Crosstalk between Gut Microbiota and Hepatocellular Carcinoma
Round 1
Reviewer 1 Report
This manuscript has great insight for the progress of knowledge in HCC field research. The Authors have tried to summarize many researches that have crosslink between GM and HCC. But at the beginning the author explained too much about the role of GM in general Chronic liver disease. It would be better if the author summarize the role of GM in HCC compare with General chronic liver disease in table of comparation, so it would be interesting and useful for the reader. The reader could see whether the role of GM in HCC has itu own impact directly to HCC or through the role in General chronic liver disease or liver cirrhosis.
Author Response
We appreciate the reviewer's input, and we have revised the manuscript accordingly and made a few sections (2.3 GM interplay with chronic liver diseases and cirrhosis could be linked to liver cancer; 2.3.1 NAFLD; 2.3.2 Alcohol-related liver disease; 2.3.3 Chronic viral hepatitis) more succinct.
We carefully reviewed the literature, and the abundance of GM changes in chronic liver disease and HCC share many similarities. The "favorable GM" and "less favorable GM" has a large overlap between chronic liver disease and HCC; thus, we added a descriptive sentence at the end of the section "GM interplay with chronic liver disease and HCC". If the reviewer believes an additional table comparing GMs abundance changes between chronic liver disease and HCC is essential, we can further revise the current Table 1 in another revision.
Reviewer 2 Report
Non relevant comments. Just want to congratulate and thanks the Authors for this outstanding review about crosstalk between GM and HCC. I have personally learned a lot and I am sure the readers will do the same when reading this outstanding work.
Author Response
We are delighted to receive Reviewer #2's positive feedback and appreciate their kind words about our work.
Reviewer 3 Report
With some minor spell check, English grammar edits, this manuscript is ready to publish. The review provides a comprehensive overview of the literature, I have nothing to add.
Author Response
We thank Reviewer #3 for their valuable input and have thoroughly checked the manuscript for any errors in spelling and grammar.
Reviewer 4 Report
This review summarizes the current researches on gut microbiota in HCC.And the authors found GM had the potential as a diagnostic biomarker for early diagnosis of HCC. What’s more, the synergistic role of GM in HCC immunotherapy promises therapeutic potential.
The content of the review is logical and comprehensive, and the pattern pictures are also exquisite, but the innovation is not that high.
But, I have one question:
There are studies on the role of GM in chemotherapy and immunotherapy of HCC. Are there any studies on GM in other treatments of HCC, such as surgery, radiotherapy, radiofrequency ablation, etc?
Author Response
We sincerely appreciate the comments from the reviewer and have added a section “ 4.1. The Gut Microbiome may influence Efficacy of Surgery and Radiotherapy” although the data are very limited but emerging at this time. We appreciate the suggestion.
4.1. The Gut Microbiome may influence Efficacy of Surgery and Radiotherapy
There are emerging data on the influence of GM on the response of HCC to surgery or radiotherapy.
Li and colleagues reported a study on patients receiving radiotherapy speculating that disruption and modulation of the GM may impact the radiosensitivity of HCC. Dysbiosis prevents antigen presentation and inhibits T-cell activity through the cGAS-STING-IFN-I pathway [75]. STING (stimulator of interferon genes) acts as an important signal adaptor responsible for cytosolic DNA‐dependent innate immunity [].
Wang and colleagues explored prospectively the effect of the GM in 24 HCC patients undergoing radiotherapy using 16S rRNA sequencing. They also suggested that resistance to radiotherapy could be affected by an altered cGAS–STING–IFN-I pathway and identified cyclic-di-AMP of prominent gut bacteria as a strong STING agonist. They concluded that these pathways may present a potential target to predict and potentially modulate response to radiotherapy in HCC [77].
A small study on 30 patients with HBV related HCC who underwent extended hepatectomy investigated the influence of GM on liver failure following the surgery by sequencing 16S rRNA. It showed that enrichment of bacterial taxa such as Allisonella, Bacteroides, Faecalibacterium, GCA-900066575, Helicobacter, Inquilinus, IS-44, Methylobacterium-Methylorubrum, Mycobacterium, Pantoea, and IS-44 was more prominent in patients who developed liver failure after surgery while taxa such as Catabacter, Papillibacter, Scardovia, Senegalimassilia, and Turicibacter were significantly enriched in patient without postoperative liver failure. Interestingly, there was no difference between pre- and post- surgery GM composition while markers of liver function (INR, bilirubin, albumin, prealbumin) strongly correlated with the composition of the gut microbiome [78] The composition of the gut microbiome was distinct in patients of different age groups which may play an additional role in decision regarding surgery [78, 79]. Furthermore, data suggests that abundance of Klebsiella can be a potential indicator of post-hepatectomy liver failure due to altered level of 3-methyl-2-oxobutanoic acid in the BCAA pathway. The investigators speculated that 3-methyl-2-oxobutanoic acid may have an additional value in targeted treatments for post-hepatectomy liver failure in patients with HCC [80].
As preliminary these data are, they nonetheless present potential avenues to further explore and use the GM as predictor of efficacy and outcome of surgery and radiotherapy as well as its therapeutic alterations to improve survival in HCC patients.
