By analyzing the frequency of bowel movements in more than 268,000 people, researchers are discovering how thiamine-processing genes shape bowel motility, link constipation and diarrhea to shared biology, and point to new therapeutic possibilities for IBS and related disorders.
Study: Genetic dissection of stool frequency implicates vitamin B1 metabolism and other active pathways in the regulation of gut motility. Image credit: LumenSt/Shutterstock.com
A recent study in Intestine focused on identifying genes and mechanisms involved in gut motility to reveal how vitamin B1 treatment affects the frequency of bowel movements (stool frequency, SF) and identifies potential treatment targets for common digestive disorders affecting millions of patients worldwide.
The role of gastrointestinal motility in food digestion
Gastrointestinal (GI) Motility refers to the coordinated muscle contractions that move food, fluid, and waste through the digestive system. This process, known as peristalsis, is controlled by the enteric nervous system and regulated by signals from the brain.
Proper digestive motility is essential for breaking down food, absorbing nutrients, and eliminating waste. This complex process is regulated by interactions between the gut-brain axis, the immune system, and the gut microbiome, with additional influences from diet, exercise, and medications.
Motility disorder is the basis of irritable bowel syndrome (IBS), other gut-brain interaction disorders, and serious conditions such as chronic intestinal pseudoobstruction. Although these are common disorders, clinicians face significant challenges in treating them, mainly due to a lack of understanding of their underlying causes. By studying the genetics of bowel motility, researchers hope to identify new treatment targets that go beyond symptom management.
The researchers believe that a comprehensive understanding of the genetics of gut motility could help identify new treatment targets. A previous study developed a unique strategy that focused on measurable disease characteristics, such as bowel motility, to identify genes that affect bowel function in IBS patients.
Strategies for measuring bowel motility
Gut motility can be accurately measured by colonic transit time. However, this method is impractical for large-scale genetic studies required to discover new genes. In contrast, the current study used a more accessible measurement of stool frequency (SF), which estimates how often people have bowel movements.
Although SF is not a perfect stand-in for gut motility, it correlates with colonic transit time and captures the full range of motility issues, from constipation to diarrhea. A previous proof of concept study tested this approach by analyzing SF genetics in five European populations. This study successfully identified biological pathways and cell types that control intestinal contractions. The present study aimed to extend the research using larger datasets, including an East Asian biobank, to enable broader genetic insights.
Study characteristics and genetic variants
The current study analyzed questionnaire data from 268,606 individuals in six biobanks, five European ancestry groups and one East Asian group. SF ranged from 0.98 to 1.42 bowel movements per day in the different populations. The prevalence of IBS followed a U-shaped pattern, with constipation dominating IBS at one end of the frequency spectrum and diarrhea 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 loci, including two that had never been associated with SF. Separate analyzes by sex revealed no additional genetic signals.
Genetics accounted for approximately 7 percent of the variance in SF among Europeans. Significant genetic overlap was observed with 164 conditions spanning digestive, cardiovascular, musculoskeletal, neurological and psychiatric domains. SF also showed genetic links to various pain-related traits.
Combining all 268,606 participants in a multiple ancestry analysis revealed 479 significant markers at 18 genomic locations. Together, these accounted for 21 independent genetic signals, including 10 newly identified loci, nearly doubling the number previously linked to stool frequency. Mendelian randomization analyzes 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 loci were identified along with 197 protein-coding genes.
Fine mapping shows that vitamin B1 is associated with gastrointestinal motility
Fine mapping identified specific genetic variants that affect gastrointestinal motility. The analysis identified three specific genetic variants with high confidence: rs12407945 in Europeans and rs2581260 and rs12022782 in the multi-ancestry analysis.
The top variant affects SLC35F3a gene that transports vitamin B1 into cells, influencing expression in the brain and digestive system and possibly integrating the control of central and enteric nervous system motility. The second variant is associated with 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 the conversion of thiamine to its biologically active form, thiamine pyrophosphate (TPP). Other genes of note include KLB, which regulates bile acid metabolism and colon transit, and COLQ, which controls gut nerve signaling and is associated with diverticular disease risk.
SLC35F3 transports thiamine into cells, while XPR1 extracts phosphates required for its activation. Analysis of 98,449 participants confirmed that higher thiamine intake was associated with higher SF in dietary observational data, thus depending on the gene variants carried by an individual. This suggests that 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 explored further for better treatment opportunities, but have not yet been tested experimentally in this context.
conclusions
This genetic analysis of SF reveals new insights into how the gut controls motility. The study revealed a surprising role for vitamin B1 metabolism in gut motility. This discovery opens up possibilities for dietary or pharmaceutical interventions targeting thiamine pathways.
Because SF is a questionnaire-based proxy for mobility 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 drugs, particularly cardiovascular drugs, could be repurposed to treat IBS and other bowel motility disorders, but further experimental and clinical research is needed.
