Microbiota: a key orchestrator of cancer therapy

Journal name:
Nature Reviews Cancer
Year published:
Published online
Corrected online


The microbiota is composed of commensal bacteria and other microorganisms that live on the epithelial barriers of the host. The commensal microbiota is important for the health and survival of the organism. Microbiota influences physiological functions from the maintenance of barrier homeostasis locally to the regulation of metabolism, haematopoiesis, inflammation, immunity and other functions systemically. The microbiota is also involved in the initiation, progression and dissemination of cancer both at epithelial barriers and in sterile tissues. Recently, it has become evident that microbiota, and particularly the gut microbiota, modulates the response to cancer therapy and susceptibility to toxic side effects. In this Review, we discuss the evidence for the ability of the microbiota to modulate chemotherapy, radiotherapy and immunotherapy with a focus on the microbial species involved, their mechanism of action and the possibility of targeting the microbiota to improve anticancer efficacy while preventing toxicity.

At a glance


  1. Local and systemic effects of the gastrointestinal microbiota.
    Figure 1: Local and systemic effects of the gastrointestinal microbiota.

    The abundant microbiota present on the gastrointestinal mucosa affects local mucosal homeostasis, functions and immunity7, 8, 9. Many of the mechanisms by which various bacterial species and their products and metabolites affect mucosal physiology and pathology have been described7, 8, 9, 10. However, the presence and composition of the gut microbiota also systemically affects the functions of most physiological systems, the pathology and the response to therapy in distant organs10. Some of the demonstrated or proposed mechanisms by which the gastrointestinal microbiota can achieve this are listed in the box at the top of the figure205. The microbiota and specific microbial species also affect neoplastic pathology both at the local level in the gastrointestinal tract145, 188, 206, 207 and systemically in organs that are not normally associated with the gut microbiota192, 193, 194, 208, 209, 210, 211, 212. Although these mechanisms have been studied primarily for the most abundant intestinal microbiota organisms, microorganisms colonizing other epithelial barriers, for example, the mouth and the skin, are also expected to mediate both local and systemic effects195, 195. In addition to its association with cancer development, the microbiota also has both a local and a systemic role in modulating the efficacy and toxicity of cancer therapy3. CNS, central nervous system; MALT, mucosa-associated lymphoid tissue.

  2. Major pathways of drug metabolism and the role of microbiota following enteral (for example, oral) or parenteral (for example, intravenous) administration.
    Figure 2: Major pathways of drug metabolism and the role of microbiota following enteral (for example, oral) or parenteral (for example, intravenous) administration.

    a | Enteral drug metabolism. Orally administered drugs (E1) sit in the stomach for 30–45 minutes before reaching the intestine and being absorbed into the liver by the portal circulation (E2). In the intestine, host and microbial enzymes induce metabolic alterations to the drug that together with direct binding to bacterial products and segregation control intestinal absorption43. In the liver, following phase I and phase II processing (first pass metabolism; E3), approximately 90% of the oral drug is metabolized and destroyed or eliminated through biliary secretion (E4). The drugs secreted into the intestine via the biliary duct can be reabsorbed via the portal circulation or excreted in stools. As a consequence, only 10% of the oral drug enters the circulation through the hepatic veins and is available to reach the target tumours and other tissues (E5). Phase I and phase II processing are also affected by the gut microbiota through the regulation of the level of host enzymes involved in drug processing. b | Parenteral drug metabolism. Following intravenous administration (P1) close to 100% of the drug enters the circulation and is available to reach the target tumours (P2); however, the drug is also distributed systemically, inducing adverse toxic reactions (P3). Any remaining drug not retained in tissues can be rapidly excreted by the kidney. Each minute 29% of the circulating drug is transported via the splanchnic circulation (hepatic, mesenteric and splenic arteries) to the liver (P4), where the drug is processed similarly to enterally administered drugs. The detoxified drugs that are secreted from the liver to the intestine through the biliary excretion route can be reactivated by bacterial enzymes, inducing intestinal toxicity. CYP450, cytochrome P450; GI, gastrointestinal.

