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Microbiota: a key orchestrator of cancer therapy

This article has been updated

Key Points

  • The human microbiota is the ensemble of bacteria and other microorganisms that inhabit the epithelial barrier surfaces of the body. The microbiota affects physiological functions, particularly metabolism, neurological and cognitive functions, haematopoiesis, inflammation and immunity.

  • The microbiota and its larger host represent a metaorganism in which the crosstalk between microorganisms and host cells is necessary for health, survival and regulation of physiological functions at the local barrier level and systemically. Mostly because of its effects on metabolism, cellular proliferation, inflammation and immunity, the microbiota regulates cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity and response to therapy.

  • The gut microbiota affects aspects of drug metabolism, pharmacokinetics, anticancer effect and toxicity. The rate of absorption and bioavailability of many oral drugs, including cancer therapies, depends on their exposure in the gut to both host and bacterial enzymes before entering the circulation.

  • The microbiota regulates the response to different types of cancer chemotherapy by affecting their mechanism of action and toxicity. The best characterized are oxaliplatin and cyclophosphamide; the anticancer activity of which is affected by the gut microbiota, which primes myeloid cells for production of reactive oxygen species in the case of oxaliplatin and facilitates the induction of an anticancer T cell response in the case of CTX.

  • The role of the microbiota in modulating the response to anticancer radiotherapy remains to be fully characterized. However, germ-free mice have been described as being less susceptible to the toxicity of radiation than conventionally raised mice, and evidence in humans and experimental animals suggests that the composition of the intestinal microbiota may affect the severity of radiation-induced mucosal toxicity.

  • The composition of the gut microbiota modulates both inflammation and adaptive immunity and thereby regulates the effectiveness of cancer immune therapies, such as adoptive T cell transfer preceded by total body irradiation, intratumoural treatment with CpG-oligodeoxynucleotides and immune checkpoint blockade with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 ligand 1 (PDL1).

  • Evidence of the important role of the microbiota in controlling cancer therapy effectiveness and toxicity is derived mainly from data in experimental animals, and translation of these findings to human clinical medicine remains challenging. Additional human data should be obtained and new technologies developed in order to safely target the microbiota to improve anticancer therapies while attenuating the toxic side effects.

Abstract

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.

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Figure 1: Local and systemic effects of the gastrointestinal microbiota.
Figure 2: Major pathways of drug metabolism and the role of microbiota following enteral (for example, oral) or parenteral (for example, intravenous) administration.
Figure 3: The gut microbiota regulates anticancer therapies.
Figure 4: Microbiota-triggered innate immune receptors.

Change history

  • 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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Correspondence to Giorgio Trinchieri.

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Glossary

Germ-free animals

Animals raised in strict sterile conditions that have no microorganisms living in or on them.

Commensalism

A symbiotic relationship between two species in which one species benefits without causing harm to the other.

Pathobionts

Resident commensal microorganisms that under certain conditions may acquire pathogenic potential.

Mutualism

A symbiotic relationship between two species that is beneficial for both species.

Xenobiotics

Foreign chemical substances, including drugs, that are not naturally produced by the organism.

Biotransformation

The chemical alteration of a xenobiotic, such as a drug, within the body.

Probiotic

Live microorganisms that are consumed by humans and animals as food supplements for their potential health-promoting qualities.

Pathogenic T helper 17 cells

(pTH17 cells). A CD4+ T cell subset that simultaneously expresses markers of TH1 cells (T-bet transcription factor, interferon–γ (IFN–γ) and CXC chemokine receptor 3 (CXCR3)) and of TH17 cells (RORγT transcription factor, interleukin-17 (IL-17) and C-C chemokine receptor 6 (CCR6)).

Cachexia

A wasting syndrome with muscle atrophy and loss of weight and adipose tissue, often associated with cancer and cancer therapy.

Bystander effect

In radiobiology, collateral damage exhibited by unirradiated cells in response to signals received from nearby irradiated cells.

Abscopal effect

In radiotherapy, a phenomenon whereby local radiotherapy induces tumour regression at sites distant from the irradiated site.

Prebiotics

Non-digestible food ingredients, often containing fibre, that promote the growth of beneficial microorganisms in the intestines.

Enterotypes

Classification of individuals based on the composition of their gut bacterial ecosystem, each enterotype having distinct clusters of organisms with characteristic predominant bacterial species.

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Roy, S., Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17, 271–285 (2017). https://doi.org/10.1038/nrc.2017.13

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