Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-beta signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-beta-signaling-deficient mice (Smad4(+/-) and Smad4(+/-) Sptbn1(+/-)), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-beta signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-beta signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-beta pathway in the treatment of CRC or other cancers.

Automated summary

Emerging data suggest a rise in chemoresistant colorectal cancer incidence in young individuals, potentially linked to alterations in the intestinal microbiome. This study investigated the impact of dysfunctional TGF-beta signaling on the microbiome and chemotherapy response in mice with CRC. Mutant mice with compromised TGF-beta signaling showed reduced beneficial bacteria in the gut and resistance to 5FU treatment, indicating implications for targeted therapy in CRC and other cancers.