Abstract
Engineering bacteria to secrete gut therapeutics has been limited by their poor autonomous sensing of pathological cues and inability to sustain localized, long-term therapeutic activity. Here we engineer nonpathogenic Escherichia coli with a blood-inducible gene circuit that secretes the barnacle-derived adhesive protein CP43K and the therapeutic gut-barrier-healing factor TFF3 in response to gastrointestinal bleeding, an indicator of severe inflammatory bowel disease (IBD). Adhesive production enables sustained bacterial attachment to inflamed tissues for up to 10 days or 7 days following a single rectal or oral administration, respectively. This effect depends on bleeding-induced adhesion. Using two mouse models of IBD, the colitis model induced by dextran sulfate sodium and the interleukin-10-knockout mouse model, we demonstrate improved weight recovery, reversed colonic shortening and reduced intestinal bleeding. Additionally, the treatment decreases intestinal inflammation, promotes mucosal repair and restores gut barrier integrity, demonstrating comprehensive therapeutic efficacy.
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Data availability
All data supporting the findings of this study are available within the main text and Supplementary Information. Data for Extended Data Fig. 1 were deposited to the National Center for Biotechnology Information Sequence Read Archive under BioProject PRJNA1365448. Source data are provided with this paper.
Change history
29 April 2026
In the version of this article initially published online, there were errors in the Reporting Summary where information in the Blinding and Data exclusion sections did not match the main article, while in the article Methods “Animal IBD model and enema administration” section, there was a typographical error where the centrifugation, now listed as “4,000 × g,” appeared originally as “150 rpm.” The article and Reporting Summary are now amended in the HTML and PDF versions of the article.
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Acknowledgements
This work was partially sponsored by the National Key R&D Program of China (2020YFA0908100 to C.Z.), the National Science Fund for Distinguished Young Scholars (32125023 to C.Z.), the National Natural Science Foundation of China (32201105 to B.A. and 32401222 to Q.Z.), the Shenzhen Science and Technology Program (ZDSYS20220606100606013 to C.Z. and KQTD20190929172538530 to P.H.), the Postdoctoral Fellowship Program of the China Postdoctoral Science Foundation (GZC20231714 to S.J.), the China Postdoctoral Science Foundation (2024T170582 and 2024M752123 to S.J.), the Research Team Cultivation Program of Shenzhen University (2023QNT017 to P.H. and 2023QNT019 to J.L.), the Shenzhen University 2035 Program for Excellent Research (2023B006 to P.H.) and the Program for Youzuzhikeyan of Shenzhen University (SZU2024YZZKY002 to P.H.). We thank the Instrumental Analysis Center of Shenzhen University. We are grateful to T. K. Lu (Massachusetts Institute of Technology) and M. Mimee (University of Chicago) for providing the prototype blood-inducible plasmid heme luciferase used in this study. Additionally, we thank Addgene for supplying the plasmid (pXW109 Hg (RS-RinA-E11)2) used in our research and L. Chen for his assistance in the preparation of Figs. 1 and 3a,b,f,h. We would also like to express our gratitude to the Center for Instrumental Analysis at the Materials Synthetic Biology Center and the Shenzhen Synthetic Biology Infrastructure at the Shenzhen Institute of Synthetic Biology.
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C.Z., P.H. and B.A. conceptualized and directed the research. B.A. and C.G. systematically designed and conducted the experiments on biosensor optimization and L-glue in vitro characterization. P.H., S.J., J.L. and X.C. designed and performed all the animal experiments. W.Z. fabricated the microfluidic devices with the guidance of Y.L. X.J. performed all the microfluidic experiments. X.D. and Q.Z. carried out the partial molecular cloning experiments. C.Y., C.C. and X.S. assisted with the PBMC coculturing and ELISA testing. Y.X., P.Y., Y.L. and S.H. assisted with characterizing the biocompatibility of recombinant barnacle proteins. B.A., C.Z., J.L. and P.H. wrote the paper with help from all authors.
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C.Z., B.A. and C.G. are coinventors on a patent application (PCT/CN2024/139020) based on the TL-glue covered in this article, filed by the Shenzhen Institutes of Advanced Technology. C.Z. is a founder and equity holder of Shenzhen PAM2L Biotechnologies. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Modulation of gut microbiota by TL-glue treatment.
Comparison of alpha diversity assessed by a, Ace index (Kruskal-Wallis test, P value 0.00114), and b, Shannon diversity index (Kruskal-Wallis test, P value 0.0469). c, Principal coordinate analysis (PCoA) based on Bray-Curtis distance revealed distinct clustering patterns of gut microbial communities among the treatment groups (Kruskal-Wallis test, P value 0.001). d, Unweighted pair-group method with arithmetic mean (UPGMA) tree plot based on Bray-Curtis. e, Column diagram of the relative abundance of gut microbiome at the family level. f, g, h, Relative abundance of Lactobacillus, Limosilactobacillus, and Escherichia-Shigella (Kruskal-Wallis test, P value 0.0017, 0.00334, 0.00469). Box plot consists of five key values: the minimum observed value (the lower whisker), the 25th percentile (Q1), the median, the 75th percentile (Q3), and the maximum observed value (the upper whisker). Data are presented as means ± s.d. (n = 6 independent experiments). Statistical analysis was performed using the Kruskal-Wallis test. *P < 0.05, **P < 0.01, ***P < 0.001.
