Review for 10.1186/s12876-025-03789-z (2025)

Title: Effect of Synbiotics on the Cardiovascular Risk Factors in Patients with Non- alcoholic
Fatty Liver: A GRADE Evidence Systematic Review, Meta-analysis
Version: 0 Date: 31 Jan 2025
Reviewer's report:
Dear Editor,
Thank you for the opportunity to review the manuscript titled "Effect of Synbiotics on the
Cardiovascular Risk Factors in Patients with Non-alcoholic Fatty Liver: A GRADE Evidence
Systematic Review, Meta-analysis." This study provides a comprehensive evaluation of the
impact of synbiotic supplementation on cardiovascular risk factors in patients with non-
alcoholic fatty liver disease (NAFLD). The authors have conducted a rigorous meta-analysis,
incorporating data from 16 randomized controlled trials (RCTs). The findings of this study are
relevant for clinicians seeking effective adjunctive therapies for managing cardiovascular risks
in NAFLD patients. The systematic approach, including the use of the GRADE system to assess
the quality of evidence, is commendable.
Statistical Comments:
Clarification of Heterogeneity: The authors report significant heterogeneity across studies,
particularly for outcomes such as blood pressure, weight, and lipid profiles (I2 values > 90%).
While this is expected in meta-analyses, it would be helpful to further explore potential sources
of heterogeneity. For example, could differences in the synbiotic strains used, treatment duration,
or participant characteristics (e.g., age or disease severity) explain some of this variability? A
more detailed subgroup analysis based on these factors would be valuable for interpreting the
results.
Statistical Methods and Sensitivity Analysis: The authors appropriately used the random-effects
model to account for heterogeneity, but additional clarification on how sensitivity analyses were
performed would strengthen the manuscript. For example, how did the exclusion of certain
studies (e.g., those with a small sample size) affect the overall estimates? Were any specific
studies identified as outliers, and if so, how did their exclusion impact the findings?
Publication Bias and Funnel Plots: The authors identified potential publication bias, especially
for outcomes like TG and BMI, through funnel plots and statistical tests (Begg’s and Egger’s
tests). The authors performed trim-and-fill analysis, but it would be helpful to provide more
information on how many studies were imputed and how this affected the final results.
Additionally, discussing the potential impact of publication bias on the overall conclusions
would improve transparency.
Clinical Comments:
Clinical Implications for NAFLD Management: The findings suggest that synbiotic
supplementation can significantly improve several cardiovascular risk factors, including weight,
blood pressure, and lipid profiles, in patients with NAFLD. The authors should further discuss
the clinical implications of these findings. Could synbiotics be incorporated into standard care
for patients with NAFLD, especially those with concurrent metabolic syndrome? The authors
could also elaborate on whether synbiotics should be used as a standalone therapy or as part of
a broader treatment regimen, including diet and lifestyle modifications.
Long-Term Effects of Synbiotics: The manuscript shows that synbiotics are effective in
improving cardiovascular risk factors in the short to medium term (e.g., 8-56 weeks). The authors
should explore the long-term effects of synbiotic supplementation, particularly its impact on
liver function and histopathological outcomes. Are the improvements in cardiovascular markers
maintained over the long term, and do these changes translate into clinical benefits, such as
reduced risk of cardiovascular events or liver disease progression?
Safety and Tolerability: Although the manuscript demonstrates the benefits of synbiotics,
the authors should briefly discuss the safety and tolerability of synbiotic supplementation in
NAFLD patients. Are there any known adverse effects associated with synbiotics, particularly
in individuals with pre-existing liver disease? Addressing safety concerns would provide a more
balanced perspective on the clinical application of this therapy.
Discussion on Gut Microbiota: The authors should expand their discussion to include the role
of gut microbiota in the context of synbiotics and cardiovascular risk factors in patients with
NAFLD. Increasing evidence suggests that gut microbiota dysbiosis can significantly influence
various metabolic and inflammatory pathways, including those related to cardiovascular disease.
Since synbiotics impact the gut microbiota, understanding these mechanisms can provide a
deeper insight into how they may contribute to improving cardiovascular health in NAFLD
patients.
The authors are encouraged to review and cite the following studies that explore the relationship
between gut microbiota, metabolic disease, and cardiovascular risk:
DOI: 10.1093/nutrit/nuad086
DOI: 10.1038/s41387-024-00281-7
DOI: 10.1016/j.clnesp.2023.07.087
DOI: 10.1097/MS9.0000000000001740
DOI: 10.3390/ijms24109087
DOI: 10.1038/s41371-022-00698-6
DOI: 10.3389/fcimb.2022.903570