Hyaluronic acid–bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis

Abstract

While conventional approaches for inflammatory bowel diseases mainly focus on suppressing hyperactive immune responses, it remains unclear how to address disrupted intestinal barriers, dysbiosis of the gut commensal microbiota and dysregulated mucosal immune responses in inflammatory bowel diseases. Moreover, immunosuppressive agents can cause off-target systemic side effects and complications. Here, we report the development of hyaluronic acid–bilirubin nanomedicine (HABN) that accumulates in inflamed colonic epithelium and restores the epithelium barriers in a murine model of acute colitis. Surprisingly, HABN also modulates the gut microbiota, increasing the overall richness and diversity and markedly augmenting the abundance of Akkermansia muciniphila and Clostridium XIVα, which are microorganisms with crucial roles in gut homeostasis. Importantly, HABN associated with pro-inflammatory macrophages, regulated innate immune responses and exerted potent therapeutic efficacy against colitis. Our work sheds light on the impact of nanotherapeutics on gut homeostasis, microbiome and innate immune responses for the treatment of inflammatory diseases.

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Fig. 1: HABN localizes in inflamed colon in DSS-treated mice.
Fig. 2: HABN exerts strong efficacy in a murine model of colitis.
Fig. 3: HABN protects colonic epithelium.
Fig. 4: HABN alters the composition of gut microbiome.
Fig. 5: HABN alleviates colitis in a delayed therapeutic setting.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information files. All relevant data can be provided by the authors upon reasonable request.

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Acknowledgements

This work was supported in part by the NIH (grant nos. R01EB022563, R01AI127070, R01CA210273, R01CA223804, U01CA210152, R01DK108901), the MTRAC for Life Sciences Hub and the Emerald Foundation. J.J.M. is a Young Investigator supported by the Melanoma Research Alliance (grant no. 348774), the DoD/CDMRP Peer Reviewed Cancer Research Program (grant no. W81XWH-16-1-0369) and a NSF CAREER Award (no. 1553831). Opinions interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The authors thank H. Atsushi for his technical help with LPMC isolation and flow cytometric analysis; the University of Michigan Medical School Host Microbiome Initiative for microbial community analysis; the University of Michigan Cancer Center Immunology Core for ELISA analysis; the ULAM In Vivo Animal Core for tissue sectioning and histological analysis of colon samples; the ULAM Pathology Core for blood analysis; and the College of Pharmacy Biochemical NMR Core at the University of Michigan.

Author information

Y.L. and J.M. designed the experiments. Y.L. performed all experiments. K.S. and N.K. contributed technical expertise, including qPCR analysis, LPMC isolation and flow cytometry analysis. Y.L. and J.M. analysed the data. M.G. aided with interpretation of data on gut microbiome analysis. S.J. contributed the initial design of bilirubin conjugates. Y.L. and J.M. wrote the paper.

Correspondence to James J. Moon.

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Lee, Y., Sugihara, K., Gillilland, M.G. et al. Hyaluronic acid–bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis. Nat. Mater. 19, 118–126 (2020). https://doi.org/10.1038/s41563-019-0462-9

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