Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2021; 27(29): 4879-4889
Published online Aug 7, 2021. doi: 10.3748/wjg.v27.i29.4879
Impact of Fusobacterium nucleatum in the gastrointestinal tract on natural killer cells
Yeon Ji Kim, Bu Kyung Kim, Seun Ja Park, Jae Hyun Kim
Yeon Ji Kim, Institute of Gastroenterology, Kosin University College of Medicine, Busan 49267, Spain
Bu Kyung Kim, Seun Ja Park, Jae Hyun Kim, Department of Internal Medicine, Kosin University College of Medicine, Busan 49267, South Korea
Author contributions: Kim YJ, Kim BK, Park SJ and Kim JH designed the study; Kim YJ performed the experiments; Kim YJ and Kim JH wrote the paper; Kim BK and Park SJ critically reviewed the manuscript for important intellectual content; Kim JH approved the manuscript.
Supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT), No. 2017R1C1B5017576.
Institutional review board statement: No human experiments were conducted and no human samples were used in this study.
Institutional animal care and use committee statement: All experimental procedures were performed with the approval of the Animal Experimentation Ethics Committee of Kosin University College of Medicine, No. KMAP-18-06.
Conflict-of-interest statement: The authors declare no conflicts of interest. The authors alone are responsible for the content of this manuscript.
Data sharing statement: Technical appendix and dataset available from the corresponding author at kjh8517@daum.net.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Jae Hyun Kim, MD, PhD, Assistant Professor, Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, South Korea. kjh8517@daum.net
Received: February 19, 2021
Peer-review started: February 19, 2021
First decision: May 13, 2021
Revised: May 17, 2021
Accepted: July 5, 2021
Article in press: July 5, 2021
Published online: August 7, 2021
Processing time: 165 Days and 21.5 Hours
Abstract
BACKGROUND

Gut microbial dysbiosis contributes to the development and progression of colorectal cancer (CRC). Natural killer (NK) cells are involved in early defense mechanisms to kill infective pathogens and tumor cells by releasing chemokines and cytokines. To better understand the relationship between the gut microbiome and CRC, it was hypothesized here that a high abundance of Fusobacterium nucleatum (F. nucleatum) in the gastrointestinal tract could cause reduced NK cell activity.

AIM

To identify associations between gastrointestinal tract F. nucleatum levels and NK cell activity.

METHODS

In vitro experiments were performed on NK cells treated with F. nucleatum, Peptostreptococcus anaerobius, and Parvimonas micra to identify the effects of gut microbiome species on NK cells. Following 24 and 48 h of treatment, NK cell counts were measured. In parallel studies, C57BL/6 mice were given broad-spectrum antibiotics in their drinking water to reduce resident gut flora. After 3 wk, the mice received the various bacterial species or phosphate-buffered saline (PBS) via oral gavage every 2 d for 6 wk. At the study end, blood samples were acquired to perform NK cell activity assessment and cytokine analysis. Intestinal tissues were collected and analyzed via immunohistochemistry (IHC).

RESULTS

The data show that after 3 wk of broad-spectrum antibiotic treatment, levels of total bacteria and F. nucleatum were markedly decreased in mice. Gavage of F. nucleatum significantly decreased NK cell activity relative to the activities of cells from mice treated with antibiotics only and PBS. The administration of F. nucleatum decreased the proportion of NK46+ cells based on IHC staining and increased the production of interleukin-1β and tumor necrosis factor-α.

CONCLUSION

High levels of F. nucleatum in the gastrointestinal tract reduced NK cell activity in mice, and the decrease in NK cell activity might be affected by increased pro-inflammatory cytokines after F. nucleatum treatment.

Keywords: Fusobacterium nucleatum; Natural killer cells; Colorectal cancer

Core Tip: Gut microbial dysbiosis contributes to the development and progression of colorectal cancer (CRC). Natural killer (NK) cells are involved in early defense mechanisms to kill infective pathogens and tumor cells by releasing chemokines and cytokines. To better understand the relationship between the gut microbiome and CRC, it was hypothesized here that a high abundance of Fusobacterium nucleatum (F. nucleatum) in the gastrointestinal tract could cause reduced NK cell activity. Accordingly, this association would impact the development of CRC in a host. To test this hypothesis, associations between the abundance of F. nucleatum in the murine gastrointestinal tract and NK cell activity were evaluated. In this study, we showed that a high abundance of F. nucleatum in the gastrointestinal tract reduced the activity of NK cells and that such outcomes might be associated with a concurrent increase in circulating levels of some pro-inflammatory cytokines, including interleukin-1β and tumor necrosis factor-α in these hosts. These findings suggest that increases in F. nucleatum in the gastrointestinal tract could be a factor in disrupting how the immune system prevents the development of CRC.