Anti-tumorigenic endogenous gut bacteria in mice and humans

The role of the gut microbiota in promoting intestinal tumorigenesis has been well documented, but little is known about the anti-tumorigenic roles of the gut microbiota. In a new study, an endogenous bacterial strain in mice and humans that blocks intestinal tumour growth has been identified for the first time.

Credit: Confocal image showing combined MUC2 immunostaining (grey) and fluorescence in situ hybridization analysis for Faecalibaculum rodentium PB1 (red) in colon tissue of wild-type mice. Nuclei are stained with DAPI (blue). Image courtesy of A. Bertocchi and C. Pozzi, Humanitas University, Italy.

“We were puzzled by the observation that germ-free mice can be either protected from or more prone to tumour development depending on the model system,” says Maria Rescigno, corresponding author of the new study. By analysing the gut microbiota in a mouse model of colorectal cancer (CRC) and wild-type mice, the researchers identified a strain of Faecalibaculum rodentium (F. PB1) that is underrepresented in the CRC mouse model early in tumorigenesis.

“Epithelial cells undergoing transformation produce different mucins, which create an unfavourable environment for bacteria colonization,” says Rescigno. “This situation leads either to the loss of protective strains or the enrichment of tumour-promoting strains.” To investigate a protective role for F. PB1, the researchers treated the Apc^Min/+ mouse model of CRC and wild-type mice with antibiotics and then F. PB1. Administering F. PB1 4–8 weeks after birth did not affect tumour development, but administration in weeks 8–12 reduced tumour growth in Apc^Min/+ mice, indicating a role for F. PB1 in colorectal tumour growth but not initiation.

Next, the researchers showed in Apc^Min/+ mice that the metabolic products of F. PB1, particularly the short-chain fatty acid butyrate, block tumour growth by inhibiting histone deacetylase activity and thereby reducing activation of NFATc3 and calcineurin, which have a role in cell proliferation. Finally, the researchers used a metagenomic dataset from patients with colorectal adenomas to identify Holdemanella biformis as the human homologue of F. PB1. They showed that the metabolic products of H. biformis can reduce tumour cell proliferation, with a corresponding increase in histone acetylation and decrease in NFATc3.

researchers identified a strain of Faecalibaculum rodentium (F. PB1) that is underrepresented in the CRC mouse model

“F. PB1 and H. biformis belong to the tumour-protecting bacteria that are lost during intestinal tumorigenesis,” concludes Rescigno. Now, the researchers hope to examine whether metabolites other than butyrate are responsible for this anti-tumorigenic effect. “We also want to analyse whether H. biformis can be used as a diagnostic tool or as a probiotic in patients with advanced colorectal adenoma,” says Rescigno.