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Gut microbiome

Anticancer action of caloric restrictions via microbiota

Nature Metabolism volume 5, pages 8–9 (2023)Cite this article

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Commensal bacteria in the gut and their metabolites modulate the tonus of cancer immunosurveillance. Mao, Huang et al. demonstrate that the anticancer effects of caloric restriction depend on the expansion of acetate-producing immunostimulatory Bifidobacterium bifidum.

In this issue of Nature Metabolism, Mao, Huang et al.6 evaluated the contribution of the intestinal microbiota to the ability of CR and IM to reduce the subcutaneous growth of MC38 colorectal cancer cells in immunocompetent C57Bl/6 mice. The gut microbiota was depleted by oral administration of a cocktail of four broad-spectrum antibiotics (ampicillin, neomycin, metronidazole and vancomycin). Surprisingly, the anticancer effects of CR, but not of IM, turned out to depend on the intestinal microbiota. Moreover, faecal microbial transplantation (FMT) from donors under CR, but not under IM, to antibiotic-treated recipients re-established the immune control of tumour progression. Indeed, CR and IM induced distinct shifts in the gut microbiota with a time-dependent expansion of Bifidobacterium in mice under CR, as compared to IM and ad libitum-fed controls. Oral gavage of Bifidobacterium bifidum turned out to restore immunosurveillance in antibiotic-treated mice under CR and to improve tumour control in ad libitum-fed controls. The anticancer effects of B. bifidum could be replicated in another cancer model — 4T1 breast cancers orthotopically implanted into immunocompetent BALB/c mice. In the MC38 model, several manipulations that reduced tumour growth, namely (i) CR without antibiotics, (ii) FMT from CR-treated donors to AL-fed mice and (iii) B. bifidum supplementation to antibiotic-treated mice under CR, all increased the infiltration of tumours by interferon-γ (IFNγ)-producing CD8+ cytotoxic T cells (CTLs). Depletion of CTLs using a suitable CD8-specific antibody reversed tumour growth control induced by CR, FMT and B. bifidum, establishing a cardinal role for immunosurveillance in these antineoplastic effects6.

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Fig. 1: Schematic overview of the gut microbiota–metabolism axis.

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Acknowledgements

G.K. and L.Z. are supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.

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Authors and Affiliations

  1. Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Laurence Zitvogel

  2. Université Paris Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France

    Laurence Zitvogel

  3. INSERM U1015, Paris, France

    Laurence Zitvogel

  4. Equipe labellisée par la Ligue contre le Cancer, Villejuif, France

    Laurence Zitvogel

  5. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) BIOTHERIS, Villejuif, France

    Laurence Zitvogel

  6. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

    Guido Kroemer

  7. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Guido Kroemer

  8. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

Authors
  1. Laurence Zitvogel
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Correspondence to Laurence Zitvogel or Guido Kroemer.

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Competing interests

G.K. has held research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys and Vascage. G.K. has consulted for Reithera. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. L.Z. has held research contracts with 9 Meters Biopharma, Daiichi Sankyo, Pilege, was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. L.Z. has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, is on the Board of Directors of Transgene, is a co-founder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota.

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Zitvogel, L., Kroemer, G. Anticancer action of caloric restrictions via microbiota. Nat Metab 5, 8–9 (2023). https://doi.org/10.1038/s42255-022-00705-7

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