Abstract
The gut microbiota modulates immune processes both locally and systemically. This includes whether and how the immune system reacts to emerging tumours, whether antitumour immune responses are reactivated during treatment with immune-checkpoint inhibitors (ICIs), and whether unintended destructive immune pathologies accompany such treatment. Advances over the past decade have established that the gut microbiota is a promising target and that modulation of the microbiota might overcome resistance to ICIs and/or improve the safety of treatment. However, the specific mechanisms through which the microbiota modulates antitumour immunity remain unclear. Understanding the biology underpinning microbial associations with clinical outcomes in patients receiving ICIs, as well as the landscape of a ‘healthy’ microbiota would provide a critical foundation to facilitate opportunities to effectively manipulate the microbiota and thus improve patient outcomes. In this Review, we explore the role of diet and the gut microbiota in shaping immune responses during treatment with ICIs and highlight the key challenges in attempting to leverage the gut microbiome as a practical tool for the clinical management of patients with cancer.
Key points
-
Growing evidence supports a role for the gut microbiota in shaping both antitumour immune responses and the development of toxicities during treatment with immune-checkpoint inhibitors (ICIs).
-
Targeting the gut microbiota provides a potentially powerful tool to overcome resistance to ICIs and/or to reduce the risk of severe toxicities.
-
Interindividual microbial heterogeneity poses a major challenge to the study of the microbiota across human populations and to the translation of microbial findings into the clinic.
-
Interventions designed to modulate the microbiota could have profound effects in augmenting the effectiveness of ICIs in a subset of patients, although this strategy is unlikely to be uniformly effective; identifying which patients will benefit is an important step.
-
A personalized approach guided by a patient’s baseline gut microbiota, systemic immune parameters and tumour characteristics will be important in order to optimally target the microbiota and thus improve the outcomes of patients receiving ICIs.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Rotte, A., Jin, J. Y. & Lemaire, V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann. Oncol. 29, 71–83 (2018).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Escudier, B. et al. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur. Urol. 72, 962–971 (2017).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Wakabayashi, G. et al. Development and clinical applications of cancer immunotherapy against PD-1 signaling pathway. J. Biomed. Sci. 26, 96 (2019).
Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2022).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Luke, J. J., Flaherty, K. T., Ribas, A. & Long, G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. 14, 463–482 (2017).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Belkaid, Y. & Naik, S. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14, 646–653 (2013).
Schluter, J. et al. The gut microbiota is associated with immune cell dynamics in humans. Nature 588, 303–307 (2020).
Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).
Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017).
Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).
Filyk, H. A. & Osborne, L. C. The multibiome: the intestinal ecosystem’s influence on immune homeostasis, health, and disease. EBioMedicine 13, 46–54 (2016).
Yi, M. et al. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J. Hematol. Oncol. 11, 47 (2018).
Marchesi, J. R. et al. The gut microbiota and host health: a new clinical frontier. Gut 65, 330–339 (2016).
O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).
Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).
Huang, A. C. & Zappasodi, R. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat. Immunol. 23, 660–670 (2022).
Weber, J. S. Biomarkers for checkpoint inhibition. Am. Soc. Clin. Oncol. Educ. Book 37, 205–209 (2017).
Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).
Blank, C. U., Haanen, J. B., Ribas, A. & Schumacher, T. N. Cancer immunology. the “cancer immunogram”. Science 352, 658–660 (2016).
Spranger, S., Sivan, A., Corrales, L. & Gajewski, T. F. Tumor and host factors controlling antitumor immunity and efficacy of cancer immunotherapy. Adv. Immunol. 130, 75–93 (2016).
Carlino, M. S., Larkin, J. & Long, G. V. Immune checkpoint inhibitors in melanoma. Lancet 398, 1002–1014 (2021).
Eggermont, A. M. M. et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol. 6, 519–527 (2020).
Young, A., Quandt, Z. & Bluestone, J. A. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol. Res. 6, 1445–1452 (2018).
Belkaid, Y. & Harrison, O. J. Homeostatic immunity and the microbiota. Immunity 46, 562–576 (2017).
Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Cahenzli, J., Koller, Y., Wyss, M., Geuking, M. B. & McCoy, K. D. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14, 559–570 (2013).
McCoy, K. D. et al. Natural IgE production in the absence of MHC class II cognate help. Immunity 24, 329–339 (2006).
