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iGEM description

Small peptides possess notable attributes. With higher mechanical stability and less immunogenicity, small peptides are highly stable and safe for human intestinal consumption. Due to their diminutive molecular size, these peptides exhibit enhanced absorption efficiency and are amenable to facile synthesis by bacterial organisms. However, existing methods for delivering short peptides into the intestine remain considerably constrained, with capsule intake representing the predominant conventional delivery approach. Meanwhile, innovative delivery strategies such as controlled-release microparticle depots, targeted delivery systems, and non-invasive delivery mechanisms are currently undergoing experimental exploration1.

Our objective is to develop a sustained-release system for small peptides tailored for intestinal delivery, boasting three key attributes: long-term release capabilities, heightened safety profiles, and broad applicability prospects. Two exemplary small peptides, QEP (Gln-Glu-Pro) and AQ (Ala-Gln) have demonstrated significant health benefits when used as nutritional supplements. QEP has been shown to mitigate glucose absorption in the intestine by inhibiting the expression of SGLT1, a glucose cotransporter protein2. AQ exhibits immune-enhancing properties and augments athletic performance3,4. Given the interchangeable nature of genes of small peptides within genetic constructs, our design affords adaptability and versatility.

Our proposed design encompasses three interconnected modules—secretion, adhesion, and QS (quorum sensing)-safety—and involves two distinct strains of engineered bacteria: peptide producers and controllers.

The secretion module is exclusively present in the peptide producer strain, facilitating the secretion of small peptides. This module features a recombinant transmembrane protein, Lpp’OmpA, integrated into the outer membrane of Escherichia coli. Synthesis of small peptides occurs in conjunction with this transmembrane protein, enabling their delivery into the surrounding environment5.

Both the peptide producer and controller strains incorporate the adhesion module, which employs HSP60 and LAP adhesins capable of binding to each other. HSP60, also present as a membrane protein on intestinal cells, interfaces with LAP through a β-barrel protein structure displayed on the outer membrane of E. coli. This arrangement results in the formation of a strain-layered matrix that securely adheres to the intestinal lining6,7.

The QS-safety module comprises two distinct components within the peptide producer and controller strains. Based on a reciprocal activation principle, whereby one strain's product induces the activation of the other's gene promoter, this module regulates the population dynamics of the peptide producer and controller strains to ensure optimal small peptide production8. Furthermore, the effective functioning of the QS-safety mechanism is contingent upon the cohabitation of both bacterial strains and the formation of the adhesion matrix. The viability of these strains is primarily sustained within the low-oxygen environment of the intestine, effectively mitigating the risk of bacterial leakage9,10.


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References


1. Vargason, A. M., Anselmo, A. C. & Mitragotri, S. The evolution of commercial drug delivery technologies. Nat Biomed Eng 5, 951–967 (2021).
2. Otto, C. et al. Antidiabetic Effects of a Tripeptide That Decreases Abundance of Na+‑D‑glucose Cotransporter SGLT1 in the Brush-Border Membrane of the Small Intestine. ACS Omega (2020).
3. Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R. & Newsholme, P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 10, 1564 (2018).
4. Hall, J. C., Heel, K. & McCauley, R. Glutamine. British Journal of Surgery 83, 305–312 (2005).
5. Nicchi, S. et al. Decorating the surface of Escherichia coli with bacterial lipoproteins: a comparative analysis of different display systems. Microb Cell Fact 20, 1–14 (2021).
6. Glass, D. S. & Riedel-Kruse, I. H. A Synthetic Bacterial Cell-Cell Adhesion Toolbox for Programming Multicellular Morphologies and Patterns. Cell 174, 649-658.e16 (2018).
7. Drolia, R. et al. Receptor-targeted engineered probiotics mitigate lethal Listeria infection. Nat Commun 11, 6344 (2020).
8. Balagaddé, F. K. et al. A synthetic Escherichia coli predator–prey ecosystem. Molecular Systems Biology 4, 187 (2008).
9. Hwang, H. J., Kim, J. W., Ju, S. Y., Park, J. H. & Lee, P. C. Application of an oxygen‐inducible nar promoter system in metabolic engineering for production of biochemicals in Escherichia coli. Biotech & Bioengineering 114, 468–473 (2017).
10. Walker, M. S. & DeMoss, J. A. Role of alternative promoter elements in transcription from the nar promoter of Escherichia coli. J Bacteriol 174, 1119–1123 (1992).

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