Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis

Abstract

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.

Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation—Driven Liver and Colorectal Cancers

“…In line, recent CAC studies in mice demonstrate that enriching high-fat diets with TNF- and IL-6-inhibiting supplements leads to the reduction of inflammation and mucosal injury in the colons of mice and ultimately to less tumor development [189,190,191,192,193]. Similar effects on tumor burden are seen by reducing obesity-induced inflammation via natural substances in the diets of obese APC Min/+ mice [194,195].…”

Chlorogenic acid improves intestinal morphology by enhancing intestinal stem‐cell activity

“…identified fatty acid components or their derivatives in high‐fat diets enhance intestinal stem‐cell function. Dietary walnut protects against obesity‐driven intestinal stem‐cell decline, and dietary copper can improve intestinal morphology by modulating intestinal stem‐cell activity in pigs 41,42 . Intestinal stem cells have attracted increasing attention as potential targets for the dietary regulation of gut health.…”

Antioxidant and Anti-Inflammatory Properties of Walnut Constituents: Focus on Personalized Cancer Prevention and the Microbiome

“…Obesity associated with visceral fat is a risk factor for CRC and contributes to elevated cancer incidence in mice [48]. Together with the Huffman laboratory [49], we evaluated whether walnuts may provide protection against obesity-related elevation in cancer risk in Apc 1638N/+ and Apc ∆14 mice by focusing on colon stem cell dynamics. Apc 1638N/+ mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD), with or without walnuts.…”