A dietary switch from a high fat to a low fat diet mitigates obesity-induced intestinal barrier dysfunction in mice: implications for pancreatic carcinogenesis.

Abstract

Consumption of high-fat diets (HFD) is linked to increased intestinal permeability and metabolic endotoxemia, which may contribute to pancreatic cancer development. We previously showed that 8-week HFD consumption altered intestinal barrier structure and function, leading to metabolic endotoxemia, higher pancreatic TLR4 expression, and accelerated pancreatic acinar-to-ductal metaplasia. Furthermore, we recently documented that a dietary switch from a HFD to a low-fat control diet (CD) ameliorates pancreatic carcinogenesis. In this study, we investigated if switching from a HFD to a CD could restore intestinal barrier integrity and function in the context of pancreatic carcinogenesis. Male and female LSL-Kras^G12D; p48-Cre (KC) mice were weaned at 5 weeks and fed either a CD (11% kcal from fat) or a HFD (HF; 60% kcal from fat) for 8 weeks. At 13 weeks, half of the HFD-fed mice continued on the HFD, while others switched to the CD for an additional 13 weeks. Consumption of a HFD during 21 weeks led to: (i) an increase in body weight; (ii) disruption in tight junction (TJ) structure and function; (iii) higher colonic TLR4 expression and activation of downstream signaling, i.e. NF-κB and ERK1/2, involved in inflammation and TJ opening; (iv) higher colonic NOX1/NOX2 and iNOS gene expression; (v) higher MMP-2 and MMP-9 activity; (vi) and higher pancreatic TLR4 expression. Switching from a high-fat to a low-fat diet mitigated HFD-associated intestinal damage, reversing all altered parameters except colonic NOX1 and NOX2 mRNA levels. In conclusion, a nutritional intervention reducing fat consumption improves intestinal barrier integrity and decreases metabolic endotoxemia offering a promising approach to mitigate obesity-associated pancreatic cancer development.