Editors' ChoiceCancer

Reduce Tumors with a Low-Carb Diet

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Science Signaling  29 Jul 2014:
Vol. 7, Issue 336, pp. ec203
DOI: 10.1126/scisignal.2005737

Most colorectal cancers are associated with mutations in the gene encoding APC, a negative regulator of the transcriptional coactivator β-catenin. Additional factors that contribute to colorectal cancer progression include defects in DNA mismatch repair, intestinal microbiota, and diets rich in carbohydrates. ApcMin/+ mice, which have a heterozygous loss of function mutation in Apc, develop spontaneous polyps in the small intestine and colon, and the number of polyps is increased by deletion of both alleles of the gene encoding the mismatch repair protein MSH2 (Msh2–/–). Belcheva et al. explored the interactions among diet, microbiota, and genetic deficiencies in ApcMin/+ Msh2–/– mice. A cocktail of oral antibiotics reduced the number of intestinal polyps in ApcMin/+ Msh2–/– mice but not ApcMin/+ mice with heterozygous deletion of Msh2 (Msh2+/–), compared with untreated mice of the same genotypes. The number of adaptive and innate immune cells in the intestine was not different between ApcMin/+ Msh2–/– and ApcMin/+ Msh2+/– mice, and the number of polyps in ApcMin/+ Msh2–/– mice was not affected by genetic disruption of immune system function. Moreover, antibiotics did not alter the frequency of mutations or the number of DNA double-strand breaks in intestinal epithelial cells of ApcMin/+ Msh2–/– mice. Feeding a low-carbohydrate diet to ApcMin/+ Msh2–/– mice reduced the number of colon polyps without affecting weight gain; however, the low-carbohydrate diet did not further reduce the number of polyps in ApcMin/+ Msh2–/– mice treated with antibiotics. Metabolic profiling indicated that the amount of the short-chain fatty acid butyrate, which is derived from microbial fermentation of carbohydrates, was reduced in the intestinal mucosa of ApcMin/+ Msh2–/– mice treated with antibiotics or fed a low-carbohydrate diet compared with that in untreated ApcMin/+ Msh2–/– mice. Giving mice the antibiotic metronidazole or feeding mice a low-carbohydrate diet reduced the abundance of members of the bacterial phylum Firmicutes, which produce butyrate, without affecting the total bacterial abundance. Oral or rectal administration of a low concentration of exogenous butyrate increased intestinal epithelial cell proliferation and the number of polyps in antibiotic-treated ApcMin/+ Msh2–/– mice but not antibiotic-treated ApcMin/+ Msh2+/– mice. Thus, dietary carbohydrates stimulate the growth of specific microbes that release metabolites that may contribute to the severity of intestinal cancer.

A. Belcheva, T. Irrazabal, S. J. Robertson, C. Streutker, H. Maughan, S. Rubino, E. H. Moriyama, J. K. Copeland, S. Kumar, B. Green, K. Geddes, R. C. Pezo, W. W. Navarre, M. Milosevic, B. C. Wilson, S. E. Girardin, T. M. S. Wolever, W. Edelmann, D. S. Guttman, D. J. Philpott, A. Martin, Gut microbial metabolism drives transformation of Msh2-deficient colon epithelial cells. Cell 158, 288–299 (2014). [PubMed]