Gene GLS May Drive Irritable Bowel Syndrome Risk Through Mannose Metabolism

Genetically predicted higher expression of the succinylation-related gene GLS is associated with increased risk of irritable bowel syndrome, and a large genetic analysis suggests this link may run partly through altered levels of circulating mannose, mannonate and specific glycerophospholipids. The finding comes from an integrated study that combined two-sample Mendelian randomization, summary-data-based Mendelian randomization and mediation analysis, published in the Egyptian Journal of Medical Human Genetics.

Irritable bowel syndrome is a functional gastrointestinal disorder affecting roughly 11 percent of the global population, marked by chronic abdominal pain and altered bowel habits. Although genome-wide association studies have identified multiple IBS-associated risk loci, the underlying pathogenic mechanisms remain elusive. The research team, led by Lian Mo and colleagues, set out to test whether succinylation-related genes—genes implicated in lysine succinylation, a post-translational modification that attaches negatively charged succinyl groups to lysine residues and can dynamically regulate enzymatic activity and metabolic pathways—might contribute to IBS risk through blood metabolites.

To build the analysis, the authors compiled 19 candidate succinylation-related genes from prior reviews of lysine succinylation and succinylation-regulated metabolism. Gene expression quantitative trait locus data came from the eQTLGen Consortium, specifically blood-derived cis-eQTLs, where instrumental SNPs were filtered at a genome-wide significance threshold of P < 5e-8 with clumping parameters of a 10,000 kb window and r2 < 0.1. Intersecting the 19 candidates with the eQTLGen dataset, which contained cis-eQTL data for 15,695 genes, identified 16 genes with usable instruments. The IBS outcome data came from the FinnGen R12 cohort, comprising 407,993 participants, including 13,268 cases and 394,725 controls.

In the first stage, the team used inverse-variance weighting as the primary two-sample Mendelian randomization method, treating gene cis-eQTLs as exposures and IBS as the outcome. SNPs with F-statistics below 10 were excluded to mitigate weak instrument bias, and quality controls included MR-Egger intercept tests, MR-PRESSO global tests, Cochran’s Q tests for heterogeneity and leave-one-out sensitivity analyses. Of the genes tested, three—GLS, LDHA and PGAM1—showed significant positive associations with IBS risk at P < 0.05. All retained instruments for these genes had F-statistics above 10: GLS had 20 valid SNPs with F-statistics ranging from 34.44 to 776.75, LDHA had 5 valid SNPs ranging from 35.82 to 405.27, and PGAM1 had 11 valid SNPs ranging from 31.56 to 859.99.

The second stage applied summary-data-based Mendelian randomization, which integrates GWAS and eQTL summary data to assess whether genetically regulated gene expression is associated with complex traits, together with the heterogeneity in dependent instruments test to distinguish a shared causal variant from linkage between distinct variants. GLS and LDHA passed both thresholds, with p_SMR below 0.05 and p_HEIDI above 0.05, and positive effect directions consistent with the initial results. GLS showed a positive association with IBS risk with b_SMR of 0.118, p_SMR of 0.042 and p_HEIDI of 0.466, while LDHA showed b_SMR of 0.197, p_SMR of 0.008 and p_HEIDI of 0.546. PGAM1, by contrast, did not pass validation, with p_SMR of 0.422, indicating that its initial association was not supported as a robust expression-trait association in this framework.

Although LDHA passed SMR validation, it had far fewer valid harmonized SNPs than GLS—5 versus 20—despite all retained instruments having F-statistics above 10. The researchers therefore selected GLS as the primary gene for metabolome-wide mediation analysis. This two-step approach calculated the total effect of GLS eQTLs on IBS, the effect of GLS eQTLs on metabolites, and the effect of metabolites on IBS, deriving the indirect effect as the product of the two component estimates and requiring a nominal P value below 0.05, a mediation proportion above 10 percent, and consistent direction between indirect and total effects. Blood metabolite GWAS summary statistics were sourced from Chen et al., covering 1,091 metabolites and 309 metabolite ratios, of which 978 traits had available clumped genetic instruments.

