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Glucosylated nanoparticles for the oral delivery of antibiotics to the proximal small intestine protect mice from gut dysbiosis

Nature Biomedical Engineering volume 6, pages 867–881 (2022)Cite this article

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Abstract

Orally delivered antibiotics can reach the caecum and colon, and induce gut dysbiosis. Here we show that the encapsulation of antibiotics in orally administered positively charged polymeric nanoparticles with a glucosylated surface enhances absorption by the proximal small intestine through specific interactions of glucose and the abundantly expressed sodium-dependent glucose transporter 1. This improves bioavailability of the antibiotics, and limits their exposure to flora in the large intestine and their accumulation in caecal and faecal contents. Compared with the standard administration of the same antibiotics, the oral administration of nanoparticle-encapsulated ampicillin, chloramphenicol or vancomycin in mice with bacterial infections in the lungs effectively eliminated the infections, decreased adverse effects on the intestinal microbiota by protecting the animals from dysbiosis-associated metabolic syndromes and from opportunistic pathogen infections, and reduced the accumulation of known antibiotic-resistance genes in commensal bacteria. Glucosylated nanocarriers may be suitable for the oral delivery of other drugs causing gut dysbiosis.

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Fig. 1: Glucosylated nanocarriers promote absorption specifically at the proximal small intestine.
Fig. 2: PGNPs reduce intestinal residues and enhance blood circulation.
Fig. 3: PGNPs-Abx effectively eliminates S. pneumoniae infection in lung.
Fig. 4: PGNPs delivery prevents antibiotic-induced dysbiosis.
Fig. 5: The SGLT1 inhibitor eliminates the protective effect of PGNPs-Abx.
Fig. 6: The PGNP-mediated delivery of antibiotics ameliorates dysbiosis-associated obesity.
Fig. 7: The PGNPs-mediated delivery of antibiotics via SGLT1 decreases dysbiosis-associated infection by C. rodentium.
Fig. 8: The PGNP-mediated delivery of antibiotics reduces antibiotic-resistance genes in gut microbiota.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All sequence data generated in this study are available from the SRA database with accession numbers PRJNA666621 and PRJNA666612. Source data are provided with this paper.

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Acknowledgements

We thank Y. Yang for analysing the metagenomic sequencing results, J. Wang for helping with animal experiments, H. Tan for helping with microbial experiments, Q. Liang, H. Pan and C. Zeng for helping with the material experiments; Z. Tian, R. Zhou, W. Pan, R. Flavell, X. Song, K. Zhang, H. Ma and W. Wen for helpful discussion and comments on this patent-pending work. This work was supported by grants from the National Key R&D Program of China (2017YFA0205600 to Y.W. and 2018YFA0508000 to S.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030101 to S.Z.), the National Natural Science Foundation of China (52025036 to Y.W., 82061148013 and 81821001 to S.Z. and 51903105 to W.J.) and the Shanghai Municipal Science and Technology Major Project (S.Z.).

Author information

Author notes

  1. These authors contributed equally: Guorong Zhang, Qin Wang, Wanyin Tao.

Authors and Affiliations

  1. Department of Digestive Disease and Intelligent Nanomedicine Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Guorong Zhang, Qin Wang, Wanyin Tao, Wei Jiang, Yucai Wang & Shu Zhu

  2. Institute of Immunology, University of Science and Technology of China, Hefei, China

    Guorong Zhang, Qin Wang, Wanyin Tao, Wei Jiang, Yucai Wang & Shu Zhu

  3. The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Guorong Zhang, Qin Wang, Wanyin Tao, Wei Jiang, Yucai Wang & Shu Zhu

  4. Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel

    Eran Elinav

  5. Microbiome & Cancer Division, DKFZ, Heidelberg, Germany

    Eran Elinav

  6. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China

    Yucai Wang & Shu Zhu

  7. School of Data Science, University of Science and Technology of China, Hefei, China

    Shu Zhu

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Contributions

G.Z. and Q.W. designed, performed and interpreted experiments. W.T. designed and analysed the 16S rRNA and metagenomic sequencing results. W.J. designed and synthesized the polymers. W.J. helped with animal experiments and cellular experiments. E.E. provided analytical tools, critical comments and suggestions; S.Z., Y.W., G.Z. and Q.W. wrote the manuscript. E.E. edited the manuscript. Y.W. and S.Z. supervised the project.

Corresponding authors

Correspondence to Yucai Wang or Shu Zhu.

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Competing interests

E.E. is a consultant at Daytwo and BiomX in topics unrelated to the subject of this work. The other authors declare no competing interests.

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Nature Biomedical Engineering thanks Jian-Dong Jiang, Xian-Zheng Zhang 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 A proposed model for how PGNPs for oral delivery of antibiotics resolve antibiotic-associated dysbiosis.

The different segments of the intestine have quite distinct appearances. Distribution of gut microbiota is increasing along the length of the intestine while the expression of glucose transporter SGLT1 along small intestine is decreasing and no detection in large intestine. When oral free antibiotics to cure bacterial infection induced damages to the gut microbiota and related adverse effects in normal mice. But, when oral nanocarrier antibiotics alleviates disruptions to the gut microbiota and keep it homeostasis.

