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Artificial-enzymes-armed Bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis

Nature Nanotechnology (2023)Cite this article

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Abstract

Inflammatory bowel disease can be caused by the dysfunction of the intestinal mucosal barrier and dysregulation of gut microbiota. Traditional treatments use drugs to manage inflammation with possible probiotic therapy as an adjuvant. However, current standard practices often suffer from metabolic instability, limited targeting and result in unsatisfactory therapeutic outcomes. Here we report on artificial-enzyme-modified Bifidobacterium longum probiotics for reshaping a healthy immune system in inflammatory bowel disease. Probiotics can promote the targeting and retention of the biocompatible artificial enzymes to persistently scavenge elevated reactive oxygen species and alleviate inflammatory factors. The reduced inflammation caused by artificial enzymes improves bacterial viability to rapidly reshape the intestinal barrier functions and restore the gut microbiota. The therapeutic effects are demonstrated in murine and canine models and show superior outcomes to traditional clinical drugs.

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Fig. 1: Characterization of artificial-enzyme-armed probiotics.
Fig. 2: Multiple ROS-scavenging abilities in vitro.
Fig. 3: Stability, targeting and retention of BL@B-SA50 in an inflamed colon.
Fig. 4: Artificial-enzymes-armed BL probiotics ameliorate DSS-induced UC.
Fig. 5: Artificial-enzymes-armed BL probiotics modulating the gut microbiota of UC.
Fig. 6: UC therapy with BL@B-SA50 in beagle dogs.

Data availability

The 16S ribosomal RNA gene sequencing data are deposited at NCBI (accession no. PRJNA917220). Source data for Figs. 1–6; Extended Data Figs. 1 and 2; and Supplementary Figs. 1, 3, 4, 8–14, 16, 18, 19, 22–29, 32, 33 and 37 are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 52273152, 51822306 and 22161132027 to Z.M.), Science Technology Department of Zhejiang Province (grant no. 2021C03121 to W.W. and Z.M.), Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (grant no. SN-ZJU-SIAS-006 to Z.M.), Zhejiang High-Level Young Talent Special Support Plan (Z.M.), the National University of Singapore Start-Up Grant (NUHSRO/2020/133/Startup/08 to X.C.), NUS School of Medicine Nanomedicine Translational Research Programme (NUHSRO/2021/034/TRP/09/Nanomedicine to X.C.) and the Lee Foundation Microbiome Education Grant (X.C.). We cordially thank Q. He from the School of Chemical and Biological Engineering at Zhejiang University and L. Zheng from Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, for their support in the X-ray absorption spectroscopy measurements and analyses.

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Authors and Affiliations

  1. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China

    Fangfang Cao, Lulu Jin, Yong Gao, Hongyang Wen, Zhefeng Qian, Chenyin Zhang, Liangjie Hong, Huang Yang, Jiaojiao Zhang, Zongrui Tong & Zhengwei Mao

  2. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    Fangfang Cao & Xiaoyuan Chen

  3. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Fangfang Cao & Xiaoyuan Chen

  4. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Yuan Ding, Hongyang Wen, Zhefeng Qian, Zongrui Tong, Weilin Wang & Zhengwei Mao

  5. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  6. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Xiaoyuan Chen

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  1. Fangfang Cao
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Contributions

Z.M., X.C., W.W. and F.C. conceived the study, designed the experiments and wrote the manuscript. F.C., L.J. and Y.G. prepared and characterized the platform. F.C. and Y.G. investigated the ROS-scavenging ability. F.C. and L.J. evaluated the bacterial experiments. F.C. and H.W. carried out the in vitro experiments. F.C., Z.Q., C.Z., Y.G. and J.Z. conducted the in vivo experiments on mice. F.C., Y.D., Z.Q., C.Z., Y.G., L.H., H.Y. and Z.T. conducted the in vivo experiments on dogs. All the authors reviewed the manuscript.