Grainger, J., Daw, R. & Wemyss, K. Systemic instruction of cell-mediated immunity by the intestinal microbiome. F1000Res 7, PMC6290979 (2018).
Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).
Teng, F. et al. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer’s patch T follicular helper cells. Immunity 44, 875–888 (2016).
Muschaweck, M. et al. Cognate recognition of microbial antigens defines constricted CD4+ T cell receptor repertoires in the inflamed colon. Immunity 54, 2565–2577.e6 (2021).
Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).
Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).
Wegorzewska, M. M. et al. Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen. Sci. Immunol. 4, eaau9079 (2019).
Lindner, C. et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota. Nat. Immunol. 16, 880–888 (2015).
Yang, C. et al. Immunoglobulin A antibody composition is sculpted to bind the self gut microbiome. Sci. Immunol. 7, eabg3208 (2022).
Zmora, N., Suez, J. & Elinav, E. You are what you eat: diet, health and the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 16, 35–56 (2019).
Alexander, M. & Turnbaugh, P. J. Deconstructing mechanisms of diet-microbiome-immune interactions. Immunity 53, 264–276 (2020).
Tan, J., Ni, D., Ribeiro, R. V., Pinget, G. V. & Macia, L. How changes in the nutritional landscape shape gut immunometabolism. Nutrients 13, 823 (2021).
Oliphant, K. & Allen-Vercoe, E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome 7, 91 (2019).
Rowland, I. et al. Gut microbiota functions: metabolism of nutrients and other food components. Eur. J. Nutr. 57, 1–24 (2018).
Wells, J. M., Rossi, O., Meijerink, M. & van Baarlen, P. Epithelial crosstalk at the microbiota–mucosal interface. Proc. Natl Acad. Sci. USA 108, 4607–4614 (2011).
Tan, J. K., McKenzie, C., Marino, E., Macia, L. & Mackay, C. R. Metabolite-sensing G protein-coupled receptors – facilitators of diet-related immune regulation. Annu. Rev. Immunol. 35, 371–402 (2017).
Tan, J. et al. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121, 91–119 (2014).
Parada Venegas, D. et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 10, 277 (2019).
Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).
Chen, J., Zhao, K. N. & Vitetta, L. Effects of intestinal microbial-elaborated butyrate on oncogenic signaling pathways. Nutrients 11, 1026 (2019).
O’Keefe, S. J. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun. 6, 6342 (2015).
Donohoe, D. R. et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4, 1387–1397 (2014).
Aune, D. et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 343, d6617 (2011).
Tang, Y., Chen, Y., Jiang, H., Robbins, G. T. & Nie, D. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 (2011).
Borthakur, A. et al. A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G1126–G1133 (2012).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Tan, J. et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 15, 2809–2824 (2016).
Tedelind, S., Westberg, F., Kjerrulf, M. & Vidal, A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J. Gastroenterol. 13, 2826–2832 (2007).
Yu, L. C. Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: exploring a common ground hypothesis. J. Biomed. Sci. 25, 79 (2018).
Chiba, M., Nakane, K. & Komatsu, M. Westernized diet is the most ubiquitous environmental factor in inflammatory bowel disease. Perm. J. 23, 18–107 (2019).
Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935.e5 (2021).
Rubio-Patino, C. et al. Low-protein diet induces IRE1α-dependent anticancer immunosurveillance. Cell Metab. 27, 828–842.e7 (2018).
Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).
Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21 (2016).
Schwerbrock, N. M. et al. Interleukin 10-deficient mice exhibit defective colonic Muc2 synthesis before and after induction of colitis by commensal bacteria. Inflamm. Bowel Dis. 10, 811–823 (2004).
Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).
Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).
Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).
Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).
Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
Chaput, N. et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28, 1368–1379 (2017).
Frankel, A. E. et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 19, 848–855 (2017).
Spencer, C. N. et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 374, 1632–1640 (2021).
Andrews, M. C. et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat. Med. 27, 1432–1441 (2021).
Lee, K. A. et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat. Med. 28, 535–544 (2022).
McCulloch, J. A. et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat. Med. 28, 545–556 (2022).
Simpson, R. C. et al. Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome. Nat. Med. 28, 2344–2352 (2022).
Harkiolaki, M. et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 30, 348–357 (2009).
