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: 10 Feb 2025
Reviewer's report:
The manuscript presents a well-designed, large-scale prospective cohort study investigating
the association between metabolic dysfunction-associated steatotic liver disease (MASLD), its
subtypes, and the risk of incident irritable bowel syndrome (IBS).
Specific Comments:
Introduction:
The introduction provides a good background on IBS and MASLD, but it could benefit from a
more detailed discussion of the potential mechanisms linking MASLD and IBS. While the liver-
brain-gut axis is mentioned, a deeper exploration of how hepatic steatosis and CMRFs might
independently or synergistically contribute to IBS pathogenesis would strengthen the rationale
for the study.
Consider briefly mentioning the limitations of prior studies that have examined the relationship
between NAFLD (now MASLD) and IBS, as this would highlight the novelty and importance
of the current study.
Methods:
The study population and exclusion criteria are well-described. However, it would be helpful to
provide more details on how the diagnosis of IBS was validated in the UK Biobank cohort. For
instance, were there any additional criteria (e.g., symptom-based criteria like Rome IV) used to
confirm IBS diagnoses beyond ICD-10 codes?
The use of FLI as a surrogate for hepatic steatosis is justified, but the manuscript should briefly
discuss the sensitivity and specificity of FLI compared to imaging or histology, especially in the
context of potential misclassification bias.
The categorization of MASLD into pure MASLD and MetALD is clear, but it would be useful
to provide more context on why these subtypes were chosen and how they might differentially
impact IBS risk.
Results:
The results are clearly presented, but the manuscript could benefit from a more detailed
discussion of the subgroup analyses. For instance, why might the association between MASLD
and IBS be stronger in females or younger individuals? Are there potential biological or social
factors that could explain these differences?
The dose-response relationship between the number of CMRFs and IBS risk is a key finding.
Consider adding a figure or table summarizing the cumulative incidence of IBS across different
CMRF categories to visually emphasize this relationship.
Discussion:
The discussion is comprehensive but could be more focused on the clinical implications of
the findings. For example, what are the potential implications for screening and management
strategies in patients with MASLD, particularly those with multiple CMRFs?
While the manuscript mentions the limitations of using FLI, it could also discuss the potential
impact of other unmeasured confounders, such as dietary patterns or psychosocial stress, which
are known to influence both MASLD and IBS.
The discussion of mechanisms is thorough but somewhat speculative. Consider citing additional
studies or proposing specific hypotheses that could be tested in future research to elucidate the
underlying pathways.
Conclusions:
The conclusions are supported by the data, but they could be more specific about the clinical
and public health implications of the findings. For example, what are the potential benefits of
early identification and management of CMRFs in MASLD patients for preventing IBS?
Minor Comments:
Table S1: Ensure that all ICD-10 codes used for exclusion criteria are listed and clearly defined.
Figure S1: Consider adding a brief description of the flowchart in the main text to guide readers.
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: 10 Feb 2025
Reviewer's report:
The manuscript presents a well-designed, large-scale prospective cohort study investigating
the association between metabolic dysfunction-associated steatotic liver disease (MASLD), its
subtypes, and the risk of incident irritable bowel syndrome (IBS).
Specific Comments:
Introduction:
The introduction provides a good background on IBS and MASLD, but it could benefit from a
more detailed discussion of the potential mechanisms linking MASLD and IBS. While the liver-
brain-gut axis is mentioned, a deeper exploration of how hepatic steatosis and CMRFs might
independently or synergistically contribute to IBS pathogenesis would strengthen the rationale
for the study.
Consider briefly mentioning the limitations of prior studies that have examined the relationship
between NAFLD (now MASLD) and IBS, as this would highlight the novelty and importance
of the current study.
Methods:
The study population and exclusion criteria are well-described. However, it would be helpful to
provide more details on how the diagnosis of IBS was validated in the UK Biobank cohort. For
instance, were there any additional criteria (e.g., symptom-based criteria like Rome IV) used to
confirm IBS diagnoses beyond ICD-10 codes?
The use of FLI as a surrogate for hepatic steatosis is justified, but the manuscript should briefly
discuss the sensitivity and specificity of FLI compared to imaging or histology, especially in the
context of potential misclassification bias.
The categorization of MASLD into pure MASLD and MetALD is clear, but it would be useful
to provide more context on why these subtypes were chosen and how they might differentially
impact IBS risk.
