Genetic study links IBS to metabolism of lipids and regulation of triglycerides

A large international study has identified 35 regions of the human genome linked to irritable bowel syndrome and has suggested that triglyceride regulation and liver metabolism may help to explain part of the condition’s biology

Irritable bowel syndrome (IBS) is a common condition that affects more than 10 per cent of the general population and can cause recurrent abdominal pain, bloating, constipation and diarrhoea. It is classed as a disorder of gut–brain interaction, which means that symptoms arise from altered communication between the digestive tract, the nervous system and the brain, rather than from a single structural abnormality that clinicians can easily detect.

Previous research – including genetic research – has established links between IBS, nerve signalling, the central nervous system and conditions such as anxiety and mood disorders. However, the precise biological mechanisms that lead to symptoms have remained difficult to define. This uncertainty has left many patients without effective, targeted treatment options and has reinforced the need for a more detailed account of the condition’s molecular basis.

A recent major study has now suggested that metabolism – and specifically the regulation of serum triglycerides – may represent an important part of the explanation. Triglycerides are a major type of fat in the blood and are closely linked to how the liver handles energy, glucose and other lipids.

An international team led by Dr. Mauro D’Amato, Professor of Medical Genetics at LUM University and Ikerbasque Research Professor at the Centre for Cooperative Research in Biosciences, CIC bioGUNE, which is a member of the Basque Research and Technology Alliance, has conducted what the researchers described as the most comprehensive assessment of IBS genetics to date.

The team analysed genetic and health data from 2,775,539 individuals across 22 biobanks worldwide and compared people with and without IBS to identify differences in elements of DNA which have been associated with risk of the condition.

The analysis identified 35 regions of the human genome linked to IBS risk and several of these genetic signals pointed towards the brain and the enteric nervous system – the network of nerves that control the gut. This finding fits with the established view that IBS is strongly influenced by altered gut–brain communication. However, the researchers also found a substantial and unexpected overlap between IBS risk and cardiometabolic traits.

Advanced computational methods allowed the team to demonstrate a likely causal link between genetic liability to IBS and raised triglyceride levels. The strongest evidence pointed to a specific variation in the glucokinase regulator gene which acts as an important regulator of glucose and lipid metabolism in the liver. This variant has already been linked to fat accumulation in the liver and increased triglyceride production. In the present study, it was identified as a key biological mechanism that may connect liver metabolism with 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 Professor D’Amato.

“The genetic link to triglyceride regulation and liver function gives us a completely novel framework for understanding the condition,” he added.

The findings have also pointed towards possible translational applications. By analysing gene-expression patterns associated with IBS risk, the researchers identified several compounds that may be able to reverse disease-related molecular signatures. These included cardiovascular and lipid-modifying drugs which has raised the possibility that existing medicines could be assessed for use in selected patients with IBS.

Such an approach would represent a shift from symptom-based treatment towards mechanism-based therapy. At present, many treatments for IBS focus on bowel habit, pain, diet or psychological factors, with variable success from patient to patient. A clearer genetic and metabolic framework could help researchers to define patient subgroups more accurately and to identify people whose symptoms may arise in part from altered metabolic pathways.

“Our findings support a more integrated view of IBS that extends beyond the traditional gut–brain axis,” added Professor D’Amato.

“The specific pathways we highlighted may contribute to mechanism-based patient stratifications and the identification of novel or existing drugs to be tested in patients who do not respond to current therapies,” he explained.

The study was conducted under the auspices of the Bellygenes Initiative which was coordinated by Professor D’Amato. The initiative is a large international collaboration involving academic and clinical partners across Europe, North America and elsewhere. It drew on data from several cohorts and major population-based biobanks, including UK Biobank, FinnGen, the US’ Million Veteran Program, All of Us and many others.

The results do not suggest that IBS is simply a metabolic disease, nor do they replace the established role of the nervous system and gut–brain interaction. Instead, they indicate that the biology of IBS may be broader than previously recognised, with liver metabolism, blood fat regulation and neural pathways all likely to contribute to risk in different patients.

The researchers said the findings could help to guide future drug-repurposing studies and more precise clinical trials. If the metabolic links are confirmed in further research, they may offer a route towards more targeted care for patients whose symptoms persist despite current therapies. 

For further reading please visit: 10.1136/gutjnl-2026-338800