Lactation stage-dependent protective effects of human milk exosomes against intestinal ischemia-reperfusion injury via lactoferrin/lysozyme-mediated Nrf2/HO-1 and NF-κB pathways

doi:10.3748/wjg.v32.i34.120518

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 32, Issue 34

This Article

(3)

(1)

(0)

(3)

Peer-Review Report of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Journal Information of This Article

Publication Name

World Journal of Gastroenterology

ISSN

1007-9327

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Sep 14, 2026; 32(34): 120518
Published online Sep 14, 2026. doi: 10.3748/wjg.v32.i34.120518

Lactation stage-dependent protective effects of human milk exosomes against intestinal ischemia-reperfusion injury via lactoferrin/lysozyme-mediated Nrf2/HO-1 and NF-κB pathways

Guang Yang, Li Liu

Guang Yang, Li Liu, Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China

Guang Yang, Department of Pediatrics, Shanxi Medical University, Jinzhong 030619, Shanxi Province, China

Author contributions: Yang G initiated research; Yang G and Liu L designed the experiments and conducted clinical data collection, performed postoperative follow-up and recorded the data, conducted the collation and statistical analysis, and wrote the original manuscript and revised the paper; and all authors read and approved the final manuscript.

AI contribution statement: No AI tools were used in writing, editing, or generating any part of this manuscript, including text, images, and data analysis.

Institutional review board statement: This study was approved by the Ethics Committee of Shanxi Medical University, Approval No. 2025009.

Institutional animal care and use committee statement: The study was approved by the Animal Ethics Committee of Tianjin Jinke Bona Biotechnology Co., Ltd, Approval No. GENINK-20240067.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All data generated or analyzed during this study are included in this published article.

Corresponding author: Li Liu, MD, Professor, Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Yanta District, Xi’an 710061, Shaanxi Province, China. liuli918@163.com

Received: March 17, 2026
Revised: April 7, 2026
Accepted: May 12, 2026
Published online: September 14, 2026
Processing time: 154 Days and 17.2 Hours

Abstract

BACKGROUND

Human milk exosomes have been reported to possess intestinal protective functions, but whether their protective effects vary by lactation stage remains unclear.

AIM

To investigate the differential protective effects of human milk exosomes from different lactation stages against intestinal ischemia-reperfusion (I/R) injury and elucidate the key protein components and underlying molecular mechanisms.

METHODS

Exosomes were isolated from colostrum (Col-Exo), transitional milk, and mature milk by ultracentrifugation and characterized. Their protective effects were compared in a Caco-2 cell hypoxia/reoxygenation model and in neonatal rat intestinal I/R. Western blot was used to detect lactoferrin (LTF) and lysozyme (LYZ) levels in exosomes and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and nuclear factor kappa B (NF-κB) pathway activities. Rescue experiments with ML385 and PMA were performed to verify pathway necessity. Correlation analysis was used to establish quantitative associations between protein abundance and pathway activity.

RESULTS

All three exosome types exhibited typical cup-shaped morphology with no significant differences in particle size, but Col-Exo showed the highest particle and protein concentrations. LTF and LYZ expression levels were significantly higher in Col-Exo than those isolated from transitional milk and mature milk. In hypoxia/reoxygenation cells and I/R rats, Col-Exo was most effective in enhancing cell viability, inhibiting apoptosis, reducing oxidative stress and inflammatory responses, restoring the expression of tight junction protein, and ameliorating intestinal mucosal injury. Mechanistic studies showed that Col-Exo significantly activated the Nrf2/HO-1 pathway and inhibited NF-κB p65 phosphorylation, and these protective effects were partially reversed by ML385 or PMA treatment. Correlation analysis revealed that LTF/LYZ abundance was positively correlated with Nrf2 expression and negatively correlated with p-p65/t-p65 ratio.

CONCLUSION

The protective effects of human milk exosomes against intestinal I/R injury are dependent on the lactation stage. Colostrum exosomes, rich in LTF and LYZ, exert optimal protection by activating the Nrf2/HO-1 pathway and inhibiting the NF-κB pathway.

Keywords: Human milk exosomes; Intestinal ischemia-reperfusion injury; Lactoferrin; Lysozyme; Nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway; Nuclear factor kappa B pathway

Core Tip: This study demonstrates that human milk exosomes protect against intestinal ischemia-reperfusion injury in a lactation stage-dependent manner. Colostrum exosomes, rich in lactoferrin and lysozyme, exhibit optimal protection by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 antioxidant pathway and inhibiting the nuclear factor kappa B inflammatory pathway. These findings provide a basis for developing exosome-based therapies for neonatal gut injury.