Engineered probiotics platform for resolvin E1 biosynthesis confers protection against inflammatory disease

Abstract

Background: The resolution of inflammation is actively driven by omega-3 polyunsaturated fatty acids (PUFAs) via their specialized pro-resolving mediator (SPM) derivatives, including resolvin E1 (RvE1), whose role has been well established. However, clinical application of these mediators is hampered by inherent instability and elevated production costs.

Methods: To surmount these obstacles, we have engineered a biosynthetic platform based on the probiotic Escherichia coli Nissle 1917 (EcN) that enables controlled, sustained RvE1 production through inducible expression of COX2 and 5-LOX, designated EcN-RvE1. The catalytic capacity, intestinal persistence, and therapeutic efficacy of the platform were evaluated in vitro and in LPS-induced acute inflammation and DSS-induced colitis murine models.

Results: In this study, we validate the capacity of EcN-RvE1 to catalyse the conversion of eicosapentaenoic acid (EPA) to RvE1 and confirm its ability to achieve long-term intestinal persistence. In murine models of acute inflammation and colitis, EcN-RvE1 exerts marked anti-inflammatory and tissue-protective effects, which are mediated by the regulation of inflammatory cytokine expression and the amelioration of gut microbiota dysbiosis. Moreover, EcN-RvE1 using Euglena gracilis as a photosynthetic protist-based source of PUFAs also exhibits protective anti-inflammatory activity.

Conclusion: Collectively, we report a probiotic engineering platform for the biosynthesis of RvE1, offering a novel strategy for harnessing the anti-inflammatory potential of PUFAs derivatives in clinical settings.

Keywords

engineered probiotics / Escherichia coli Nissle 1917 / gut microbiota / inflammation resolution / resolvin E1

References

[1] Nathan C, Ding A. Nonresolving inflammation. Cell. 2010; 140(6): 871-882.

[2] Bender EC, Tareq HS, Suggs LJ. Inflammation: a matter of immune cell life and death. NPJ Biomed Innov. 2025; 2(1): 7.

[3] Fan JB, Li QY, Feng XF, et al. The “cytokine storm” in infection and sepsis: win the battle but lose the war. Mil Med Res. 2026; 12(1): 95.

[4] Barnes PJ. How corticosteroids control inflammation: quintiles Prize Lecture 2005. Br J Pharmacol. 2006; 148(3): 245-254.

[5] Cross RK. Safety considerations with the use of corticosteroids and biologic therapies in mild-to-moderate ulcerative colitis. Inflamm Bowel Dis. 2017; 23(10): 1689-1701.

[6] Nathan C. Points of control in inflammation. Nature. 2002; 420(6917): 846-852.

[7] Zhao H, Wu L, Yan G, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021; 6(1): 263.

[8] Perretti M, Montero-Melendez T. Resolution Pharmacology: state-of-the-art and therapeutic landscape. Pharmacol Rev. 2025; 77(6):100097.

[9] Soliman AM, Soliman M, Shah SSH, et al. Molecular dynamics of inflammation resolution: therapeutic implications. Front Cell Dev Biol. 2025; 13:1600149.

[10] Serhan CN, Chiang N, Dalli J, Levy BD. Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol. 2014; 7(2):a016311.

[11] Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014; 510(7503): 92-101.

[12] Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014; 40(3): 315-327.

[13] Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8(5): 349-361.

[14] Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005; 6(12): 1191-1197.

[15] Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci U S A. 1984; 81(17): 5335-5339.

[16] Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2–nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000; 192(8): 1197-1204.

[17] Serhan CN, Hong S, Gronert K, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med. 2002; 196(8): 1025-1037.

[18] Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chem Rev. 2011; 111(10): 5922-5943.

[19] Arita M, Bianchini F, Aliberti J, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005; 201(5): 713-722.

[20] Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J Biol Chem. 2010; 285(5): 3451-3461.

[21] Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007; 178(6): 3912-3917.

[22] Arita M, Yoshida M, Hong S, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci U S A. 2005; 102(21): 7671-7676.

[23] Hasturk H, Kantarci A, Ohira T, et al. RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB J. 2006; 20(2): 401-403.

[24] Seki H, Fukunaga K, Arita M, et al. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J Immunol. 2010; 184(2): 836-843.

[25] Yasmeen N, Selvaraj H, Lakhawat SS, et al. Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators. Biochem Pharmacol. 2023; 209:115437.

[26] Hasturk H, Abdallah R, Kantarci A, et al. Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler Thromb Vasc Biol. 2015; 35(5): 1123-1133.

[27] Ogawa N, Kobayashi Y. Total synthesis of resolvin E1. Tetrahedron Letters. 2009; 50(44): 6079-6082.