Results:
The results are clearly presented, but the manuscript could benefit from a more detailed
discussion of the subgroup analyses. For instance, why might the association between MASLD
and IBS be stronger in females or younger individuals? Are there potential biological or social
factors that could explain these differences?
The dose-response relationship between the number of CMRFs and IBS risk is a key finding.
Consider adding a figure or table summarizing the cumulative incidence of IBS across different
CMRF categories to visually emphasize this relationship.
Discussion:
The discussion is comprehensive but could be more focused on the clinical implications of
the findings. For example, what are the potential implications for screening and management
strategies in patients with MASLD, particularly those with multiple CMRFs?
While the manuscript mentions the limitations of using FLI, it could also discuss the potential
impact of other unmeasured confounders, such as dietary patterns or psychosocial stress, which
are known to influence both MASLD and IBS.
The discussion of mechanisms is thorough but somewhat speculative. Consider citing additional
studies or proposing specific hypotheses that could be tested in future research to elucidate the
underlying pathways.
Conclusions:
The conclusions are supported by the data, but they could be more specific about the clinical
and public health implications of the findings. For example, what are the potential benefits of
early identification and management of CMRFs in MASLD patients for preventing IBS?
Minor Comments:
Table S1: Ensure that all ICD-10 codes used for exclusion criteria are listed and clearly defined.
Figure S1: Consider adding a brief description of the flowchart in the main text to guide readers.
Please review this paper.
user
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: 10 Feb 2025
Reviewer's report:
The manuscript presents a well-designed, large-scale prospective cohort study investigating
the association between metabolic dysfunction-associated steatotic liver disease (MASLD), its
subtypes, and the risk of incident irritable bowel syndrome (IBS).
Specific Comments:
Introduction:
The introduction provides a good background on IBS and MASLD, but it could benefit from a
more detailed discussion of the potential mechanisms linking MASLD and IBS. While the liver-
brain-gut axis is mentioned, a deeper exploration of how hepatic steatosis and CMRFs might
independently or synergistically contribute to IBS pathogenesis would strengthen the rationale
for the study.
Consider briefly mentioning the limitations of prior studies that have examined the relationship
between NAFLD (now MASLD) and IBS, as this would highlight the novelty and importance
of the current study.
Methods:
The study population and exclusion criteria are well-described. However, it would be helpful to
provide more details on how the diagnosis of IBS was validated in the UK Biobank cohort. For
instance, were there any additional criteria (e.g., symptom-based criteria like Rome IV) used to
confirm IBS diagnoses beyond ICD-10 codes?
The use of FLI as a surrogate for hepatic steatosis is justified, but the manuscript should briefly
discuss the sensitivity and specificity of FLI compared to imaging or histology, especially in the
context of potential misclassification bias.
The categorization of MASLD into pure MASLD and MetALD is clear, but it would be useful
to provide more context on why these subtypes were chosen and how they might differentially
impact IBS risk.
Results:
The results are clearly presented, but the manuscript could benefit from a more detailed
discussion of the subgroup analyses. For instance, why might the association between MASLD
and IBS be stronger in females or younger individuals? Are there potential biological or social
factors that could explain these differences?
The dose-response relationship between the number of CMRFs and IBS risk is a key finding.
Consider adding a figure or table summarizing the cumulative incidence of IBS across different
CMRF categories to visually emphasize this relationship.
Discussion:
The discussion is comprehensive but could be more focused on the clinical implications of
the findings. For example, what are the potential implications for screening and management
strategies in patients with MASLD, particularly those with multiple CMRFs?
While the manuscript mentions the limitations of using FLI, it could also discuss the potential
impact of other unmeasured confounders, such as dietary patterns or psychosocial stress, which
are known to influence both MASLD and IBS.
The discussion of mechanisms is thorough but somewhat speculative. Consider citing additional
studies or proposing specific hypotheses that could be tested in future research to elucidate the
underlying pathways.
Conclusions:
The conclusions are supported by the data, but they could be more specific about the clinical
and public health implications of the findings. For example, what are the potential benefits of
early identification and management of CMRFs in MASLD patients for preventing IBS?
Minor Comments:
Table S1: Ensure that all ICD-10 codes used for exclusion criteria are listed and clearly defined.
Figure S1: Consider adding a brief description of the flowchart in the main text to guide readers.
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