Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the non-steroidal anti-inflammatory drug (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 seven 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 anti-tumor 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.

Supplementary Table from Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer

<p>Supplementary Results for Figures S1-S4</p>

<p>Supplementary Figure S2A and S2B: miR qPCR Assay Comparison</p>

<p>Supplementary Figure S1A and S1B: miR Extraction Methods Comparison</p>