(P12-018-25) Effect of Switching From a High-Fat Diet to a Low-Fat Diet on Mucosal Barrier Dysfunction: Implications for Pancreatic Carcinogenesis

Objectives: Consumption of high-fat diets (HFD) are associated with intestinal permeability and endotoxemia, which may accelerate the progression of pancreatic carcinogenesis. We recently observed that in a mouse model of pancreatic cancer [p48-Cre; LSL-KrasG12D (KC)], consumption of a HFD (60% calories from fat) for 8 weeks led to metabolic endotoxemia and disruption of tight junction structure. At the pancreas, consumption of a HFD led to increased TLR4 expression and accelerated acinar-to-ductal metaplasia. However, the effects of a dietary switch from a HFD to a low-fat diet (LFD) on intestinal barrier function and downstream effectors related to pancreatic carcinogenesis remains unclear. The aim of this study was to investigate whether switching mice from a HFD to a LFD could mitigate HFD-induced disruptions in mucosal barrier function in the context of pancreatic carcinogenesis.

Methods: Male and female KC mice (N=7-13) were weaned at 5 weeks of age and fed a low-fat control diet (CD; 10.5% fat) or a high-fat diet (HFD; 60% fat) for 21 weeks. To assess the effects of a dietary switch from a HFD to a low-fat diet, a subset of mice were fed the HFD for 8 weeks, then switched to a CD for 13 weeks. At 26 weeks of age, all mice were euthanized and various tissues were collected.

Results: Consumption of a HFD for 21 weeks led to: i) an increase in body weight; ii) disruption of tight junction structure (ZO-1 and occludin); iii) activation of proinflammatory cascades (NF-κB) downstream the TLR4 receptor; iv) and increased MMP-2 and MMP-9 activity. These effects were mitigated by switching mice from a HFD to a CD. In male mice, the dietary switch prevented HFD-induced decreases in the number of goblet cells (GC) per crypt. Consumption of the HFD led to a reduction in colonic mRNA levels of Klf4, a transcription factor involved in GC terminal differentiation, which was not reverted by the dietary intervention. A similar trend was observed in the expression of GC-produced Tff3. Overall, there was a lower incidence of pancreatic cancer in the dietary switch group (0/17; 0%) in comparison to the HFD group (2/21; 10%).

Conclusions: Our preliminary findings suggest that consumption of the HFD compromised mucosal barrier function and integrity in mice, which can be partially reversed by switching from a HFD to a CD.

Funding Sources: University of California, Davis and NIFA-USDA