Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2022; 28(26): 3164-3176
Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3164
Bifidobacterium infantis regulates the programmed cell death 1 pathway and immune response in mice with inflammatory bowel disease
Lin-Yan Zhou, Ying Xie, Yan Li
Lin-Yan Zhou, Ying Xie, Yan Li, Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Author contributions: Zhou LY obtained funding, processed the samples, analyzed the raw data, and wrote manuscript; Xie Y processed the samples, obtained and managed data; Li Y conceived the study protocol, critically revised the manuscript, and approved the final version.
Supported by the Doctoral Start-up Foundation of Liaoning Province, No. 2021-BS-114.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Shengjing Hospital of China Medical University.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals, No. 2017PS353K.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yan Li, PhD, Chief Doctor, Professor, Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Road, Heping District, Shenyang 110004, Liaoning Province, China. liy@sj-hospital.org
Received: December 6, 2021
Peer-review started: December 6, 2021
First decision: January 8, 2022
Revised: January 12, 2022
Accepted: June 16, 2022
Article in press: June 16, 2022
Published online: July 14, 2022
Processing time: 218 Days and 19 Hours
Abstract
BACKGROUND

Inflammatory bowel disease (IBD) is caused by an abnormal immune response. Programmed cell death 1 (PD-1) is an immunostimulatory molecule, which interacts with PD ligand (PD-L1) playing a prime important role among autoimmune diseases. Bifidobacterium infantis (B. infantis) can promote the differentiation of CD (cluster of differentiation) 4+ T cells into regulatory T cells (Tregs). Tregs participate in the development of IBD and may be related to disease activity. B. infantis amplify the expression level of PD-1, PD-L1 and Tregs’ nuclear transcription factor forkhead box protein 3 (Foxp3). But the mechanism of B. infantis on PD-1/PD-L1 signaling remains unclear.

AIM

To explore the mechanism of B. infantis regulating the immune response in IBD.

METHODS

Forty-eight-week-old BALB/c mice were randomly divided into five groups: The control group, dextran sulphate sodium (DSS) model group, DSS + B. infantis group, DSS + B. infantis + anti-PD-L1 group, and DSS + anti-PD-L1 group. The control group mice were given drinking water freely, the other four groups were given drinking water containing 5% DSS freely. The control group, DSS model group, and DSS + anti-PD-L1 group were given normal saline (NS) 400 μL daily by gastric lavage, and the DSS + B. infantis group and DSS + B. infantis + anti-PD-L1 group were given NS and 1 × 109 colony-forming unit of B. infantis daily by gastric lavage. The DSS + B. infantis + anti-PD-L1 group and DSS + anti-PD-L1 group were given 200 μg of PD-L1 blocker intraperitoneally at days 0, 3, 5, and 7; the control group, DSS + anti-PD-L1 group, and DSS + B. infantis group were given an intraperitoneal injection of an equal volume of phosphate buffered saline (PBS). Changes in PD-L1, PD-1, Foxp3, interleukin (IL)-10, and transforming growth factor β (TGF-β) 1 protein and gene expression were observed. Flow cytometry was used to observe changes in CD4+, CD25+, Foxp3+ cell numbers in the blood and spleen.

RESULTS

Compared to the control group, the expression of PD-1, Foxp3, IL-10, and TGF-β1 was significantly decreased in the intestinal tract of the DSS mice (P < 0.05). Compared to the control group, the proportion of CD4+, CD25+, Foxp3+ cells in spleen and blood of DSS group was visibly katabatic (P < 0.05). B. infantis upgraded the express of PD-L1, PD-1, Foxp3, IL-10, and TGF-β1 (P < 0.05) and increased the proportion of CD4+, CD25+, Foxp3+ cells both in spleen and blood (P < 0.05). After blocking PD-L1, the increase in Foxp3, IL-10, and TGF-β1 protein and gene by B. infantis was inhibited (P < 0.05), and the proliferation of CD4+, CD25+, Foxp3+ cells in the spleen and blood was also inhibited (P < 0.05). After blocking PD-L1, the messenger ribonucleic acid and protein expression of PD-1 were invariant.

CONCLUSION

It is potential that B. infantis boost the proliferation of CD4+, CD25+, Foxp3+ T cells in both spleen and blood, as well as the expression of Foxp3 in the intestinal tract by activating the PD-1/PD-L1 pathway.

Keywords: Bifidobacterium infantis; Enteritis; Programmed cell death ligand; T-Lymphocytes

Core Tip: Bifidobacterium infantis (B. infantis) can be used as a therapeutic agent to treat inflammatory bowel disease. It regulates the intestinal microbiota, alleviates inflammation, and regulates the immune response. We found that B. infantis increases the expression of forkhead box protein 3 (Foxp3) and the proliferation of Foxp3+ T cells, and activates the programmed cell death 1 (PD-1)/ PD ligand 1 pathway.