Horai, R. et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity 43, 343–353 (2015).
Gil-Cruz, C. et al. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science 366, 881–886 (2019).
Fluckiger, A. et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 369, 936–942 (2020).
Bessell, C. A. et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 5, e135597 (2020).
Daillere, R. et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45, 931–943 (2016).
Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).
Overacre-Delgoffe, A. E. & Hand, T. W. Regulation of tissue-resident memory T cells by the microbiota. Mucosal Immunol. 15, 408–417 (2022).
Derosa, L. et al. Microbiota-centered interventions: the next breakthrough in immuno-oncology? Cancer Discov. 11, 2396–2412 (2021).
Fessler, J., Matson, V. & Gajewski, T. F. Exploring the emerging role of the microbiome in cancer immunotherapy. J. Immunother. Cancer 7, 108 (2019).
Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).
Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019).
Griffin, M. E. et al. Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy. Science 373, 1040–1046 (2021).
Ansaldo, E. & Belkaid, Y. How microbiota improve immunotherapy. Science 373, 966–967 (2021).
Mager, L. F. et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 369, 1481–1489 (2020).
Lam, K. C. et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell 184, 5338–5356.e21 (2021).
Wang, H. et al. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab. 34, 581–594.e8 (2022).
Mirji, G. et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci. Immunol. 7, eabn0704 (2022).
Tintelnot, J. et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 615, 168–174 (2023).
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. Open 3, e202895 (2020).
Botticelli, A. et al. Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment. J. Transl. Med. 18, 49 (2020).
Coutzac, C. et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat. Commun. 11, 2168 (2020).
Han, K. 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).
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).
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.e10 (2019).
Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e5 (2019).
Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Prim. 6, 38 (2020).
Luoma, A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655–671.e22 (2020).
Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).
Routy, B. et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).
Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).
Singh, R. K. et al. Influence of diet on the gut microbiome and implications for human health. J. Transl. Med. 15, 73 (2017).
Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).
Xing, P. et al. Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis. J. Immunother. Cancer 7, 341 (2019).
Teulings, H. E. et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J. Clin. Oncol. 33, 773–781 (2015).
Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).
Fuca, G. et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open. 4, e000457 (2019).
Bai, X. et al. Early use of high-dose-glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy. Clin. Cancer Res. 27, 5993–6000 (2021).
Huang, E. Y. et al. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm. Bowel Dis. 21, 963–972 (2015).
Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019).
Wang, F., Yin, Q., Chen, L. & Davis, M. M. Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. Proc. Natl Acad. Sci. USA 115, 157–161 (2018).
Sun, S. et al. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 117, 27509–27515 (2020).
He, Y. et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease mdels. Nat. Med. 24, 1532–1535 (2018).
Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).
Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).
Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).
Vieira-Silva, S. et al. Species–function relationships shape ecological properties of the human gut microbiome. Nat. Microbiol. 1, 16088 (2016).
Louca, S. et al. Function and functional redundancy in microbial systems. Nat. Ecol. Evol. 2, 936–943 (2018).
Finlay, B. B. et al. Can we harness the microbiota to enhance the efficacy of cancer immunotherapy? Nat. Rev. Immunol. 20, 522–528 (2020).
Gharaibeh, R. Z. & Jobin, C. Microbiota and cancer immunotherapy: in search of microbial signals. Gut 68, 385–388 (2018).
Gibbons, S. M. Microbial community ecology: function over phylogeny. Nat. Ecol. Evol. 1, 32 (2017).
Patnode, M. L. et al. Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans. Cell 179, 59–73.e13 (2019).
Bhatt, A. P., Redinbo, M. R. & Bultman, S. J. The role of the microbiome in cancer development and therapy. CA Cancer J. Clin. 67, 326–344 (2017).
Riviere, A., Selak, M., Lantin, D., Leroy, F. & De Vuyst, L. Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front. Microbiol. 7, 979 (2016).
Baxter, N. T. et al. Dynamics of human gut microbiota and short-chain fatty acids in response to dietary interventions with three fermentable fibers. mBio 10, e02566-18 (2019).
Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).
Costea, P. I. et al. Enterotypes in the landscape of gut microbial community composition. Nat. Microbiol. 3, 8–16 (2018).
Rinninella, E. et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 7, 14 (2019).
