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Session: Personalized Dietary Therapy for Cancer Treatment and Survivorship (Oral 29)

(OR29-02-24) Nutritional Modulation of Diet-Induced Obesity on Intestinal Barrier Dysfunction: Implications for Pancreatic Carcinogenesis

Monday, July 1, 2024
4:12 PM – 4:24 PM CT
Location:  W183

    Presenting Author(s)

  • JM

    Jazmin Machuca, BS

    Graduate Student
    University of California, Davis
    Costa Mesa, California, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • Joanna Wirkus, RDN, CSO

    PhD Candidate
    University of California, Davis
    Davis, California, United States

  • AE

    Aya Ead

    University of California, Davis

  • Gerardo G. Mackenzie, PhD (he/him/his)

    Associate Professor
    University of California, Davis
    Davis, California, United States

  • PO

    Patricia Oteiza, Ph.D.

    Professor
    University of California, Davis
    Davis, California, United States

Objectives: The gut-pancreas axis has been a topic of interest since it has been hypothesized that its alteration may be correlated with the development of certain types of diseases including pancreatic cancer. We have previously shown in a mouse model of pancreatic cancer [LSL-KrasG12D/+; p48Cre/+(KC)], that mice fed a high-fat diet (60% calories from fat) for 8 weeks: i) induced endotoxemia; ii) decreased colonic tight junction protein expression (ZO-1 and occludin); iii) increased colonic TLR-4 expression; iv) increased activation of redox-sensitive and TLR-4-triggered pathways, i.e. NF-κB, JNK1/2; and v) increased pancreatic TLR-4 expression. The purpose of this study was to investigate whether a dietary switch from a high-fat diet to a low-fat diet (11% calories from fat) could mitigate or reverse high-fat diet induced intestinal permeabilization and alterations in colonic physiology in the context of pancreatic ductal adenocarcinoma (PDAC).

Methods: Male and female KC mice (N=7-12) were weaned at 5 weeks of age and fed a low-fat diet (11% calories from fat) or a high-fat diet (60% calories from fat) for 8 weeks. At this time, a subgroup of KC mice on the high-fat diet remained on this diet while another subgroup switched to a low-fat diet for an additional 13 weeks. After 21 weeks on the diets, KC mice were then euthanized and the intestine and colon collected. Cellular mechanisms were assessed by western blot.

Results: Compared to mice fed a low-fat diet, consumption of a high-fat diet during 21 weeks caused: i) an increase in body weight ii) a disruption of tight junction structure and function; iii) an increase in colonic TLR-4 expression and downstream proinflammatory cascades (NF-κB); and iv) an increase in MMP-2 and MMP-9 activity, involved in tight junction proteins degradation. These adverse effects of high-fat diet consumption were either reversed or mitigated in mice that switched from a high-fat diet to a low-fat diet.

Conclusions: Our findings highlight the importance of switching from a high-fat diet to a low-fat diet, and the associated weight loss, for the mitigation of intestinal permeabilization that can ultimately lead to systemic inflammation and contribute to PDAC development.

Funding Sources: NIFA-USDA and the Oncology Dietetic Practice Group of the Academy of Nutrition