[28] Allard M, Barnes K, Chen X, et al. Total synthesis of resolvin E1. Tetrahedron Letters. 2011; 52(21): 2623-2626.

[29] Serhan CN. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 2017; 31(4): 1273-1288.

[30] Isabella VM, Ha BN, Castillo MJ, et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol. 2018; 36(9): 857-864.

[31] Charbonneau MR, Isabella VM, Li N, Kurtz CB. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun. 2020; 11(1): 1738.

[32] Sonnenborn U, Schulze J. The non-pathogenic Escherichia coli strain Nissle 1917 – features of a versatile probiotic. Microbial Ecology in Health and Disease. 2009; 21(3-4): 122-158.

[33] Riglar DT, Silver PA. Engineering bacteria for diagnostic and therapeutic applications. Nat Rev Microbiol. 2018; 16(4): 214-225.

[34] Liu J, Wang L, Pang B, et al. Engineered probiotics platform for oral delivery of antibody as a high-compliance alternative for immune-mediated inflammatory diseases. Cell Rep Med. 2026; 7(1):102523.

[35] Qiao C, Wang L, Huang C, et al. Engineered bacteria manipulate cysteine metabolism to boost ferroptosis-based pancreatic ductal adenocarcinoma therapy. Adv Mater. 2025; 37(6):2412982.

[36] Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012; 120(15): e60-72.

[37] Guzman LM, Belin D, Carson MJ, Beckwith J. Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter. J Bacteriol. 1995; 177(14): 4121-4130.

[38] Dalli J, Colas RA, Walker ME, Serhan CN. Lipid mediator metabolomics via LC-MS/Ms profiling and analysis. Methods Mol Biol. 2018; 1730: 59-72.

[39] Schebb NH, Kampschulte N, Hagn G, et al. Technical recommendations for analyzing oxylipins by liquid chromatography–mass spectrometry. Sci Signal. 2025; 18(887):eadw1245.

[40] Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res. 1990; 49(2): 186-196.

[41] Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003; 3(2): 169-176.

[42] Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990; 98(3): 694-702.

[43] Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014; 104(1): 15.25.1-15.25.14.

[44] Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982; 78(3): 206-209.

[45] Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009; 9(11): 799-809.

[46] Salem N, Eggersdorfer M. Is the world supply of omega-3 fatty acids adequate for optimal human nutrition? Curr Opin Clin Nutr Metab Care. 2015; 18(2): 147-154.

[47] Qi B, Fraser T, Mugford S, et al. Production of very long chain polyunsaturated omega-3 and omega-6 fatty acids in plants. Nat Biotechnol. 2004; 22(6): 739-745.

[48] Gissibl A, Sun A, Care A, Nevalainen H, Sunna A. Bioproducts from Euglena gracilis: synthesis and applications. Front Bioeng Biotechnol. 2019; 7: 108.

[49] Nakashima A, Suzuki K, Asayama Y, et al. Oral administration of Euglena gracilis Z and its carbohydrate storage substance provides survival protection against influenza virus infection in mice. Biochem Biophys Res Commun. 2017; 494(1-2): 379-383.

[50] Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012; 336(6086): 1268-1273.

[51] Caporaso JG, Lauber CL, Walters WA, et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci U S A. 2011; 108(1): 4516-4522.

[52] Youssef N, Sheik CS, Krumholz LR, Najar FZ, Roe BA, Elshahed MS. Comparison of species richness estimates obtained using nearly complete fragments and simulated pyrosequencing-generated fragments in 16S rRNA gene-based environmental surveys. Appl Environ Microbiol. 2009; 75(16): 5227-5236.

[53] Hess M, Sczyrba A, Egan R, et al. Metagenomic discovery of biomass-degrading genes and genomes from cow rumen. Science. 2011; 331(6016): 463-467.

[54] Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012; 13(9): R79.

[55] O'Riordan KJ, Moloney GM, Keane L, Clarke G, Cryan JF. The gut microbiota-immune-brain axis: therapeutic implications. Cell Rep Med. 2025; 6(3):101982.

[56] Ullah A, Shen B. Modulating the gut-liver Axis: anti-inflammatory mechanisms of probiotics and prebiotics in MASLD. Probiotics Antimicro Prot. 2026. Published online June 12, 2026.

[57] Narem RSR, Mathakala V, Sallabathula ST, Peddiboyina VL, Devi Palempalli UM. Probiotics as emerging adjuncts in metabolic associated fatty liver disease therapy-a systemic review. BMC Gastroenterol. 2026; 26(1): 156.

[58] Campbell EL, Bruyninckx WJ, Kelly CJ, et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity. 2014; 40(1): 66-77.

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.