Engineered Probiotic-Based Biomaterials for Inflammatory Bowel Disease Treatment

Abstract

Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a "living" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.

Keywords: engineered probiotic-based materials; inflammatory bowel disease; living materials; probiotics.

Figure 1

Comparison of intestinal homeostasis in healthy and IBD conditions and possible pathogenic factors. The current research results on the pathogenesis of IBD are still unclear, and it is generally believed to be related to individual lifestyle habits, immune status, dietary habits, and genetic background. In healthy organisms, the intestinal epithelium maintains a state of immune tolerance. However, upon exposure to inflammatory stimuli, the protective mucus layer and the epithelial cell barrier can become compromised. This leads to abnormal stimulation of immune cells by immunogenic substances, triggering a local immune response. If the antigens are not promptly eliminated, inflammation ensues, further damaging the intestinal barrier. This creates a vicious cycle, perpetuating long-term intestinal inflammation. Created with https://BioRender.com.

Figure 2

Therapeutic probiotics. Intestinal microbiota mainly regulates other organs and systems of the body through metabolic pathways (such as secretion of SCFAs, bacteriocins, etc.), immune pathways (stimulating the intestinal tract to maintain normal immune homeostasis and regulate immune factor levels), and neural pathways (affecting neurotransmitter levels). Multiple pathways are mixed with each other. Dietary intervention or exogenous supplementation of probiotics, prebiotics, or synbiotics can help to achieve adjuvant therapeutic effects on various diseases. Created with https://BioRender.com.

Figure 3

Overview of the main mechanism of probiotics in the treatment of IBD. Probiotics have various therapeutic effects on IBD, different probiotics may have different degrees of therapeutic effects, it can be roughly divided into immune regulation, antioxidant, anti-inflammatory, repairing intestinal barriers, and helping the body resist pathogenic microorganisms. A: Immunomodulation: promotion of anti-inflammatory factor expression and inhibition of pro-inflammatory factor expression; B: Neutralization of ROS; C: Probiotics can upregulate mucus protein secretion by goblet cells (C1), enhance tight junction protein function (C2), and intestinal epithelial cell function (C3) by secreting SCFAs (C4); D: Probiotics can inhibit pathogenic bacterium growth by the Secretion of bacteriocins (D1) and reduce pathogenic bacteria adhesion through occupancy effect (D2). Created with https://BioRender.com.

Figure 4

Schematic illustration of complex oxidant interaction mechanism between human cell and probiotics, highlighting the intricate interplay involving ROS. An increase in ROS can directly oxidize Keap1 protein, resulting in the escape of NRF2 and NF-κB from the inhibition of Keap1, entering the nucleus, and initiating an antioxidant stress response. Within the nuclear domain, NRF2 binds to ARE, which can start the transcription of a series of antioxidant enzymes and detoxification enzymes. This transcriptional activity culminates in a reduced production of ROS and mitigation of oxidative damage, thus inhibiting activation of NF-κB and production of inflammatory factors. Conversely, NF-κB can enters the nucleus and binds to the NRF2 promoter region, inhibiting the transcription of NRF2. Upon interaction with ARE, NF-κB will activate the transcription of inflammatory factors and immune related genes, thereby triggering inflammation and immune responses. Secretions from specific strain promote NRF2 pathway expression, while their secreted antioxidant enzymes synergistically enhance cellular antioxidant capacity. Created with https://BioRender.com.

Figure 5

The important role of SCFAs in alleviation of DSS-induced UC. A: Gut microbial metabolic pathways associated with SCFAs. B: SCFAs contents. C: Relationship between SCFAs and gut microbiota. D: Relationship between SCFAs and inflammatory cytokines. LP082: L. plantarum HNU082 treated group; SASP: salazosulfasalazine treated group; DSS: colitis group. Reproduced with permission from , copyright 2022, ASM Journals.

Figure 6

Schematic illustration of encapsulated probiotics based on different targeting strategies. A: NO-responsive poly-γ-glutamic acid hydrogel microcapsule. Reproduced with permission from , copyright 2022, John Wiley and Sons. B: ROS-responsive HA hydrogel. Reproduced with permission from , copyright 2022, Elsevier. C: H₂S-triggered HA hydrogel. Reproduced with permission from , copyright 2020, America Chemical Society.

Figure 7

Illustration of molecular interaction, encapsulate methods and materials of engineered probiotics. Different encapsulation materials are combined with strains through various forces, and according to the different preparation methods, the strains exhibit various improvements in physical and chemical properties. Created with https://BioRender.com.

