Dietary omega-3 (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 (HFD) 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: 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 randomized into one of four groups: i) a control diet containing approximately 11% total calories from fat with an ω-6:ω-3 FA ratio of 10:1 (C); ii) the control diet with high levels of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (Cω3); iii) a HFD containing 60% total calories from fat with an ω-6:ω-3 FA ratio of approximately 10:1 (HF); iv) a HFD with high levels of ω-3 FA with an ω-6:ω-3 FA ratio of 1:1 (HFω3).

Results: Consumption of a HFD for 8 weeks caused: i) disruption of tight junction structure and function; ii) decreased Goblet cell number, iii) higher colonic TLR4 and NOX1 expression; iv) activation of TLR4-triggered pathways, i.e. NF-κB, JNK1/2; v) elevated plasma LPS levels; v) higher pancreatic TLR4 expression, and vi) 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 FA have protective effects during early-stage pancreatic carcinogenesis through the regulation of intestinal permeability and endotoxemia.