Extended Data Fig. 2 SGLT1 aids the uptake of PGNPs into cells.

a, Representative confocal images showing SGLT1-mediated endocytosis of PGNPs in SGLT1-expressing HEK293T cells. PNPs or PGNPs (red), SGLT1 (green), and nucleus (blue). Scale bars, 5 μm (left panel), 1 μm (middle and right panels). b, Quantification of the percentage of PNPs or PGNPs co-localized with SGLT1 during the internalization in confocal images. n = 3. All values are expressed as mean ± s.e.m. Statistical significance was determined using two-tailed Student’s t-test in b. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. a and b are representative of two independent experiments.

Source data

Extended Data Fig. 3 PGNPs co-localized with recycling endosome.

a, Representative confocal images showing the co-localization of PGNPs-DiD with Rab11 in SGLT1-expressing HEK293T cells. PGNPs-DiD (red), Rab11 (green), nucleus (blue). Scale bars, 10 μm. b, The percentage of co-localized PGNPs-DiD and Rab11 was quantified in (a). n = 18 images from three biologically independent samples. c, Representative confocal images showing the co-localization of PGNPs with Rab11 in proximal small intestine. PGNPs-DiD (purple), Rab11 (green), and nucleus (blue). Scale bars, 10 μm. d, The percentage of co-localized PGNPs-DiD and Rab11 was quantified in (c). n = 9 images from three mice. e, Schematic representation showing that PGNPs can be taken up and transported through SGLT1-mediated endocytosis and transcytosis in intestinal epithelial cells. All values are expressed as mean ± s.e.m. a–d are representative of two independent experiments.

Source data

Extended Data Fig. 4 PGNPs-Amp effectively eliminate Listeria monocytogenes in a bacteremia model.

a, Study design: mice were received an intravenous injection with 2 × 106 CFUs of Listeria monocytogenes. Free Amp (40 mg kg−1) or Amp (40 mg kg−1)-loaded PGNPs was orally administered into mice. Control mice did not receive antibiotic treatment. Bacterial loads in blood, liver, spleen were determined at 24 h post infection. b, The appearance of the infected liver and spleen in mice with indicated treatments at 24 h post infection. c–e, Quantification of bacteria CFUs in the blood (c), liver (d), and spleen (e) at 24 h post infection. n = 6 mice. All values are expressed as mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test in (c, d and e). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. b–e are representative of two independent experiments.

Source data

Extended Data Fig. 5 PGNPs delivery of antibiotics show minimized alteration of the microbiota.

PCoA analysis of microbiota community composition in mice treated with free Abx or Abx-loaded NPs and the recovery trajectory are marked by analyzing unweighted UniFrac distances.

Source data

Extended Data Fig. 6 PGNPs delivery of antibiotics reduces the microbiota alteration in small intestine.

C57BL/6 mice were orally administered with free or ampicillin (20 mg kg−1) and vancomycin (20 mg kg−1)-loaded PGNPs for 5d. Control mice had no antibiotic exposure. Both SI-P and SI-D content were collected for 16 s rRNA sequencing at the end of treatment. a,d, Alpha diversity quantified as observed species in SI-P (a) or SI-D (d) in indicated groups. b,e, Unweighted UniFrac principal-coordinates analysis (PCoA) of samples with indicated treatments in SI-P (b) and SI-D (e). c,f, Relative abundance of family-level taxonomy in fecal microbiota was presented as a percentage of the total detected sequences in SI-P (c) and SI-D (f). n ≥ 3 mice. All values are expressed as mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test in a and d. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 7 Microbiota alterations upon Antibiotics (Abx) and HFD treatments.

Three-week-old C57BL/6 J male mice were administrated with free antibiotics or ampicillin (20 mg kg−1) and vancomycin (20 mg kg−1)-loaded nanoparticles for 5 successive days. Control mice had no antibiotics exposure. All mice were treated with HFD from age of 7 weeks. Fecal pellets were collected on the day end of the HFD treatment for 16S rRNA sequencing. a, The observed species number of gut microbiota. b, PCA plot generated from unweighted UniFrac distance matrix displaying the distinct clustering pattern of gut microbiota. c, Relative abundances of the gut commensal microorganisms at the family level. n = 5 mice. All values are expressed as the mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test in a. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 8 Fecal bile acids levels after short-time antibiotics treatment following with a high-fat diet exposure.

Bile acids levels altered by free Abx or PGNPs-Abx were analyzed by mass spectrometer. n = 5 mice. All values are expressed as mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, no significance.

Source data

Extended Data Fig. 9 Fecal microbiota transplantation (FMT) from free Abx- but not PGNPs-Abx- treated mice results in metabolic alteration.

Donor mice were given Water, PGNPs, free Abx, or PGNPs-Abx daily for 5 days. Fecal pellets were collected for FMT. Fecal bacteria were transplanted into recipient mice after Abx treatment and followed by HFD feeding to induce obesity. Serum and liver cholesterol levels were measured after 13 weeks HFD. n = 5 mice. All values are expressed as mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, no significance. Data is representative of two independent experiments.

Source data

Extended Data Fig. 10 Quantification of pathological scores of cecum sections from the C. rodentium infected mice.

n = 6 mice. All values are expressed as mean ± s.e.m. Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, no significance.

Source data

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Zhang, G., Wang, Q., Tao, W. et al. Glucosylated nanoparticles for the oral delivery of antibiotics to the proximal small intestine protect mice from gut dysbiosis. Nat. Biomed. Eng 6, 867–881 (2022). https://doi.org/10.1038/s41551-022-00903-4

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