Figure 8

Images of bulk encapsulated probiotics with different materials and methods. SEM images of alginate-silk sericin-maltitol co-encapsulated L. casei TISTR 1463 with (A1) and without (A2) silk sericin coating. Reproduced with permission from , copyright 2022, Elsevier. SEM images of calcium pectin beads surface morphology (B1) and the distribution (B2) of L. paraplantarum L-ZS9 within it. Reproduced with permission from , copyright 2022, Elsevier. SEM image of encapsulated L. rhamnosus based on robocasting 3D-printing technology (C). Reproduced with permission from , copyright 2023, Elsevier. SEM image (D) of the surface of L. casei 01 beads coated with alginate plus hi-maize starch. Reproduced with permission from , copyright 2016, Elsevier. SEM images of hydrogel beads encapsulated with L. rhamnosus GG (LGG^®) after freeze-dry: surface view (E1, E3) and fractural section (E2, E4). Reproduced with permission from , copyright 2023, Elsevier. SEM images of HA hydrogel-encapsulated L. reuteri (F1, F2). Reproduced with permission from , copyright 2022, Elsevier. SEM images (G) of electrospun LGG incorporated in fibrous mats from calcium caseinate-pullulan-LGG fibers. Reproduced with permission from , copyright 2022, Elsevier. SEM images (H1) and confocal microscopy images (H2) of L. plantarum-loaded poly(ethylene oxide) nanofibers. Reproduced with permission from , copyright 2019, Elsevier. SEM images of calcium-alginate (I1) and calcium-alginate-sucrose (I2) encapsulated LGG^®. Reproduced with permission from , copyright 2022, Elsevier. UHR FE-SEM images of pectin resistant starch-pectic oligosaccharide hydrogel beads encapsulated L. bulgaricus (J). Reproduced with permission from , copyright 2023, Elsevier.

Figure 9

Images of single encapsulated bacteria with different materials and methods. TEM images of uncoated (A1, A3, A5) and Lipid coated bacteria (A2, A4, A6). Reproduced with permission from , copyright 2019, Springer Nature. TEM images of apoptotic bodies (B1, Abs), naked Salmonella Typhimurium VNP 20009 (B2, VNP) and VNP coated with different tumor cell membranes (B3-B8). Reproduced with permission from , copyright 2022, Elsevier. SEM images of Escherichia coli Nissle 1917 (EcN) (C1) and EcN- Eudragit^® L100-55 (C2), TEM images of EcN (C3) and EcN-Eudragit^® L100-55 (C4). Reproduced with permission from , copyright 2020, John Wiley and Sons. TEM images of EcN (D1), ECN with 1 layer (D2, SEcN₁) and 4 layers (D3, SEcN₄) of silk fibroin. Reproduced with permission from , copyright 2021, John Wiley and Sons. SEM images of armored (E1) and naive EcN (E2), cross-sectional TEM images of naive (E3) or armored EcN (E4). Reproduced with permission from , copyright 2022, Springer Nature.

Figure 10

Schematic illustrations of chemically modified probiotics using different strategies and molecules. A: Surface-thiolated ECN. Reproduced with permission from , copyright 2022, Springer Nature. B: Iridium (III) photosensitizer-bacteria hybrid. Reproduced with permission from. Reproduced with permission from , copyright 2020, John Wiley and Sons. C: Bioorthogonal functionalized EcN. Reproduced with permission from , copyright 2024, Elsevier. D: Ternary photosensitive bacteria. Reproduced with permission from , copyright 2023, America Chemical Society. E: DBCO and Azido group modified bacteria. Reproduced with permission from , copyright 2022, America Chemical Society.

Figure 11

Main mechanisms of action of engineered probiotics. A: Modulation of the immune system. B: Exclusion of pathogens. C: Biosensing and disease diagnosis. D: Modification of host metabolism. Reproduced with permission from , copyright 2023, Portland Press, Ltd.

Figure 12

Recombinant probiotics for expressing anti-inflammatory mediators. A: A vector map of the lactococcal secretion vector and schematic representations of gene maps of the vector. Reproduced with permission from , copyright 2015, Springer Nature. B: Schematics of the IFN L1 production-secretion cassette for genomic integration. Reproduced with permission from , copyright 2023, America Chemical Society. C: Gene route design and Western blot detection results of constitutive engineered bacteria EcN-TNF-α Nanobodies (Nb, top) and EcN-IL10 (bottom). Reproduced with permission from , copyright 2024, Springer Nature. D: Gene constructs for expression of IL-6 binding affibody ZIL on the surface of L. lactis NZ9000, and SDS-PAGE, Western blot analysis of whole lysates. E: confocal immunofluorescence microscopy images. F: flow cytometry analysis. Reproduced with permission from , copyright 2022, Springer Nature.

Figure 13

Schematic illustration of the future development direction of probiotics. Created with https://BioRender.com.