Advances and optimization strategies in bacteriophage therapy for treating inflammatory bowel disease

Abstract

In the advancement of Inflammatory Bowel Disease (IBD) treatment, existing therapeutic methods exhibit limitations; they do not offer a complete cure for IBD and can trigger adverse side effects. Consequently, the exploration of novel therapies and multifaceted treatment strategies provides patients with a broader range of options. Within the framework of IBD, gut microbiota plays a pivotal role in disease onset through diverse mechanisms. Bacteriophages, as natural microbial regulators, demonstrate remarkable specificity by accurately identifying and eliminating specific pathogens, thus holding therapeutic promise. Although clinical trials have affirmed the safety of phage therapy, its efficacy is prone to external influences during storage and transport, which may affect its infectivity and regulatory roles within the microbiota. Improving the stability and precise dosage control of bacteriophages-ensuring robustness in storage and transport, consistent dosing, and targeted delivery to infection sites-is crucial. This review thoroughly explores the latest developments in IBD treatment and its inherent challenges, focusing on the interaction between the microbiota and bacteriophages. It highlights bacteriophages' potential as microbiome modulators in IBD treatment, offering detailed insights into research on bacteriophage encapsulation and targeted delivery mechanisms. Particular attention is paid to the functionality of various carrier systems, especially regarding their protective properties and ability for colon-specific delivery. This review aims to provide a theoretical foundation for using bacteriophages as microbiome modulators in IBD treatment, paving the way for enhanced regulation of the intestinal microbiota.

Keywords: bacteriophage therapy; encapsulation and targeted delivery; gut microbiota; inflammatory bowel disease (IBD) treatment; microbiome modulation.

Figure 1

(A) Conventional phage therapy targeting gut dysbiosis associated with pathogenic microbiome. (B) Administered phages actively diminish the population of pathogenic bacteria, eliminate harmful bacterial genes, and mitigate the absorption of detrimental metabolites in situ. [Adapted from (82, 83)].

Figure 2

A comprehensive exploration of bacteriophage-derived tools and strategies for precisely modulating the human microbiome. (A) Determining the designated target. Bacteriophages will be sourced from diverse environments using cultivation-independent techniques and replicated through cell-free systems or innovative cultivation methods. Identification of bacterial and functional targets will leverage advancements in culturing methods and multi-omics approaches. (B) Technology. The isolated phages and phage enzymes will be harnessed to modulate the human microbiota using various technologies. CRISPR/Cas9 will be transported to the target bacteria utilizing modified phage vectors. VT, viral-tagging. (C) Strategies. Moreover, to transport specific genes with diverse functions for modifying target bacteria. The ultimate objective is to reinstate a resilient microbiome in diseases associated with dysbiosis, such as inflammatory bowel disease (IBD), colorectal cancer (CRC), and so forth. [Adapted from (95)].

Figure 3

The pH range, composition of digestive fluids, and transit times across different segments of the gastrointestinal tract. Encapsulation within micro-/nanoparticles or stimulus-responsive systems allows targeted triggering or sustained release at specific sites. The encapsulation of multiple emulsion drops/multiple concentric shells also extends the circulation time of bacteriophages. [Adapted from (110)].

Figure 4

The preparation processes and microstructures of various carriers with encapsulated phages are outlined. (A) Depicts the preparation process of electrospun fibers and the microscopic structure of phages encapsulated through the electrospinning technique. (B) Illustrates the fabrication process and microstructure of multiple emulsions containing phages. (C) Presents a schematic of liposome preparation and the microscopic structures of encapsulated phages: (i) phages encapsulated in liposomes via the thin film hydration method, and (ii) phages in liposomes through a microfluidic process. (D) Describes the preparation mechanism and microstructure of hydrogels with encapsulated phages: (i) chitosan-coated alginate hydrogel loaded with phages using the extrusion-dripping method, (ii) Eudragit S100/alginate hydrogel with phages produced through a microfluidic technique, and (iii) Eudragit S100/alginate hydrogel with phages via membrane emulsification. (E) Provides a production diagram and microstructure of dry particles with phages: (i) phages in particles through lyophilization, (ii) dried particles with phages via the electrospraying process, and (iii) solid particles containing phages through the spray drying method. [Adapted from (82)].