Related Experiment Video
Updated: Sep 21, 2025
Non-invasive Assessment of the Efficacy of New Therapeutics for Intestinal Pathologies Using Serial Endoscopic Imaging of Live Mice
Published on: March 10, 2015
Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine
Laura W Bowers1, Elaine M Glenny2, Arunima Punjala3
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Abstract:
Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.
Prevention Relevance:
Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.
Insights
Weight loss and NSAID sulindac treatment significantly reduced colon tumor multiplicity and burden in obese mice. These interventions may offer a strategy for managing colon cancer risk in obesity.
Area of Science:
- Oncology
- Gastroenterology
- Metabolic Diseases
Background:
- Obesity is a significant risk factor for colon cancer development and progression.
- The precise mechanisms by which obesity promotes colon carcinogenesis are not fully elucidated.
- Obesity is linked to enhanced tumor growth and an immunosuppressive tumor microenvironment.
Purpose of the Study:
- To investigate the efficacy of weight loss and/or sulindac treatment in suppressing obesity-driven colon cancer.
- To explore the molecular and immunological changes associated with these interventions.
- To identify potential microbial targets involved in obesity-related colon cancer.
Main Methods:
- Utilized a mouse model of colon cancer induced by azoxymethane.
- Administered low-fat diet (LFD) or high-fat diet (HFD) to induce obesity.
- Randomized obese mice to continue HFD or switch to LFD (formerly obese).
- Treated subgroups with the NSAID sulindac.
- Analyzed tumor multiplicity, burden, transcriptomic profiles, and fecal microbiome composition.
Main Results:
- Obese mice exhibited significantly higher tumor multiplicity and burden compared to control and formerly obese groups.
- Weight loss (FOb-LFD) and sulindac treatment, individually or combined, reversed the protumor effects of obesity.
- Transcriptomic analysis revealed modulation of invasion-related genes and promotion of an antitumor immune landscape.
- Specific fecal microbes (Coprobacillus, Prevotella, Akkermansia muciniphila) were correlated with tumor multiplicity and affected by sulindac and weight loss.
Conclusions:
- Both weight loss and sulindac treatment effectively mitigate obesity-associated colon cancer progression in mice.
- These interventions alter tumor-related gene expression and promote a favorable immune environment.
- Findings support further investigation into NSAID use for colon cancer risk reduction in obese individuals, especially those with limited weight loss capacity.
