Title: Associations of the gut, cervical, and vaginal microbiota with cervical cancer: A
systematic review and meta-analysis
Version: 0 Date: 16 Jan 2025
Reviewer's report:
Dear Editor,
Thank you for the opportunity to review the manuscript titled "Associations of the Gut,
Cervical, and Vaginal Microbiota with Cervical Cancer: A Systematic Review and Meta-
Analysis." The manuscript provides a comprehensive and timely review of how alterations in
the microbiota from different anatomical regions, including the gut, cervix, and vagina, may be
involved in the development and progression of cervical cancer (CC). The systematic approach
and meta-analysis of microbiota diversity in CC patients compared to healthy controls add
significant value to the understanding of cancer-associated dysbiosis and its potential therapeutic
implications.
Statistical Comments:
Heterogeneity and Study Design Considerations: The manuscript reports significant
heterogeneity in microbiota diversity indices (e.g., Shannon index for cervical samples), which
suggests that variability in study design and patient characteristics may be influencing the results.
It would be beneficial for the authors to explore potential sources of heterogeneity, such as the
geographic regions of the studies, the age range of participants, or variations in sample collection
techniques. Addressing these factors could help clarify the robustness of the findings.
Inconsistent Treatment-Associated Microbiota Alterations: While the manuscript discusses
changes in microbiota due to antineoplastic therapies, the findings are inconsistent across
studies. The authors should consider providing a more detailed explanation of how different
treatment regimens (e.g., chemotherapy, radiation, or combined modalities) may contribute
to these inconsistencies. A deeper analysis of the timing of microbiota sampling relative to
treatment cycles could help clarify the potential impact of therapies on the microbiome.
Impact of Sequencing Methods on Results: The manuscript mentions that various sequencing
technologies were used in the included studies (e.g., 16S rRNA gene sequencing, shotgun
metagenomic sequencing). While these methods have their strengths, the authors should
acknowledge the potential limitations and biases introduced by different sequencing techniques.
A more thorough discussion of how sequencing platform differences might affect microbial
diversity and taxonomic profiling would improve the overall validity of the conclusions.
Clinical Comments:
Role of the Microbiome in Cervical Cancer Risk: The manuscript highlights important
associations between microbiota dysbiosis and cervical cancer, particularly with regard to the
depletion of Lactobacillus species. I would encourage the authors to expand on how these
microbial changes may influence cancer risk and progression. For example, the reduction
in Lactobacillus may disrupt the vaginal ecosystem, potentially allowing for the overgrowth
of pathogenic bacteria. Discussing these mechanisms could offer further insights into how
microbiota alterations contribute to carcinogenesis.
Gut Microbiome and Systemic Health Implications: Although the manuscript focuses primarily
on the vaginal and cervical microbiota, the gut microbiome is increasingly recognized as a
critical player in cancer progression and overall immune system modulation. A brief discussion
on how the gut microbiome interacts with the genital tract microbiota via the gut-vaginal axis
could provide a more comprehensive view of the microbiota's role in cervical cancer. This could
also open up new avenues for potential interventions aimed at restoring microbiome balance.
Potential for Microbiota-Targeted Therapies: Given the emerging evidence that microbial
dysbiosis can influence cancer progression, it would be valuable for the authors to explore the
clinical potential of microbiota-targeted therapies. For example, interventions such as probiotics,
prebiotics, or dietary changes might help modulate the microbiota in a way that prevents or
mitigates cervical cancer. Discussing the clinical feasibility of such approaches, particularly
in combination with existing cancer treatments, could enhance the manuscript's relevance to
practitioners in the field.
Microbiome and Immunotherapy: The manuscript touches on the influence of the microbiome
on cancer therapies, particularly in the context of antineoplastic treatments. However, the role
of the microbiome in modulating the immune response to therapies such as immunotherapy is
an area of growing interest. The authors could briefly mention the potential of the microbiome
to impact the efficacy of immunotherapies, especially in the context of cancer treatments where
immune modulation is crucial for success. This connection could offer a new dimension to the
understanding of cancer treatment outcomes.
Importance of the Gut in the GI System: I recommend that the authors include a paragraph
discussing the critical role of the gut microbiome within the gastrointestinal system, particularly
how alterations in the gut microbiota are linked to a wide range of diseases, including
cancer. The gut microbiota has been implicated not only in gastrointestinal diseases but also
in systemic conditions through the gut-brain and gut-vaginal axes. Studies such as DOI:
10.1097/MS9.0000000000001740 and DOI: 10.1186/s13643-023-02299-x provide valuable
insights into how gut microbiota imbalances can influence both metabolic and oncological
outcomes. Additionally, research such as https://doi.org/10.1093/nutrit/nuad086, DOI: 10.1038/
s41392-023-01406-7, and DOI: 10.7759/cureus.47072 emphasizes the interconnectedness of the
gut microbiota with other organ systems and its potential role in the development of diseases.
Cite these articles in your reference list as well.