Extended Data Fig. 2 Oral administration of the engineered living glue system in both healthy and IBD mouse models.
a, Schematic illustration of a L100-55 polymer-based bacterial coating strategy. b, TEM images comparing coated bacteria with uncoated (naked) E. coli. c, Bacterial survival after coating (n = 8 independent experiments; data are presented as mean ± s.d., **P = 0.0017). d, Schematic illustration of oral administration and fecal CFU quantification. e, Representative in vivo fluorescence images of both IBD and healthy mice over 10 days, showing bacterial localization and persistence. f, Quantification of fecal CFUs from both IBD and healthy mice following oral delivery of bacteria (n = 5 independent experiments; data are presented as mean ± s.d.). g, Plasmid retention in fecal bacteria was calculated as the percentage of colonies growing on dual-antibiotic plates (ampicillin and chloramphenicol) relative to those on non-selective plates. h, Representative H&E-stained sections and i, colon damage scores of distal colon tissues from each treatment group (n = 4 independent experiments, mean ± s.d., ****P < 0.0001, **P = 0.0015). Statistical analysis was conducted using a two-tailed Student’s t-test.
Extended Data Fig. 3 Evaluation of in vivo anti-IBD efficacy of living glues on IL-10−/− mice model.
a, Body weight changes and b, Disease activity index (DAI) recorded over 42 days post-treatments (n = 5 independent experiments, mean ± SD, a: NS (P = 0.0811), *P = 0.0422, *P = 0.0339, NS (P = 0.9161), ****P < 0.0001, b: NS (P = 0.4651), *P = 0.0249, *P = 0.0125, ****P < 0.0001). DAI scoring criteria are listed in Supplementary Table 2. c, Colon lengths (n = 5 independent experiments, mean ± s.d., ****P < 0.0001, *P = 0.0209, NS (P = 0.3138), *P = 0.0118, *P = 0.0226) and d, digital images of ex vivo gut tissues of experimental mice. e, Spleen weight (n = 5 independent experiments, mean ± s.d., ***P = 0.0002, NS (P = 0.6275), NS (P = 0.357), *P = 0.0278, *P = 0.0216) and f, digital images of ex vivo spleen tissues of experimental mice. g, Representative hematoxylin & eosin (H&E)-stained sections and h, colon damage scores of distal colon tissues from each treatment group (n = 4 independent experiments, mean ± s.d., ****P < 0.0001, NS (P = 0.0558), NS (P = 0.4651), *P = 0.0278, *P = 0.0125). The lower panel in g, shows close-up views. Scale bars = 200 and 50 μm, respectively. Scoring criteria for h are provided in Supplementary Table 3. i-j, Representative immunofluorescence staining images and k, l, m, n, semi-quantitative analysis of colon tissue sections post-treatment in mice (n = 3 independent experiments, mean ± s.d., k: ***P = 0.0002, NS (P = 0.6275), NS (P = 0.357), *P = 0.0278, ***P = 0.0003, l: ****P < 0.0001, NS (P = 0.8266), NS (P = 0.0836), **P = 0.0046, **P = 0.0023, m: ***P = 0.0001, NS (P = 0.8187), ***P = 0.0002, **P = 0.0062, **P = 0.0073, n: ***P = 0.0008, NS (P = 0.9168), NS (P = 0.0233), *P = 0.0151, ***P = 0.0046). Blue: DAPI, Red: Mucin 2, Green: E-Cadherin, Pink: ZO 1, Yellow: Occludin, Black: overlay. Scale bar = 50 μm. o, p, q, r, Levels of cytokines IL-1β, TNF, IL-6, and TGFβ from tissue homogenates, determined by ELISA (n = 5 independent experiments, mean ± s.d., o: ****P < 0.0001, NS (P = 0.6722), NS (P = 0.5671), ***P = 0.0001, ***P = 0.0002, p: ****P < 0.0001, NS (P = 0.6138), NS (P = 0.8608), *P = 0.0106, ***P = 0.0005, q: ****P < 0.0001, NS (P = 0.5395), NS (P = 0.3443), **P = 0.0045, **P = 0.0053, r: NS (P = 0.9077), NS (P = 0.8673), NS (P = 0.8097), **P = 0.0017, ***P = 0.0004). Statistical analysis was conducted using a two-tailed Student’s t-test.
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Ge, C., Jiang, S., Dong, X. et al. Engineered living glues secrete therapeutic proteins for treatment of inflammatory bowel disease. Nat Biotechnol (2026). https://doi.org/10.1038/s41587-025-02970-9
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DOI: https://doi.org/10.1038/s41587-025-02970-9
