest evidence pointed to a specific variation in the GCKR gene, which acts as a master regulator of glucose and lipid metabolism in the liver. This variant, already known to promote fat accumulation in the liver and increase triglyceride production, was identified as a key mechanism connecting liver metabolism to IBS risk.

"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 Prof. D'Amato. "The genetic link to triglyceride regulation and liver function gives us a completely new framework for understanding the condition."

Importantly, the study also pointed to potential translational applications. By analysing gene-expression patterns associated with IBS risk, the team identified several compounds capable of reversing disease-related molecular signatures; among these were cardiovascular and lipid-modifying drugs, thus opening the door to possible drug repurposing strategies and mechanism-based therapies.

"Our findings support a more integrated view of IBS that extends beyond the traditional gut-brain axis," added Prof 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."

The study was conducted under the auspices of the "bellygenes initiative" coordinated by Prof. D'Amato, a large international collaboration involving academic and clinical, partners across Europe, North America and other regions, and drawing on data from several cohorts and major population-based biobanks including UK Biobank, FinnGen, the Million Veteran Program, All of Us and many others.