Genetic dissection of stool frequency implicates vitamin B1 metabolism and other actionable pathways in the modulation of gut motility.
Level 3 - non-randomized controlled study
multiancestry genome-wide association meta-analysis with Mendelian randomization and cohort interaction analysis
PubMed 41558814 · doi:10.1136/gutjnl-2025-337059
What was done
Researchers conducted a multiancestry genome-wide association study (GWAS) meta-analysis of stool frequency in 268,606 European and East Asian individuals. They estimated heritability, genetic correlations with other traits, applied Mendelian randomization to evaluate causal effects on irritable bowel syndrome (IBS), and fine-mapped loci to prioritize candidate genes. They followed up thiamine-related findings by testing dietary thiamine intake and gene-diet interactions involving candidate loci (SLC35F3 and XPR1) in 98,449 UK Biobank participants.
What was found
Stool frequency heritability was 7.0% in Europeans and 5.6% in East Asians. Significant genetic correlations were observed with gastrointestinal and psychiatric disorders (r_g = 0.18–0.47) and cardiovascular traits (r_g = 0.12–0.14), along with causal effects on IBS. The meta-analysis identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signaling (COLQ). Fine-mapping highlighted vitamin B1 metabolism genes SLC35F3 and XPR1. In 98,449 UK Biobank participants, dietary thiamine intake was positively associated with stool frequency (p < 0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p < 0.0001).
Why it matters
This study establishes specific genetic determinants of bowel movement frequency and identifies vitamin B1 metabolism as an actionable pathway regulating gut transit, offering potential targets for motility disorders.
Limits
Stool frequency served as an indirect self-reported proxy for gastrointestinal transit rather than direct physiological transit measurements. The study was restricted to European and East Asian cohorts, limiting generalizability to other ancestries. Dietary thiamine intake relies on self-reported dietary data, and causal clinical efficacy remains to be established in prospective randomized trials.
Cited by
- supports Vitamin B1 (thiamine) stimulates and supports gastrointestinal peristalsis.