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Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy

Nature Biomedical Engineering volume 3, pages 717–728 (2019)Cite this article

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Abstract

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that—in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours—oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.

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Fig. 1: Screening for phages with pro-tumoural and anti-tumoural effects in CRC.
Fig. 2: Phages eliminating F. nucleatum-induced chemotherapy resistance in vitro.
Fig. 3: In vitro anticancer effect of IDNPs.
Fig. 4: A-phage-mediated tumour targeting.
Fig. 5: Anticancer effects in mice bearing luciferase-expressing orthotopic CT26 tumours and in C57BL/6J ApcMin/+ mice developing spontaneous colonic tumours.

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Data availability

The authors declare that the main data that support the results of this study are available within the paper and the Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 51690152, 51533006 and 51833007).

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  1. These authors contributed equally: Di-Wei Zheng, Xue Dong.

Authors and Affiliations

  1. Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan, China

    Di-Wei Zheng, Xue Dong, Pei Pan, Ke-Wei Chen, Jin-Xuan Fan, Si-Xue Cheng & Xian-Zheng Zhang

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Contributions

D.-W.Z. and X.-Z.Z. conceived the project and designed the experiments. X.D. and D.-W.Z. synthesized materials. P.P and K.-W.C. performed in vitro microbiological experiments. X.D. performed in vitro cell experiments. D.-W.Z., X.D. and J.-X.F. collected and analysed the data. X.D., P.P. and K.-W.C. performed in vivo experiments. D.-W.Z., X.D., S.-X.C. and X.-Z.Z. co-wrote the manuscript. All of the authors discussed the results and reviewed the manuscript.

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Correspondence to Xian-Zheng Zhang.

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Supplementary Methods, Supplementary Figs. 1–17 and Supplementary Tables 1–6.

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Zheng, DW., Dong, X., Pan, P. et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat Biomed Eng 3, 717–728 (2019). https://doi.org/10.1038/s41551-019-0423-2

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