Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and

related mortality. Thus, given the alarmingly high rates of obesity in the US and globally,

it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts

have been increasingly recognized to mitigate cancer risk, and contain many bioactive

constituents with antioxidant and anti-inflammatory properties that could potentially

counteract pathways thought to be initiators of obesity-related cancer. Therefore, the

purpose of this study was to determine if walnuts could preserve intestinal homeostasis,

and attenuate tumorigenesis and growth in the context of obesity and a high calorie

diet. To this end, we studied effects of walnuts on these parameters under different

dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and

ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the

metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet

(LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts

(HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and

preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore,

walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared

to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number

of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially

limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style

diet. In summary, these data demonstrate that walnuts confer significant protection

against intestinal tumorigenesis and growth and preserve ISC function in the context

of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence

connecting walnuts as a potentially effective dietary strategy to break the obesity-colon

cancer link.

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