Resistant starch (RS) is not digested in the small intestine and is available for fermentation by the colonic microbiota, producing metabolites including short chain fatty acids (SCFAs). We hypothesized that diets containing resistant starch, serving as a prebiotic, will have inhibitory effects, mediated through the products of microbial fermentation, on the canonical Wnt signaling pathway. To test this hypothesis, we examined the molecular and morphologic effects of diets containing resistant starches on the early stage of colorectal carcinogenesis in azoxymethane-induced rat and mouse models. The first study examined the effects of diets containing naturally occurring resistant starch from Latin American corn strains, GUAT (18.6%) and AR (5.4%), and their hybrid, ARxGUAT (8.6%), for effects on the pre-neoplastic stages of azoxymethane-induced colonic epithelial damage in Fisher 344 rats. Genes of the Wnt signaling pathway were selected and analyzed for expression levels by semi-quantitative, real-time polymerase chain reaction analysis (semi-qRT-PCR). In the second study, the effects of diets including a stearic-acid complexed high-amylose cornstarch (SA-HA7) (31.1%), a high amylose starch (HA7) (19.0%), a chemically modified starch (OS-HA7) (4.7%), were compared with normal corn starch (CS) (3.7%), for the effects on azoxymethane-induced colonic epithelial damage in A/J mice, as tested by mRNA levels of the same genes as the first study. Being able to demonstrate inhibitory effects of resistant starch, on the Wnt pathway will provide a potential means to prevent the initiation and proliferation of colorectal carcinogenesis. In the first study, the GUAT diet did not inhibit development of the putative preneoplastic lesion, aberrant crypt focus (ACF). However, mRNA encoding â-catenin was significantly decreased in AOM-injected rats fed the GUAT diet compared with the saline-injected rats fed the GUAT diet, while no similar decrease was seen in diets low in resistant starch. In the second study, mice fed a diet containing a high level of resistant starch, SA-HA7, had lower mRNA expression of several targets, with the exception of â-catenin mRNA, relative to the mice fed the control diet. Overall, this suggests a potential ability of resistant starch to regulate â-catenin expression, and thus the Wnt signaling pathway.