Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU
Zhanhuai Wang1, Lindsay M Hopson2, Stephanie S Singleton2
1Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Abstract:
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-β 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-β-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-β 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-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers.
Insights
Altered gut microbiomes in mice with colorectal cancer (CRC) due to impaired TGF-β signaling reduced chemotherapy effectiveness. Restoring beneficial bacteria in wild-type mice improved response to 5-Fluorouracil (5FU).
Area of Science:
- Oncology
- Microbiology
- Immunology
Background:
- Colorectal cancer (CRC) incidence is rising in younger populations, often presenting with chemoresistance.
- Alterations in the gut microbiome are implicated as a potential risk factor for CRC development and progression.
- Transforming growth factor-beta (TGF-β) signaling plays a critical role in intestinal homeostasis and cancer development.
Purpose of the Study:
- To investigate the impact of TGF-β signaling deficiency on the intestinal microbiome composition in a mouse model of CRC.
- To evaluate the efficacy of the chemotherapeutic agent 5-Fluorouracil (5FU) in CRC mice with altered TGF-β signaling and gut microbiota.
- To determine if microbiome alterations resulting from dysfunctional TGF-β signaling affect CRC chemoresistance.
Main Methods:
- Utilized azoxymethane and dextran sodium sulfate to induce CRC in Smad4+/- and Smad4+/-Sptbn1+/- TGF-β-signaling-deficient mice.
- Employed shotgun metagenomic sequencing to analyze gut microbiota composition in wild-type (WT) and mutant mice with CRC.
- Assessed the response to 5FU chemotherapy in relation to TGF-β signaling status and gut microbiome profiles.
Main Results:
- TGF-β-signaling-deficient mice with CRC exhibited reduced abundances of beneficial gut bacteria, including Bacteroides and Parabacteroides, compared to WT mice.
- Mutant mice with CRC demonstrated resistance to 5FU chemotherapy.
- Specific bacterial species (e.g., E. boltae, B. dorei) reduced in CRC mice only recovered after 5FU treatment in WT mice, indicating impaired microbiome recovery in mutants.
Conclusions:
- Dysfunctional TGF-β signaling leads to significant alterations in the intestinal microbiome composition in CRC.
- These microbiome changes are associated with chemoresistance to 5FU in CRC.
- Targeting the TGF-β pathway or modulating the gut microbiome may offer novel therapeutic strategies for chemoresistant CRC.