Corresponding authors

Correspondence to Weilin Wang, Xiaoyuan Chen or Zhengwei Mao.

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Competing interests

X.C., Z.M. and F.C. are inventors on a patent application (international patent application no. PCT/CN2021/116214) based on the technology presented in this manuscript. All other authors declare no competing interests.

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Nature Nanotechnology thanks Alejandra De Moreno de LeBlanc, Kam Leong, Hui Wei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Comparison of UC therapy between BL@B-SA50 and clinical therapy.

(a) C57BL/6 mice were provided with water or 3% DSS-containing water for 4 days. On days 4, 5, 6 and 7, mice were orally administered with Medium, 5-ASA (30 mg kg–1), DEX (1 mg/kg), MPS (1 mg/kg) or BL@B-SA50 (BL: 2.5 × 108 CFU kg–1, B-SA: 1.25 mg/kg). (b) Daily body weight changes in each group for 9 days. Data were normalized as a percentage of the body weight at day 0. (c) Changes in DAI. (d) Lengths and (e) pictures of mice colon with indicated treatments on day 8. (f) C57BL/6 mice were provided with water or 3% DSS-containing water for 4 days. On days 4, 5, 6 and 7, mice were orally administered with Medium, BL (2.5 × 108 CFU/kg) + 5-ASA (30 mg/kg), BL (2.5 × 108 CFU/kg) + DEX (1 mg/kg), BL (2.5 × 108 CFU/kg) + MPS (1 mg/kg) or BL@B-SA50 (BL: 2.5 × 108 CFU/kg, B-SA: 1.25 mg/kg). (g) Daily body weight changes in each group for 9 days. Data were normalized as a percentage of the body weight at day 0. (h) Changes in DAI. (i) Lengths and (j) pictures of mice colon with indicated treatments on day 8. Data are presented as mean ± s. d. from n = 5 biological replicates. Statistical analysis was calculated by unpaired Student’s two-sided t test. 1P, 2P, 3P, 4P and 5P, in (b, c) denote the statistical significance of Health, BL@B-SA50, MPS, DEX and 5-ASA group relative to the Control group, while in (g, h) denotes the statistical significance of Health, BL@B-SA50, BL + MPS, BL + DEX and BL + 5-ASA group relative to the Control group, respectively. P in (d, i) denotes the statistical significance relative to the Control group. #P in (d, i) denotes the statistical significance of BL@B-SA50 relative to the Health group.

Extended Data Fig. 2 CD therapy with BL@B-SA50.

(a) C57BL/6 mice were pre-sensitized by absorption of TNBS solution through the skin. After one week, TNBS solutions were slowly administered into the colon lumen of mice to induce CD. Then, mice were orally administered with Medium or B-SA (1.25 mg/kg), BL (2.5 × 108 CFU/kg), BL (2.5 × 108 CFU kg−1) + B-SA (1.25 mg/kg), BL@B-SA50 (BL: 2.5 × 108 CFU/kg, B-SA: 1.25 mg/kg) for four days. (b) Daily bodyweight development after administering TNBS solution into the colon lumen. Data were normalized as a percentage of the bodyweight at day 8. (c) Changes in DAI. (d) Lengths and (e) picture of mice colon with indicated treatments on day 13. Data are presented as mean ± s. d. from n = 5 biological replicates. Statistical analysis was calculated by unpaired Student’s two-sided t test. 1P, 2P, 3P, 4P and 5P, in (b, c) denotes the statistical significance of Health, BL@B-SA50, BL + B-SA, BL and B-SA group relative to the Control group, respectively. P in (d) denotes the statistical significance relative to the Control group. #P in (d) denotes the statistical significance of BL@B-SA50 relative to the Health group.

Supplementary information

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Cao, F., Jin, L., Gao, Y. et al. Artificial-enzymes-armed Bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis. Nat. Nanotechnol. (2023). https://doi.org/10.1038/s41565-023-01346-x

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