Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients
Min-Woo Chung, Moon-Ju Kim, Eun Jeong Won, Yu Jeong Lee, Yong-Woon Yun, Sung Bum Cho, Young-Eun Joo, Jun-Eul Hwang, Woo Kyun Bae, Ik-Joo Chung, Myung Geun Shin, Jong Hee Shin
Min-Woo Chung, Sung Bum Cho, Young-Eun Joo, Jun-Eul Hwang, Woo Kyun Bae, Ik-Joo Chung, Department of Internal Medicine, Chonnam National University Hospital and College of Medicine, Hwasun 58128, Jeollanam-do, South Korea
Moon-Ju Kim, Eun Jeong Won, Yu Jeong Lee, Department of Parasitology and Tropical Medicine, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, South Korea
Eun Jeong Won, Myung Geun Shin, Department of Laboratory Medicine, Chonnam National University Hwasun Hospital, Hwasun 58128, Jeollanam-do, South Korea
Yong-Woon Yun, Department of Preventive Medicine, Chonnam National University Medical School, Hwasun-eup, Hwasun 58128, Jeollanam-do, South Korea
Jong Hee Shin, Department of Laboratory Medicine, Chonnam National University Hospital, Gwangju 61469, South Korea
Author contributions: Won EJ conceived of the study, participated in the study design and data analysis, and was responsible for writing and submission of the final manuscript; Kim MJ and Lee YJ carried out the experimental studies; Chung MW, Cho SB, Joo Y, Yun YW and Kim MJ analyzed and interpreted the data; Yun YW interpreted the statistical data; Hwang JE, Bae WK, Chung IJ, Shin MG and Shin JH were responsible for patient care and sample acquisition; All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.
Supported by the National Research Foundation of Korea (NRF) Grant funded by the Ministry of Education, Science, and Technology, No. NRF-2019R1C1C1004605, No. NRF-2019M3E5D1A02067953, and No. NRF-2021M3E5D1A0201518021.
Institutional review board statement: This study was carried out in accordance with all relevant institutional guidelines. The Ethics Committee of Chonnam National University Hwasun Hospital approved this study (CNUHH-2019-134) and written informed consent was obtained from all subjects.
Conflict-of-interest statement: All authors declare having no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Eun Jeong Won, MD, PhD, Professor, Department of Parasitology and Tropical Medicine, Chonnam National University Medical School, 322, Seoyang-ro, Hwasun-eup, Hwasun 58128, Jeollanam-do, South Korea.
parasite.woni@jnu.ac.kr
Received: May 20, 2021
Peer-review started: May 20, 2021
First decision: June 13, 2021
Revised: June 18, 2021
Accepted: November 3, 2021
Article in press: November 3, 2021
Published online: November 14, 2021
Processing time: 173 Days and 20.5 Hours
BACKGROUND
Immunotherapy has revolutionized the clinical outcomes of intractable cancer patients. Little is known about the intestinal nonpathogenic bacterial composition of hepatocellular carcinoma (HCC) patients treated by immunotherapy.
AIM
To determine whether there is a correlation between gut bacterial composition and prognosis in HCC patients.
METHODS
From September 2019 to March 2020, we prospectively collected fecal samples and examined the gut microbiome of 8 advanced HCC patients treated with nivolumab as a second- or third-line systemic treatment. Fecal samples were collected before the start of immunotherapy. Fecal samples of patients with progression during treatment were collected at the time of progression, and fecal samples of patients who showed good response to nivolumab were collected after 5-7 mo as follow-up. Metagenomic data from 16S ribosomal RNA sequencing were analyzed using CLC Genomics Workbench. Microbiome data were analyzed according to therapeutic response.
RESULTS
All 8 patients were male, of which 6 had underlying chronic hepatitis B. A higher Shannon index was found in the responders than in the non-responders after nivolumab therapy (P = 0.036). The unweighted beta diversity analysis also showed that the overall bacterial community structure and phylogenetic diversity were clearly distinguished according to therapeutic response. There was no significant difference in the diversity or composition of the patient gut microbiome according to the immunotherapy used. Several taxa specific to therapeutic response were designated as follows: Dialister pneumosintes, Escherichia coli, Lactobacillus reteri, Streptococcus mutans, Enterococcus faecium, Streptococcus gordonii, Veillonella atypica, Granulicatella sp., and Trchuris trichiura for the non-responders; Citrobacter freundii, Azospirillum sp. and Enterococcus durans for the responders. Of note, a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio can serve as predictive markers of non-response, whereas the presence of Akkermansia species predicts a good response.
CONCLUSION
The current presumptive study suggests a potential role for the gut microbiome as a prognostic marker for the response to nivolumab in treatment of HCC patients.
Core Tip: Immune check point inhibitors are known to be an effective treatment option for advanced hepatocellular carcinoma (HCC), not only for second-line, but also as a first-line treatment. However, there are few predictive or prognostic markers for which patient group will have a good treatment response to immunotherapy or systemic therapy for HCC until now. Our study shows that non-responders to nivolumab in HCC patients have dysbiotic fecal composition, whereas a high Prevotella/Bacteroides ratio can predict a better response to nivolumab, highlighting a potential role for the gut microbiome as a prognostic marker for the response to nivolumab therapy.
