The Editors in chief of GUT, Professors Matias A. Avila, William Grady and Thomas Rösch, have selected Professor Mauro D’Amato from the Gastrointestinal Genetics Lab, CIC bioGUNE – BRTA, Derio, Spain, the Department of Medicine and Surgery, LUM University, Casamassima, Italy, and Ikerbasque, Basque Foundation for Science, Bilbao, Spain, to do the next #GUTBlog.

The #GUTBlog focusses on the paper entitled “Genetic dissection of stool frequency implicates vitamin B1 metabolism and other actionable pathways in the modulation of gut motility” which was published in paper copy in GUT in August 2026. Professor D’Amato is the senior author.

Professor D’Amato writes:

“DNA ties gut motility to vitamin B1, and points to a drug cabinet worth exploring

Bowel habits are not exactly dinner-table conversation. But for those of us who study the genetics of gastrointestinal disease, how often someone opens their bowels turns out to be a surprisingly powerful clue. Stool frequency reflects gut motility (how quickly the gut moves things along) and when that goes wrong, the consequences range from uncomfortable to debilitating: constipation, diarrhoea, irritable bowel syndrome (IBS). These conditions affect millions of people, yet the biological mechanisms behind them remain frustratingly elusive. In our recent paper published in Gut, I think we have made a meaningful step forward.

A simple question, asked at scale

The challenge with studying gut motility genetically is a practical one. The gold-standard measure, colonic transit time, requires specialist equipment and is simply not feasible in the large cohorts needed for large-scale genetic studies. So I had the idea of using stool frequency (how often people open the bowels) as an indirect proxy: not perfect, but it correlates with colonic transit and can be captured from questionnaire data in biobanks.

By pooling data from 268,606 individuals of European and East Asian ancestry, we performed genome-wide association studies and their meta-analysis (GWAS) with a straightforward goal: find the DNA variants that influence how often people go to the toilet, and use those signals to work backwards to the biology.

What the genome told us

We identified 21 independent genomic regions associated with stool frequency, ten of which were entirely new. Several signals pointed to pathways already known to be involved in gut movement, like bile-acid signalling and cholinergic nerve transmission, which was reassuring. But the result that genuinely surprised us came from fine-mapping two of the top signals. Both converged on genes involved in vitamin B1 (thiamine) metabolism: SLC35F3, which encodes a thiamine transporter, and XPR1, a phosphate exporter essential for activating thiamine inside cells. Vitamin B1 had never been on the radar as a regulator of gut motility.

To test whether this genetic signal had real-world relevance, we looked at dietary data from nearly 100,000 UK Biobank participants and found that higher thiamine intake was significantly associated with more frequent bowel movements, and that this relationship was itself shaped by a person’s genetic makeup at those two loci. That gene-diet interaction was, to me, one of the most compelling findings in the paper.

A drug cabinet worth exploring

Beyond the vitamin B1 story, we ran a computational drug signature analysis, with a method that translates genetic findings into a gene expression fingerprint to screen large pharmacological databases for compounds that could mimic or counteract that signature. This can flag existing drugs for repurposing or point to entirely new therapeutic targets.

The results were striking. Among hundreds of candidate compounds, we found drugs already used for gut conditions, including serotonin-targeting agents, acetylcholinesterase inhibitors used to treat delayed gastric emptying, and antihistamines. But what I found most intriguing was the appearance of cardiovascular drugs, particularly calcium channel blockers such as verapamil, nimodipine and felodipine. This was not entirely out of the blue (our genetic correlation analyses had already flagged an unexpected overlap between stool frequency and cardiovascular traits), but seeing it reinforced by the drug analysis adds a layer of biological coherence that warrants serious follow-up. Could drugs developed for the heart have meaningful effects on gut motility? Worth asking.

What comes next

One needs to caution that these findings do not translate directly into clinical recommendations. What they definitely do, however, is to provide a map, a set of mechanistic leads grounded in human genetic data, that can now be tested in the laboratory and, eventually, in clinical trials. The vitamin B1 pathway is perhaps the most immediately actionable, given that thiamine is a well-characterised, safe and widely available nutrient. But the broader pharmacological landscape that emerged from this work is equally exciting.

More than anything, I hope this study makes the case that studying simple, measurable traits at scale is a powerful strategy for uncovering the biology of complex gut disorders. We asked a basic question “what makes some people go to the toilet more often than others?”, and the answer turned out to involve pathways with real therapeutic potential. That, to me, is what genetics is for.”

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