Dietary ω-3 Fatty Acids Mitigate Intestinal Barrier Integrity Alterations in Mice Fed a High-Fat Diet: Implications for Pancreatic Carcinogenesis

Background: Although body fatness is a recognized risk factor for pancreatic ductal adenocarcinoma (PDAC), the underlying mechanisms of how fat composition affects pancreatic carcinogenesis are poorly understood. High-fat diets (HFDs) can disrupt intestinal barrier function, potentially accelerating carcinogenesis. Omega-3 (ω-3) polyunsaturated fatty acids (FAs) have anti-inflammatory properties and help preserve intestinal integrity.

Objective: The objective of this study was to evaluate how ω-3 FAs affect the colonic barrier in the context of HFD-induced changes, in a mouse model of PDAC [p48-Cre; LSL-KrasG12D (KC)].

Methods: Male and female KC mice were randomly assigned into 1 of the following 4 groups: 1) a control diet containing ∼11% total calories from fat with an ω-6:ω-3 FA ratio of 10:1 (C), 2) the control diet with high concentrations of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (Cω3), 3) an HFD containing 60% total calories from fat with an ω-6:ω-3 FA ratio of approximately 10:1 (HF), and 4) an HFD with high concentrations of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (HFω3).

Results: Consumption of an HFD for 8 wk caused: 1) disruption of tight junction structure and function; 2) decreased goblet cell number; 3) higher colonic Toll-like receptor 4 (TLR4) and NADPH oxidase 1 expression; 4) activation of TLR4-triggered pathways, that is, NF-κB, c-Jun N-terminal kinase; 5) elevated plasma lipopolysaccharide concentrations; and 6) higher pancreatic TLR4 expression, and 7) accelerated acinar-to-ductal metaplasia. All of these events were mitigated in mice fed the HFω3.

Conclusions: Our findings support the concept that, in the context of obesity, ω-3 FAs have protective effects during early-stage pancreatic carcinogenesis through the regulation of intestinal permeability and endotoxemia.