From Physiology to Genetics: A New Lens on Gut Motility, With Mauro D’Amato, PhD

Gut motility plays a central role in digestive health, yet the biological mechanisms that regulate how frequently the bowel moves and why this varies so widely among individuals remain incompletely understood. This challenge is especially pronounced in disorders of gut–brain interaction, such as irritable bowel syndrome (IBS), where symptoms like constipation and diarrhea reflect underlying dysmotility but arise from complex, multifactorial processes.

In a new study published in Gut, Mauro D’Amato, PhD, Ikerbasque Research Professor and head of the Gastrointestinal Genetics Lab at CIC bioGUNE, and colleagues took an unconventional approach to this challenge, examining gut motility as a physiological trait. Specifically, they analyzed stool frequency as a measurable outcome across large populations, with the goal of identifying genetic mechanisms that influence bowel movement patterns and could ultimately be targeted therapeutically.

“The problem in studying these diseases, I do genetics, so I try to identify what could be the eventual genetic causes or partial cause of these diseases, is that they're very complex. There are so many factors playing a role,” D’Amato explained to HCPLive. “Instead of looking at the actual disease, we had the idea to look at the physiology, with the idea that if we identify genes that are relevant to gut motility, we identify mechanisms relevant to gut motility, and then eventually we can target these mechanisms to cure or treat alterations of the of the gut motility and peristalsis.”

He and a team of investigators performed a multiancestry genome-wide association study (GWAS) meta-analysis of stool frequency in 268,606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomization was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritize candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank.

Results showed strong genetic correlations with gastrointestinal and psychiatric disorders (rg=0.18–0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (rg=0.12–0.14) were supported by drug signature enrichment analyses.

They identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3, a thiamine transporter, and XPR1, a phosphate exporter essential for thiamine activation.

In 98,449 UK Biobank participants, thiamine intake was positively associated with SF (P <.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (P <.0001).

“I’ve already heard people saying ‘Oh, well, how much vitamin B? What should I eat every day now?’ We're not there yet, at least this is not what we do in the lab,” D’Amato explained, describing the need for future animal studies and eventual human clinical trials to determine whether vitamin B1 supplementation can meaningfully improve real-world outcomes.

He additionally pointed to study findings highlighting both established and unexplored compounds behind the regulation of gut motility, the latter of which offers a potential next wave of candidates to be tested.

Editors’ Note: D’Amato reports no relevant disclosures.

References

1. Díaz-Muñoz C, Bozzarelli I, Lopera-Maya EA, et al. Genetic dissection of stool frequency implicates vitamin B1 metabolism and other actionable pathways in the modulation of gut motility. Gut doi:10.1136/gutjnl-2025-337059

2. CIC bioGUNE. DNA ties gut motility to vitamin B1. EurekAlert! January 20, 2026. Accessed January 23, 2026. https://www.eurekalert.org/news-releases/1112772