  3. The gut microbiota regulates anticancer therapies.
    Figure 3: The gut microbiota regulates anticancer therapies.

    In physiological conditions, the commensals in the intestinal lumen are prevented from translocating through the intestinal mucosa by an intact epithelial barrier covered by a mucus layer that is poorly permeable to microorganisms. Treatment with platinum (Pt) drugs, total body irradiation (TBI), cyclophosphamide (CTX) and anti-cytotoxic T lymphocyte- associated antigen 4 (CTLA4) all cause damage to the mucus layer, which disrupts barrier integrity and enables bacteria to penetrate the lamina propria, which lies beneath the epithelium. Translocated bacteria activate innate immune cells and initiate local and systemic inflammation. Mechanisms of gut-associated toxicity and tumour clearance vary based on treatment type, and the microbial species that have been demonstrated to affect these mechanisms are listed at the top of the figure. Gut commensals, through myeloid differentiation primary response 88 (MYD88)- associated receptors, prime myeloid cells for the generation of reactive oxygen species (ROS), which, in the presence of Pt–DNA adducts formed in response to cisplatin or oxaliplatin, cause DNA damage62, 74. TBI used to condition patients before they receive adoptive T cell therapy induces mucosal damage and translocation of commensals, which through Toll-like receptor 4 (TLR4) signalling activate dendritic cells to sustain proliferation and cytotoxic functions of the transferred T cells153. CTX induces immunological cell death of tumour cells, which elicits the generation of antitumour pathogenic T helper 17 (pTH17) cells, TH1 cells and cytotoxic T lymphocytes (CTLs); CTX also induces damage to the mucosa and translocation of commensal bacteria that activate tumour antigen-presenting dendritic cells, enhancing the antitumour immune response61, 82. During CpG-oligodeoxynucleotide (ODN)–anti-interleukin-10 receptor (IL-10R) therapy, the gut microbiota, through TLR4 signalling, primes tumour-infiltrating myeloid cells to respond to the TLR9 agonist CpG-ODN, producing tumour necrosis factor (TNF) and other inflammatory cytokines that induce haemorrhagic necrosis of the tumour and an antitumour immune response62. Anti-CTLA4 immunotherapy promotes both antitumour and anti-commensal immunity; the anti-commensal immunity against specific genera, such as Burkholderiales and Bacteroidales (Bacteroides thetaiotaomicron and Bacteroides fragilis), results in mucosal damage and bacterial translocation but also serves as an adjuvant for the antitumour response33. The efficacy of anti- programmed cell death protein 1 ligand 1 (PDL1) therapy in generating antitumour immunity by preventing programmed cell death protein 1 (PD1) interaction with PDL1 is enhanced by the presence in the gut microbiota of Bifidobacterium spp. (Bifidobacterium breve, Bifidobacterium longum and Bifidobacteri-um adolescentis)152. A. shahii, Alistipes shahii; B. intestinihominis, Barnesiella intestinihominis; E. hirae, Enterococcus hirae; L. acidophilus, Lactobacillus acidophilus; L. johnsonii, Lactobacillus johnsonii.

