Review for 10.1186/s12876-025-03819-w (2025)

Title: The Double-Edged Sword: Impact of Antibiotic Use on Immunotherapy Efficacy in
Advanced Hepatocellular Carcinoma
Version: 2 Date: 20 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-The retrospective nature of the study introduces the possibility of selection bias. The groups
are not randomized, and there could be confounding factors (e.g., severity of infections, co-
morbidities) that influence antibiotic use and the response to immunotherapy. This limitation
should be more clearly acknowledged, and strategies like propensity score matching or
multivariate adjustment should be discussed if they were employed.
-The study defines the "60-day treatment window" for antibiotic use as the key inclusion
criterion, but the rationale for selecting this specific period is not explained. A clearer
justification for this timeframe would help readers understand the potential clinical relevance
of this choice.
-The study does not differentiate between types of antibiotics (e.g., broad-spectrum vs. targeted
antibiotics), which could have different effects on the gut microbiome and immune system.
Antibiotic classes may have differential effects on immune modulation, and specifying this
would be a valuable addition.
-Although the study suggests that ATBs affect immunotherapy efficacy, there is little discussion
of the underlying biological mechanisms, such as how antibiotics may alter the gut microbiome
and immune system. This biological context would enhance the understanding of why ATBs
may reduce survival in HCC patients on ICIs. The gut microbiome and immune modulation are
key aspects that should be elaborated upon.
-While the study suggests that antibiotics may reduce the efficacy of immunotherapy in advanced
HCC, the discussion could go further in offering concrete recommendations. For example,
should antibiotics be avoided altogether in these patients, or is it more important to select specific
types of antibiotics? These practical recommendations would be beneficial for clinicians in
making evidence-based decisions.
-While the authors propose changes in gut microbiota as a key mechanism influencing ICI
efficacy, the discussion does not delve deeply into the biological processes that could explain this
interaction. For instance, how the altered microbiome affects immune cell activity, particularly
T-cell function, could be explored in more detail. Though this is a complex area, expanding on
potential pathways would enhance the biological plausibility of the hypothesis.
-The authors briefly mention differences in findings across studies, attributing these
discrepancies to factors such as sample size and disease-specific characteristics. However,
the explanation could benefit from a more nuanced discussion of how these factors might
specifically influence outcomes. For example, it would be valuable to explore whether
differences in ICI drugs, dosing schedules, or the microbial composition of patients in different
studies could also contribute to varying results. A deeper analysis of the conflicting findings
would make the discussion more comprehensive.
-Although the authors acknowledge that patients receiving ATBs typically have poorer health
conditions, the discussion could go further in addressing how these confounders were controlled
for in the analysis. The impact of comorbidities, liver function, or prior treatments on the
results is important to consider, as they could influence both the need for antibiotics and
the effectiveness of immunotherapy. A more thorough discussion of how these factors were
addressed would improve the reliability of the conclusions.