Vieira-Silva, S. et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature 581, 310–315 (2020).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Vieira-Silva, S. et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat. Microbiol. 4, 1826–1831 (2019).
Manor, O. et al. Health and disease markers correlate with gut microbiome composition across thousands of people. Nat. Commun. 11, 5206 (2020).
Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015).
Zmora, N. et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174, 1388–1405.e21 (2018).
Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).
Jordan, E. J. et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017).
Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).
McQuade, J. L., Daniel, C. R., Helmink, B. A. & Wargo, J. A. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 20, e77–e91 (2019).
Cullin, N., Azevedo Antunes, C., Straussman, R., Stein-Thoeringer, C. K. & Elinav, E. Microbiome and cancer. Cancer Cell 11, 1317–1341 (2021).
Jansen, Y. J. L. et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 20, 1239–1251 (2019).
Simpson, R. C., Shanahan, E., Scolyer, R. A. & Long, G. V. Targeting the microbiome to overcome resistance. Cancer Cell 39, 151–153 (2021).
Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).
Zhu, C. et al. Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in 4 days: a pilot study. Nutr. Res. 77, 62–72 (2020).
Reynolds, A. et al. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet 393, 434–445 (2019).
McDonald, D. et al. American gut: an open platform for citizen science microbiome research. mSystems 3, e00031-18 (2018).
Benus, R. F. et al. Association between Faecalibacterium prausnitzii and dietary fibre in colonic fermentation in healthy human subjects. Br. J. Nutr. 104, 693–700 (2010).
Mousavi, D. C. et al. Network analysis of gut microbiome throughout a whole foods based high fiber dietary intervention reveals complex community dynamics in melanoma survivors [abstract]. Cancer Res. 83 (Suppl. 8), LB109 (2023).
Jiang, Y. A controlled high fiber dietary intervention alters metabolome and gut microbiome in melanoma survivors [abstract]. Cancer Res. 83 (Suppl. 8), LB348 (2023).
Li, Y. et al. Prebiotic-induced anti-tumor immunity attenuates tumor growth. Cell Rep. 30, 1753–1766.e6 (2020).
Popov, S. V., Ovodova, R. G., Markov, P. A., Nikitina, I. R. & Ovodov, Y. S. Protective effect of comaruman, a pectin of cinquefoil Comarum palustre L., on acetic acid-induced colitis in mice. Dig. Dis. Sci. 51, 1532–1537 (2006).
Ferrere, G. et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 6, e145207 (2021).
Holmes, Z. C. et al. Microbiota responses to different prebiotics are conserved within individuals and associated with habitual fiber intake. Microbiome 10, 114 (2022).
Ward, N. L. et al. Antibiotic treatment induces long-lasting changes in the fecal microbiota that protect against colitis. Inflamm. Bowel Dis. 22, 2328–2340 (2016).
Fong, W., Li, Q. & Yu, J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 39, 4925–4943 (2020).
Hattori, N. et al. Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model. Cancer Sci. 110, 147–156 (2019).
Cao, H. et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int. J. Cancer 140, 2545–2556 (2017).
Pinato, D. J. et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 5, 1774–1778 (2019).
Derosa, L. et al. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur. Urol. 78, 195–206 (2020).
Jing, Y. et al. Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy. J. Immunother. Cancer 10, e003779 (2022).
Zhao, L. et al. Association of blood biochemical indexes and antibiotic exposure with severe immune-related adverse events in patients with advanced cancers receiving PD-1 inhibitors. J. Immunother. 45, 210–216 (2022).
Abu-Sbeih, H. et al. Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis. J. Immunother. Cancer 7, 242 (2019).
Vehreschild, M. et al. An open randomized multicentre phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones. J. Antimicrob. Chemother. 77, 1155–1165 (2022).
Messaoudene, M. et al. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 therapy demonstrated by transplantation of human feces into tumor-bearing mice [abstract 1306]. J. Immunother. Cancer 10 (Suppl. 2), A1356–A1357 (2022).
Sanders, M. E., Merenstein, D. J., Reid, G., Gibson, G. R. & Rastall, R. A. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat. Rev. Gastroenterol. Hepatol. 16, 605–616 (2019).
Veiga, P., Suez, J., Derrien, M. & Elinav, E. Moving from probiotics to precision probiotics. Nat. Microbiol. 5, 878–880 (2020).
