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Targeting the gut microbiota for cancer therapy

Nature Reviews Cancer volume 22, pages 703–722 (2022)Cite this article

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Abstract

Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The poor response to immunotherapy in patients treated with antibiotics supports this influential role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analysed the underlying mechanisms. A better understanding of the taxonomy of the species involved and of the mechanisms of action has since been achieved. Defined bacterial species have been shown to promote an improved response to immune-checkpoint inhibitors by producing different products or metabolites. However, a suppressive effect of Gram-negative bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on the microbiota composition of patients can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, interest in modulating the microbiota composition to improve patient responsiveness to therapy has been mounting. Clinical proof-of-concept studies have demonstrated that faecal microbiota transplantation or dietary interventions might be utilized clinically to improve the success rate of immunotherapy in patients with cancer. Here, we review recent advances and discuss emerging strategies for microbiota-based cancer therapies.

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Fig. 1: The gut microbiota modulates cancer therapy and can be targeted to enhance therapy efficacy and prevent adverse effects.
Fig. 2: Gut microbiota regulation of the response to anti-PD1 immune-checkpoint blockade.

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Authors and Affiliations

  1. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Miriam R. Fernandes, Poonam Aggarwal, Raquel G. F. Costa, Alicia M. Cole & Giorgio Trinchieri

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  1. Miriam R. Fernandes
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  2. Poonam Aggarwal
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  3. Raquel G. F. Costa
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  4. Alicia M. Cole
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  5. Giorgio Trinchieri
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The authors contributed equally to all aspects of the article.

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Correspondence to Giorgio Trinchieri.

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The authors declare no competing interests.

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Nature Reviews Cancer thanks Bertrand Routy, Susan Bullman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

16S rRNA gene amplicon sequencing

The most widely used technique for microbial taxonomic classification that sequences the variable regions of the 16S rRNA gene.

α-Diversity

In microbial ecology, the measure of how evenly distributed the microbial taxa are within a single sample.

Adoptive T cell therapy

(ACT). A transfusion of T lymphocytes that can enhance antitumour immunity. Patient T lymphocytes are augmented and oftentimes altered before they are given back to the patient.

Allogeneic haematopoietic stem cell transplantation

(allo-HSCT). A therapeutic option for haematopoietic malignancies. Patients receive high-dose chemotherapy or chemoradiotherapy (known as conditioning therapy) to eliminate malignant cells; subsequent infusion of haematopoietic stem cells aims to restore haematopoiesis.

Area under the receiver operating characteristic curve

(AUROC). A graphical evaluation metrics to assess the performance of a classification model at various threshold settings.

Bacteraemia

Presence of viable bacteria in the blood that can be asymptomatic and physiological or can reflect a pathological infection.

Biofilm

Formed by consortia of microorganisms, usually bacteria, in which microbial cells are embedded in an extracellular matrix of polymeric substances and stick to each other, forming a thin layer coating a surface.

Chimeric antigen receptor (CAR) T cells

A form of immunotherapy in which a patient’s T cells are collected and genetically engineered to express specific chimeric antigen receptors that can target proteins expressed on cancer cells. The cells are then given back to the patient to exhibit anticancer effects.

Contigs

Overlapping DNA sequences that can be combined to provide a contiguous representation of a genomic region.

CpG-oligodeoxynucleotide

(CpG-ODN). DNA molecules that contain CpG motifs. They elicit potent immunostimulatory effects by binding to TLR9 and can enhance anticancer responses when combined with chemotherapy, radiation therapy or immunotherapy.

Enteric microbiotypes

Distinct, ecologically balanced microbial communities within the human gut microbiota.

Fasting mimetic diets

A diet plan in which the patient abstains from eating food for predetermined periods.

Faecal microbiota transplantation

(FMT). A clinical procedure that transfers, via colonoscopy, naso-enteric tube or capsules, faecal microbiota from a donor into another individual. Successfully used to treat opportunistic enteric infections in immunosuppressed patients caused by bacteria such as Clostridioides difficile.

Gnotobiotic mice

Mice colonized with a specific community of known microorganisms.

