Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel


The performance of immune-checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here we show in multiple murine tumour models that inulin—a widely consumed dietary fibre—formulated as a ‘colon-retentive’ orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses and amplify the antitumour activity of the checkpoint inhibitor anti-programmed cell death protein-1 (α-PD-1). Orally delivered inulin-gel treatments increased the relative abundances of key commensal microorganisms and their short-chain-fatty-acid metabolites, and led to enhanced recall responses for interferon-γ+CD8+ T cells as well as to the establishment of stem-like T-cell factor-1+PD-1+CD8+ T cells within the tumour microenvironment. Gels for the in situ modulation of the gut microbiome may be applicable more broadly to treat pathologies associated with a dysregulated gut microbiome.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: In situ modulation of the gut microbiome with colon-retentive inulin gel for improving cancer immunotherapy.
Fig. 2: Improving the antitumour efficacy of α-PD-1 therapy with oral candidate agents.
Fig. 3: Distinct gut microbial communities promoted by treatment with inulin plus α-PD-1.
Fig. 4: Colon-retentive inulin gel for the modulation of the microbial communities of the gut.
Fig. 5: Oral inulin gel potently amplifies the therapeutic efficacy of α-PD-1 therapy.
Fig. 6: The interplay between the gut microbiota, metabolites and antitumour efficacy.
Fig. 7: The interplay between the gut microbiota, metabolites and induction of stem-like memory CD8+ T cells.
Fig. 8: Therapeutic efficacy of inulin gel plus α-PD-1 therapy in multiple tumour models.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request. The bacterial 16S rRNA sequencing data have been deposited in the NCBI Sequence Read Archive (accession number: PRJNA715170).


  1. 1.

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    CAS  Article  Google Scholar 

  2. 2.

    Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369–2379 (2016).

    CAS  Article  Google Scholar 

  4. 4.

    Gilbert, J. A. et al. Current understanding of the human microbiome. Nat. Med. 24, 392–400 (2018).

    CAS  Article  Google Scholar 

  5. 5.

    Schmidt, T. S. B., Raes, J. & Bork, P. The human gut microbiome: from association to modulation. Cell 172, 1198–1215 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Cryan, J. F., O’Riordan, K. J., Sandhu, K., Peterson, V. & Dinan, T. G. The gut microbiome in neurological disorders. Lancet Neurol. 19, 179–194 (2020).

    CAS  Article  Google Scholar 

  7. 7.

    Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    CAS  Article  Google Scholar 

  8. 8.

    Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    CAS  Article  Google Scholar 

  9. 9.

    Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    CAS  Article  Google Scholar 

  10. 10.

    Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    CAS  Article  Google Scholar 

  12. 12.

    Zitvogel, L., Ma, Y., Raoult, D., Kroemer, G. & Gajewski, T. F. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359, 1366–1370 (2018).

    CAS  Article  Google Scholar 

  13. 13.

    Helmink, B. A., Khan, M. W., Hermann, A., Gopalakrishnan, V. & Wargo, J. A. The microbiome, cancer, and cancer therapy. Nat. Med. 25, 377–388 (2019).

    CAS  Article  Google Scholar 

  14. 14.

    Giles, E. M., D’Adamo, G. L. & Forster, S. C. The future of faecal transplants. Nat. Rev. Microbiol. 17, 719 (2019).

    CAS  Article  Google Scholar 

  15. 15.

    Skelly, A. N., Sato, Y., Kearney, S. & Honda, K. Mining the microbiota for microbial and metabolite-based immunotherapies. Nat. Rev. Immunol. 19, 305–323 (2019).

    CAS  Article  Google Scholar 

  16. 16.

    Wang, J., Man, G. C. W., Chan, T. H., Kwong, J. & Wang, C. C. A prodrug of green tea polyphenol (–)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer. Cancer Lett. 412, 10–20 (2018).

    CAS  Article  Google Scholar 

  17. 17.

    Makki, K., Deehan, E. C., Walter, J. & Bäckhed, F. The impact of dietary fiber on gut microbiota in host health and disease. Cell Host Microbe 23, 705–715 (2018).

    CAS  Article  Google Scholar 

  18. 18.

    Paulose, J. K., Wright, J. M., Patel, A. G. & Cassone, V. M. Human gut bacteria are sensitive to melatonin and express endogenous circadian rhythmicity. PLoS ONE 11, e0146643 (2016).

    Article  Google Scholar 

  19. 19.

    Stewart, M. L., Savarino, V. & Slavin, J. L. Assessment of dietary fiber fermentation: effect of Lactobacillus reuteri and reproducibility of short-chain fatty acid concentrations. Mol. Nutr. Food Res. 53, S114–S120 (2009).

    Article  Google Scholar 

  20. 20.

    La Rosa, S. L. et al. The human gut Firmicute Roseburia intestinalis is a primary degrader of dietary β-mannans. Nat. Commun. 10, 905 (2019).

    Article  Google Scholar 

  21. 21.

    Zhao, J. et al. Fiber-rich foods affected gut bacterial community and short-chain fatty acids production in pig model. J. Funct. Foods 57, 266–274 (2019).