O’Toole, P. W., Marchesi, J. R. & Hill, C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat. Microbiol. 2, 17057 (2017).
Khalesi, S. et al. A review of probiotic supplementation in healthy adults: helpful or hype. Eur. J. Clin. Nutr. 73, 24–37 (2019).
Suez, J. et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 174, 1406–1423.e16 (2018).
Spencer, C. N. et al. The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors [abstract]. Cancer Res. 17 (Suppl. 13), 2838 (2019).
Dizman, N. et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat. Med. 28, 704–712 (2022).
Mullish, B. H. et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Gut 67, 1920–1941 (2018).
Baunwall, S. M. D. et al. Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an updated systematic review and meta-analysis. EClinicalMedicine 29-30, 100642 (2020).
Baruch, E. N. et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 371, 602–609 (2020).
Davar, D. et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 371, 595–602 (2021).
Routy, B. et al. Microbiome modification with fecal microbiota transplant from healthy donors before anti-PD1 therapy reduces primary resistance to immunotherapy in advanced and metastatic melanoma patients [abstract 614]. J. ImmunoTher. Cancer 10 (Suppl. 2), A646 (2022).
Wang, Y. et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24, 1804–1808 (2018).
Wang, Y. et al. Fecal transplantation improved patients’ reported outcome after immune checkpoint inhibitor colitis. Am. J. Gastroenterol. 117, e508–e509 (2022).
Spreafico, A. et al. First-in-class microbial ecosystem therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial). Ann. Oncol. 34, 520–530 (2023).
Oliva, I. G. et al. MCGRAW trial: evaluation of the safety and efficacy of an oral microbiome intervention (SER-401) in combination with nivolumab in first line metastatic melanoma patients [abstract 607]. J. Immunother. Cancer 10 (Suppl. 2), A638 (2022).
Reardon, D. et al. EO2401 microbiome derived therapeutic vaccine + nivolumab, with/without standard continuous, or low-dose symptom directed, bevacizumab, in recurrent glioblastoma: phase 1–2 EOGBM1–18/ROSALIE study [abstract 642]. J. Immunother. Cancer 10 (Suppl. 2), A673 (2022).
Maia, A. et al. Strong immune response to therapeutic vaccination with EO2401 microbiome derived therapeutic vaccine + nivolumab: interim report of the EOGBM1–18/ROSALIE study [abstract 641]. J. Immunother. Cancer 10 (Suppl. 2), A672 (2022).
da Silva, I. P. et al. Ipilimumab versus ipilimumab plus anti-PD-1 for metastatic melanoma – Authors’ reply. Lancet Oncol. 22, e343–e344 (2021).
Ascierto, P. A. et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J. Clin. Oncol. 41, 2724–2735 (2023).
Acknowledgements
E.R.S. acknowledges financial support from the à Beckett Cancer Research Trust (University of Sydney Fellowship). R.A.S. is supported by a National Health and Medical Research Council of Australia (NHMRC) Investigator Grant (APP2018514). G.V.L. is supported by NHMRC Investigator Grant (2021/GNT2007839) and by the University of Sydney Medical Foundation.
Author information
Authors and Affiliations
Contributions
R.C.S. researched data for the manuscript. All authors made a substantial contribution to discussions of content, writing the manuscript and reviewing and/or editing the manuscript prior to submission.
Corresponding author
Ethics declarations
Competing interests
R.A.S. has acted as a consultant and/or adviser to Amgen, Bristol-Myers Squibb, Evaxion, F. Hoffmann-La Roche Ltd, GlaxoSmithKline, MetaOptima Technology Inc, Merck Sharp & Dohme, Myriad Genetics, NeraCare Inc, Novartis, Provectus Biopharmaceuticals Australia and Qbiotics. G.V.L. has acted as a consultant and/or adviser to Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics and Regeneron. The other authors declare no competing interests.
Peer review
Peer reviewer information
Nature Reviews Clinical Oncology thanks B. Routy, Y. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Simpson, R.C., Shanahan, E.R., Scolyer, R.A. et al. Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol 20, 697–715 (2023). https://doi.org/10.1038/s41571-023-00803-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41571-023-00803-9
This article is cited by
-
Clinical and translational attributes of immune-related adverse events
Nature Cancer (2024)
