Review for 10.1186/s12876-025-04165-7 (2025)

Title: Long-term risk of irritable bowel syndrome associated with MASLD, MASLD type and
different cardiometabolic risk factors: a large-scale prospective cohort study
Version: 1 Date: 31 Jan 2025
Reviewer's report:
Dear Editor,
Thank you for the opportunity to review the manuscript titled "Long-term risk of irritable
bowel syndrome associated with MASLD, MASLD type, and different cardiometabolic risk
factors: a large-scale prospective cohort study." This study provides valuable insights into the
association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the
risk of developing irritable bowel syndrome (IBS). The use of a large cohort from the UK
Biobank with long-term follow-up strengthens the robustness of the findings, offering important
contributions to understanding the relationship between liver disease and gut health.
Statistical Comments:
Clarification of Statistical Models: While the authors present multiple statistical models to
assess the association between MASLD and IBS, further explanation on the choice of variables
for adjustment would benefit the readers. For example, how did the authors decide to include
certain covariates such as depression and anxiety in the final model? A brief justification for the
inclusion of these variables in the model, considering their potential role as mediators, would
improve the transparency of the analysis.
Consideration of Time-Dependent Covariates: The Cox proportional hazard model assumes that
the effect of the predictors remains constant over time. Given the long follow-up period, it would
be valuable to test the assumption of proportional hazards and consider whether time-dependent
covariates, such as changes in lifestyle factors (e.g., weight, diet, or physical activity), might
influence the association over time.
Sensitivity Analysis: The authors perform sensitivity analyses to check the robustness of their
findings, which is commendable. However, it would be helpful to explore additional sensitivity
analyses using alternative methods, such as competing risks models, to further validate the
findings and address the possibility of reverse causality or unmeasured confounding.
Clinical Comments:
Clinical Relevance of Findings: The study's findings have significant clinical implications,
suggesting that MASLD, particularly with increased cardiometabolic risk factors, is associated
with a higher risk of developing IBS. The authors could further discuss how these findings could
be applied in clinical practice. For example, should patients with MASLD be regularly screened
for IBS, and could managing MASLD (e.g., through lifestyle interventions or pharmacologic
therapies) reduce the risk of developing IBS? Addressing these practical clinical questions would
enhance the manuscript’s relevance to healthcare providers.
Gut-Liver Axis in IBS Development: The manuscript provides a strong argument for the
potential role of MASLD and cardiometabolic risk factors in IBS development, but more
emphasis on the gut-liver axis could be beneficial. The authors could elaborate on the
mechanisms by which liver dysfunction might impact gut health, such as through microbiota
changes, inflammatory pathways, and gut permeability. This would deepen the understanding
of how MASLD might contribute to IBS pathogenesis beyond simple associations (cite
the following articles and use their content  DOI: 10.1186/s13643-023-02299-x,  DOI:
10.2174/0115733998284844240102110559, DOI: 10.1016/j.numecd.2024.05.017.
Role of Dietary Interventions: Given the impact of diet on both MASLD and IBS, the authors
could discuss whether dietary interventions might play a role in mitigating the risk of IBS in
MASLD patients. For instance, how might low-fat or anti-inflammatory diets influence both
liver health and gut function in individuals with MASLD and IBS?