Graft-versus-host disease

(GvHD). A clinical condition following haematopoietic stem cell transplantation in which the bone marrow or stem cells from the donor recognize the recipient’s body as foreign and damage cells from different tissues. GvHD can be acute or chronic and is a major cause of toxicity and lethality following transplantation.

Immune-related adverse events

(irAEs). Frequently observed upon immune activation in patients undergoing immune-checkpoint blockade therapy for cancer treatment. Common examples include colitis, dermatitis, and hyperthyroidism or hypothyroidism.

Ketogenic diets

A diet plan in which the patient limits carbohydrate intake and increases fat and protein intake.

Machine learning

The branch of artificial intelligence that can automatically improve its system using algorithms that learn from input data patterns.

Nucleotide-binding oligomerization domain-containing protein 2

(NOD2). An intracellular innate receptor mainly expressed in haematopoietic myeloid cells that recognizes bacterial muramyl dipeptide.

Operon

A cluster of genes in prokaryotes that are transcribed together to give a polycistronic mRNA molecule encoding multiple proteins that are often part of the same biochemical pathway.

Pathobionts

Commensal microbes that opportunistically emerge as pathogens when the ecology of the healthy microbiota is perturbed, leading to their selection and unchecked expansion.

Polyphenol

A member of a large family of micronutrients with anti-oxidant and health-promoting activity, characterized by multiple units of phenol and present in plant-based food.

Primary bile acids

Bile acids (BAs) derived from cholesterol and are synthesized in the liver. They are often converted into secondary BAs by bacteria in the colon.

Prophage

A bacteriophage genome, incorporated into the circular chromosome of a bacterium or present within it as an extrachromosomal plasmid and able to produce phages if activated.

Quorum sensing

(QS). Bacterial cell-to-cell communication mediated by autoinducers that accumulate in the environment when bacteria interact at high densities.

Secondary BAs

BAs that are synthesized by microbial action in the colon. They have important roles in immunity, inflammation, tumorigenesis and disease.

Shotgun metagenomic sequencing

A technique that sequences all genomic DNA from a sample, thus giving highly accurate microbial taxonomical classifications and functional gene information.

Short-chain fatty acid

(SCFA). Metabolites, such as acetate, butyrate and propionate, that are produced by microbes in the colon by the fermentation of dietary fibres and starch and have various roles in inflammation, metabolism and disease.

Stereotactic body radiation therapy

A procedure using multiple precisely focused radiation beams to target a tumour sparing surrounding normal tissues.

Stimulator of interferon genes

(STING). A broadly expressed transmembrane intracellular innate receptor that induces type I interferon production. STING signalling is induced by cyclic dinucleotides that are released by intracellular bacteria or endogenous cyclic GMP-AMP synthase (cGAS) signalling following interaction with cellular or microbial intracellular DNA. STING is also an adaptor protein for several other cytoplasmic innate receptors.

Toll-like receptor

A class of innate receptors that recognize conserved molecules of microbial origin and activate pro-inflammatory pathways. TLR2, which mainly recognizes bacterial peptidoglycans from Gram-positive bacteria, and TLR4, which mainly recognizes lipopolysaccharides from Gram-negative bacteria, are broadly expressed on haematopoietic myeloid cells. TLR9, which recognizes unmethylated CpG-containing oligonucleotides from bacteria and viruses, is expressed primarily on human and mouse B cells and plasmacytoid dendritic cells while in mice, it is also expressed on myeloid cells.

Total body irradiation

(TBI). A form of radiotherapy commonly used to eradicate or suppress the patient’s immune system before haematopoietic stem cell transplantation to prevent immunological rejection of the donor cells.

Transkingdom gene network analysis

A data-driven systems-biology approach that identifies key causal players in a biological system, including species from different taxonomic kingdoms, for example, Animalia, Monera and Fungi.

Xeno-antigens

Antigens shared among different species.

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Fernandes, M.R., Aggarwal, P., Costa, R.G.F. et al. Targeting the gut microbiota for cancer therapy. Nat Rev Cancer 22, 703–722 (2022). https://doi.org/10.1038/s41568-022-00513-x

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