In situ gut microbiota editing: enhancing therapeutic efficacy for bacterial colitis by compatible oral hydrogel microspheres with phages

Yufan Yang, Runze Li, Qiang Zhong, Yating Guo, Renwei Wu, Huanchun Chen, Rui Zhou, Ranfeng Ye, Krystyna Dąbrowska, Tomasz K. Prajsnar, Graham P. Stafford, Geng Zou (), Yang Zhou (), Jinquan Li () and Zhiyong Song ()
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Yufan Yang: Huazhong Agricultural University
Runze Li: Huazhong Agricultural University
Qiang Zhong: Huazhong Agricultural University
Yating Guo: Huazhong Agricultural University
Renwei Wu: Huazhong Agricultural University
Huanchun Chen: Huazhong Agricultural University
Rui Zhou: Huazhong Agricultural University
Ranfeng Ye: Huazhong Agricultural University
Krystyna Dąbrowska: Polish Academy of Sciences, Faculty of Medicine, Wrocław University of Science and Technology
Tomasz K. Prajsnar: Jagiellonian University
Graham P. Stafford: The University of Sheffield
Geng Zou: Shanxi Agricultural University
Yang Zhou: Huazhong Agricultural University
Jinquan Li: Huazhong Agricultural University
Zhiyong Song: Huazhong Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Gut microbiota editing represents a promising therapeutic strategy for dysbiosis-associated diseases. Bacteriophages (phages), with their host specificity, enable precise microbial manipulation but face challenges such as environmental vulnerability and low bioavailability, which limit their in vivo efficacy. Here, we develop double-responsive hydrogel microspheres (HMs) via electrohydrodynamic spraying to enhance oral phage delivery. Composed of sodium alginate, hyaluronic acid, and Eudragit S100, these HMs achieve 90% encapsulation efficiency for a Salmonella-targeting phage cocktail. Such formulation significantly protects phages from gastric conditions, prolongs their intestinal retention, and enables responsive payload release in the colon. In a murine model of Salmonella Typhimurium (STm)-induced colitis, HMs-encapsulated phages (HMs-Phages) reduce intestinal STm burden by nearly 2000-fold and lower levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) to 60% of those in infected group. Notably, HMs-Phages achieve potent antibacterial efficacy comparable to ciprofloxacin while selectively targeting STm. This targeted strategy circumvents antibiotics-associated microbiota dysbiosis and diarrhea, thereby effectively restoring gut homeostasis and improving host physical health. By integrating targeted pathogen eradication with microbiota conservation, this work provides a precise toolkit for gut microbiota editing and phage therapy, offering substantial advantages over antibiotics for managing dysbiosis-related diseases.

Date: 2025
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DOI: 10.1038/s41467-025-65498-1

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