A recent study focused on identifying genes and mechanisms involved in gut motility to uncover how vitamin B1 processing influences bowel movement frequency (stool frequency, SF) and identifies potential treatment targets for common digestive disorders that affect millions of patients worldwide.
Study
The current study analyzed questionnaire data from 268,606 people across six biobanks, five European ancestry groups, and one East Asian group. SF ranged from 0.98 to 1.42 bowel movements per day across the different populations. IBS prevalence followed a U-shaped pattern, with constipation predominant IBS at one end of the frequency spectrum and diarrhea predominant IBS at the other.
In the European meta-analysis, a total of 7,879,955 genetic variants were analyzed, yielding 3,083 significant genetic markers at 12 independent genomic locations, including two that had never been linked to SF. Separate analyses by sex did not reveal any additional genetic signals.
Genetics accounted for about 7 percent of the variation in SF among Europeans. A significant genetic overlap was observed with 164 conditions spanning digestive, cardiovascular, musculoskeletal, neurological, and psychiatric domains. SF also showed genetic connections to various pain-related traits.
Combining all 268,606 participants in a multi-ancestry analysis revealed 479 significant markers across 18 genomic locations. Together, these corresponded to 21 independent genetic signals, including 10 newly identified loci, nearly doubling the number previously linked to stool frequency. Mendelian randomization analyses revealed bidirectional causal effects between SF and diverticular disease, while also showing that SF has causal effects on IBS, but IBS does not causally influence SF. Hemorrhoids were found to have a negative causal effect on SF, suggesting a protective effect against higher stool frequency. A total of 21 genetic locations were identified along with 197 protein-coding genes.
Findings
Fine mapping determined specific genetic variants that influence GI motility. The analysis pinpointed three specific genetic variants with high confidence: rs12407945 in Europeans, and rs2581260 and rs12022782 in the multi-ancestry analysis.
The top variant affects SLC35F3, a gene that transports vitamin B1 into cells, influencing expression in the brain and digestive tract and potentially integrating central and enteric nervous system control of motility. The second variant links to hemorrhoids, but its mechanism remains unclear. The third affects XPR1, a phosphate exporter also linked to blood pressure. Phosphate export by XPR1 is essential for converting thiamine into its biologically active form, thiamine pyrophosphate (TPP). Other notable genes include KLB, which regulates bile acid metabolism and colonic transit, and COLQ, which controls gut nerve signaling and is associated with diverticular disease risk.
SLC35F3 transports thiamine into cells, while XPR1 exports phosphate needed to activate it. Analysis of 98,449 participants confirmed that higher thiamine intake was associated with higher SF in observational dietary data, with the effect depending on which gene variants a person carried. This suggests these genes regulate how the body uses vitamin B1 to control gut motility rather than acting through a single organ or pathway.
Drug signature analysis computationally prioritized 831 compounds that could speed up or slow down gut motility based on gene expression patterns. These could be further explored for better treatment opportunities, but have not yet been tested experimentally in this context.
Conclusion
This genetic analysis of SF reveals new insights into how the gut controls motility. The study uncovered a surprising role for vitamin B1 metabolism in gut motility. This discovery opens possibilities for dietary or drug interventions targeting thiamine pathways.
Because SF is a questionnaire-based proxy for motility, and dietary thiamine intake was assessed observationally rather than through intervention trials, the authors emphasize the need for mechanistic studies and clinical validation. Many existing medications, particularly cardiovascular drugs, could be repurposed to treat IBS and other gut motility disorders, but further experimental and clinical investigation is required.
Source:
https://www.news-medical.net/news/20260123/Genetic-study-links-vitamin-B1-metabolism-to-gut-motility-and-IBS-risk.aspx