  4. Microbiota-triggered innate immune receptors.
    Figure 4: Microbiota-triggered innate immune receptors.

    Microbial products (microorganism-associated molecular patterns; MAMPs) and endogenous ligands, often released following tissue damage (damage-associated molecular patterns; DAMPs) interact with membrane-bound and cytoplasmic innate immune receptors regulating nutrition, metabolism, tissue homeostasis, inflammation, innate and adaptive immunity and, to a lesser extent, morphogenesis213, 214, 215, 216, 217. The gut microbiota promotes platinum cancer therapy by signalling through myeloid differentiation primary response 88 (MYD88), an adaptor for both the Toll-like receptor (TLR) and the interleukin-1 receptor (IL-1R) families61, 62. ? denotes that the identity of the receptors are yet to be determined. Activation of TLR4 by MAMPs primes tumour myeloid cells to respond to the TLR9 agonist CpG-oligodeoxynucleotide (ODN), induces mucosal bacterial translocation following total body irradiation (TBI), which favours optimal anticancer activity of adoptive T cell transfer and mediates mucosal toxicity by methotrexate62, 86, 87. In response to immunogenic cell death mediated by oxaliplatin or cyclophosphamide (CTX), activation of TLR4 by DAMPs in combination with NOD-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome activation induces antitumour T cell activation77. Activation of TLR2 by MAMPs protects against mucosal damage induced by chemotherapy or radiation86, 87, 88, 130, 131, 132. Radiation activates TLR3 and the inflammasome absent in melanoma 2 (AIM2) by inducing leakage of cellular RNA and double-strand DNA breaks, respectively, resulting in massive cell death and tissue damage127, 128, 129. The cytoplasmic nucleotide-binding oligomerization domain-containing 2 (NOD2) receptor recognizing bacterial muramyl dipeptides participates in the regulation of intestinal mucosa homeostasis and protects against chemotherapy-induced mucosal damage and bacterial translocation82, 92. The N-formyl peptide receptors (FPRs) recognize bacterial peptides as well as endogenous ligands218. FPR2 expressed on apical and lateral membranes of the colonic crypt has a crucial role in regulating intestinal homeostasis and inflammation219. The ability of anthracycline to elicit antitumour T cell immunity requires the interaction of FPR1 on dendritic cells with the endogenous ligand annexin-A1, which promotes stable contacts between dying cancer cells and dendritic cells79. A. shahii, Alistipes shahii; COX2, cyclooxygenase 2; HMGB1, high mobility group protein B1; L. acidophilus, Lactobacillus acidophilus; L. reuteri, Lactobacillus reuteri; L. rhamnosus, Lactobacillus rhamnosus; LPS, lipopolysaccharide; MDR1, multi-drug resistance protein 1; NOX, NADPH oxidase; NRF2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; TNF, tumour necrosis factor.

Change history

Corrected online 04 April 2017
In this article the sentence 'however, in one study, overgrowth of Parabacteroides distasonis in mice treated with broad-spectrum antibiotics was observed to abrogate its antitumour effect' was incorrectly referenced. The correct reference for this sentence is 61.


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  1. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Soumen Roy &
    • Giorgio Trinchieri

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The authors declare no competing interests.

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  • Soumen Roy

    Soumen Roy is currently working in the field of gut microbiota, cancer and experimental immunology in the laboratory of G. Trinchieri, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA. He is interested in the role of the gut microbiota in modulating anticancer therapy-induced systemic toxicity. During his postdoctoral training in the laboratory of Lisa Cunningham, National Institute on Deafness and other Communication Disorders (NIDCD), NIH, he worked on developing a sound preconditioning-based co-therapy to prevent hearing loss from anticancer drug-induced ototoxicity. He obtained his Doctoral degree in the field of hearing research and targeted nanomedicine in the laboratory of Anneliese Schrott Fisher, Innsbruck Medical University, Austria.

  • Giorgio Trinchieri

    Giorgio Trinchieri is a National Institutes of Health (NIH) Distinguished Investigator and Director of the Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH. He received his M.D. from the University of Torino, Italy in 1973. Before his position at NCI, he served in multiple capacities at the Basel Institute for Immunology, Switzerland, the Medical Genetics Institute at the Medical School of Torino, the Wistar Institute and Department of Medicine of the University of Pennsylvania, Philadelphia, USA, the Swiss Institute for Experimental Cancer Research in Epalinges, Switzerland, the Schering Plough Laboratory for Immunological Research in Dardilly, France, and the Laboratory for Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, USA. For many years he has been interested in the interplay between inflammation/innate resistance and adaptive immunity, and in the role of pro-inflammatory cytokines and interferons in the regulation of haematopoiesis, innate resistance and immunity against infections and tumours. His laboratory's main focus is the role of inflammation, innate resistance, immunity and commensal microbiota in carcinogenesis, cancer progression and prevention or therapy of cancer.

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