The mediation analysis pointed to a coherent metabolic picture. GLS showed positive effects on mannose, with a mediation proportion of 26.27 percent and P of 0.012, and on mannonate, with a mediation proportion of 47.15 percent and P of 0.002, both of which were positively associated with IBS risk. At the same time, GLS showed negative effects on glycerophospholipids, including 1-(1-enyl-palmitoyl)-GPC (p-16:0), with a mediation proportion of 25.76 percent and P of 0.031, and 1-arachidonoyl-GPE (20:4n6), with a mediation proportion of 11.73 percent and P of 0.048, both of which exhibited protective associations with IBS. GLS also downregulated two protective metabolic ratios, glucose/mannose and phosphate/mannose, with mediation proportions of 24.64 percent and 30.81 percent respectively, generating positive indirect effects because reducing protective mediators increases risk.

The authors note that the ratio-based findings are mathematically consistent with the rise in mannose, since mannose serves as the denominator of both ratios; an increase in mannose, if not matched by proportional increases in glucose or phosphate, would lower the ratio values. They caution that the mannose and ratio-based mediation signals are not statistically independent and may partly reflect the same underlying mannose-related metabolic disturbance. Direct evidence regarding the intestinal or IBS-related biological significance of the glucose/mannose and phosphate/mannose ratios remains limited, so these mediators should be interpreted as protective metabolic indicators whose reduction by GLS contributes to increased risk rather than as independent risk-promoting metabolites.

Biologically, GLS encodes glutaminase, a key enzyme in glutamine catabolism. Prior work cited by the authors suggests that glutamine, as the primary energy source for intestinal epithelial cells, may alleviate IBS symptoms by enhancing tight junction protein expression and restoring barrier integrity, and that GLS succinylation enhances glutaminase activity and promotes glutamine catabolism. The mannose signal also fits a broader context: low-FODMAP diets, which restrict fermentable carbohydrates, can improve IBS symptoms and are incorporated into international management guidelines, and mannose as a poorly absorbed monosaccharide may aggravate symptoms through osmotic effects or colonic fermentation. However, studies in inflammatory bowel disease patients have found that mannose can suppress pathological endoplasmic reticulum stress in intestinal epithelial cells, and the authors stress that direct evidence linking mannose itself to IBS symptoms remains limited, so the mediation signal should be interpreted cautiously.

Several limitations temper the conclusions. The succinylation-related status of GLS was based on prior literature, and protein succinylation was not directly measured. Both eQTL and metabolite GWAS data were derived from blood rather than intestinal tissue, limiting tissue-specific inference about gut mechanisms. Reverse causation and horizontal pleiotropy cannot be fully excluded with summary-level data, the mediation framework assumes no exposure–mediator interaction and no unmeasured mediator–outcome confounding, and the metabolite-wide screen was conducted without adjustment for multiple testing, so false-positive associations cannot be excluded, particularly for results with P values close to 0.05. The SMR effect size for GLS was modest, with an odds ratio of 1.125 and a p_SMR value close to the significance threshold. The authors frame the results as candidate metabolite-mediated pathways requiring further experimental and clinical validation rather than established causal mechanisms.

Subject of Research: Genetic and mediation analysis of the succinylation-related gene GLS and metabolite-mediated pathways in irritable bowel syndrome risk

Article Title: Succinylation-related gene GLS regulates mannose and glycerophospholipid metabolism to promote irritable bowel syndrome: an integrated study combining Mendelian randomization, SMR, and mediation analysis

Article References: Mo, L., Zhou, Y., Wu, Y., Wei, L.-F., Cai, S.-Y., Sun, Y.-M., Tang, L.-S., & Yuan, J.-Y. (2026). Succinylation-related gene GLS regulates mannose and glycerophospholipid metabolism to promote irritable bowel syndrome: an integrated study combining Mendelian randomization, SMR, and mediation analysis. Egyptian Journal of Medical Human Genetics, 27(1), Article 74. https://doi.org/10.1186/s43042-026-00905-w

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00905-w

Keywords: irritable bowel syndrome, GLS, succinylation, Mendelian randomization, SMR, mannose, mannonate, glycerophospholipids, eQTL, FinnGen, metabolite mediation, glutaminase