    CAS  Article  Google Scholar 

  22. 22.

    Cao, Y. & Mezzenga, R. Design principles of food gels. Nat. Food 1, 106–118 (2020).

    Article  Google Scholar 

  23. 23.

    Sun, M. et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat. Commun. 9, 3555 (2018).

    Article  Google Scholar 

  24. 24.

    de Groot, P. F. et al. Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial. Diabetologia 63, 597–610 (2020).

    Article  Google Scholar 

  25. 25.

    Balmer, M. L. et al. Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44, 1312–1324 (2016).

    CAS  Article  Google Scholar 

  26. 26.

    Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297 (2019).

    CAS  Article  Google Scholar 

  27. 27.

    Siddiqui, I. et al. Intratumoral Tcf1+ PD-1+ CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211 (2019).

    CAS  Article  Google Scholar 

  28. 28.

    Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    CAS  Article  Google Scholar 

  29. 29.

    Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013 (2018).

    CAS  Article  Google Scholar 

  30. 30.

    Hatae, R. et al. Combination of host immune metabolic biomarkers for the PD-1 blockade cancer immunotherapy. JCI Insight 5, e133501 (2020).

    Article  Google Scholar 

  31. 31.

    Hinoi, T. et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 67, 9721–9730 (2007).

    CAS  Article  Google Scholar 

  32. 32.

    Nomura, M. et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw. 3, e202895 (2020).

    Article  Google Scholar 

  33. 33.

    Botticelli, A. et al. Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment. J. Transl. Med. 18, 1–10 (2020).

    Article  Google Scholar 

  34. 34.

    Li, Y. et al. Prebiotic-induced anti-tumor immunity attenuates tumor growth. Cell Rep. 30, 1753–1766 (2020).

    CAS  Article  Google Scholar 

  35. 35.

    Senghor, B., Sokhna, C., Ruimy, R. & Lagier, J.-C. Gut microbiota diversity according to dietary habits and geographical provenance. Hum. Microbiome J. 7–8, 1–9 (2018).

    Article  Google Scholar 

  36. 36.

    Salgia, N. J. et al. Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti–PD-1 immune checkpoint inhibitors. Eur. Urol. 78, 498–502 (2020).

    CAS  Article  Google Scholar 

  37. 37.

    Derosa, L., Routy, B., Kroemer, G. & Zitvogel, L. The intestinal microbiota determines the clinical efficacy of immune checkpoint blockers targeting PD-1/PD-L1. Oncoimmunology 7, e1434468 (2018).

    Article  Google Scholar 

  38. 38.

    Khan, M. A. W., Ologun, G., Arora, R., McQuade, J. L. & Wargo, J. A. Gut microbiome modulates response to cancer immunotherapy. Dig. Dis. Sci. 65, 885–896 (2020).

    CAS  Article  Google Scholar 

  39. 39.

    King, D. E., Mainous, A. G. 3rd & Lambourne, C. A. Trends in dietary fiber intake in the United States, 1999–2008. J. Acad. Nutr. Diet. 112, 642–648 (2012).

    Article  Google Scholar 

  40. 40.

    Kozich, J. J., Westcott, S. L., Baxter, N. T., Highlander, S. K. & Schloss, P. D. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl. Environ. Microbiol. 79, 5112–5120 (2013).

    CAS  Article  Google Scholar 

Download references


This work was supported by the NIH (grant nos R01AI127070, R01EB022563, R01CA210273, U01CA210152, R01DK125087, P30CA046592). J.J.M. is supported by an NSF CAREER Award (grant no. 1553831). D.N. is supported by NCI grant nos R01CA227622, R01CA222251 and R01CA204969; a Rogel Cancer Center grant and a Forbes Scholar Award. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for the provision of MHC-I tetramers and C. H. Kim for the provison of GPR43−/− mice. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. We thank M. E. Aikins for critical review of the manuscript, Y. Xu for ELISPOT tests, K. Saud for rheology tests, J. Lu for help with the microbiota data analysis and H. He for helping with the animal studies. Figure 1 was created by the authors using

Author information




K.H. and J.J.M. designed the study. K.H. and J.X. performed the experiments. J.N., X.S. and X.H. provided technical help with the flow cytometry, NMR and matrix-assisted laser desorption/ionization–time-of-flight analyses. A.A., O.A., J.H.J. and D.N. assisted with the measurement of metabolites. B.P. and G.Y.C. aided with the colon tumorigenesis study. N.K. assisted with the gut microbiome studies. K.H. and J.J.M. interpreted the data and wrote the paper.

Corresponding author

Correspondence to James J. Moon.

Ethics declarations

Competing interests

A patent application (WO/2021/061789) for in situ modulation of the gut microbiome has been filed, with J.J.M., K.H., J.X. and X. H. as inventors.

Additional information

Peer review information Nature Biomedical Engineering thanks Bertrand Routy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Han, K., Nam, J., Xu, J. et al. Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel. Nat Biomed Eng 5, 1377–1388 (2021).

Download citation


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing