(P12-008-25) Feeding an Intermittent Ketogenic Diet Modulates the Gut Microbiome but Fails to Improve Pancreatic Cancer -Associated Cachexia in Mice

Objectives: Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with a low survival rate. Approximately 50-80% of patients diagnosed with PDA suffer from the loss of adipose tissue and skeletal muscle mass, a phenomenon known as cachexia. Furthermore, the gut microbiota is gaining attention as a new target for cachexia. In this study, we aimed to implement new dietary intervention strategies for PDA and cancer-associated cachexia with the goal of delaying the onset of PDA-associated cachexia. Previous studies in our lab supported that a strict ketogenic diet (KD), a diet with a composition of extremely low carbohydrate and high-fat contents, in combination with the chemotherapeutic drug gemcitabine, increases the mean overall survival and maintains muscle strength in a pancreatic cancer mouse model (KPC mice), compared to mice fed a control diet (CD). Unfortunately, adherence to a strict KD is challenging for patients with PDA. Thus, we hypothesize that in KPC mice, intermittent KD (iKD) feeding will induce periods of ketosis, modulate the gut microbiome, and decrease the severity of motor deficits, yielding similar effects as administering a strict KD.

Methods: We used the clinically relevant mouse model of PDA– LSL-Kras^G12D;LSL-p53^R172H;Pdx-1-Cre (KPC) mice. Four-month-old female KPC mice (n=6-8/group) were fed either a control diet (CD), a ketogenic diet (KD), or an intermittent feeding of the KD (iKD; one week a KD and one week a CD) for 2 months. Fecal samples were collected at 4 weeks and 8 weeks. Muscle strength was determined by grip strength and wire hanging tests. Microbiota composition was assessed by 16S sequencing. Relative abundance and diversity were assessed.

Results: KPC mice fed a strict KD or an iKD showed increased ketone body levels and changes in gut microbiome composition and abundance. However, there was no significant effect on preserving muscle strength, and no differences in mTOR signaling or NF-κB signaling, two pathways involved in muscle physiology pathways, compared to mice fed a CD.

Conclusions: Although feeding an iKD modulated the gut microbiome, it failed to mitigate the muscle strength decline in KPC mice.

Funding Sources: This study was supported by the University of California Cancer Research Coordinating Committee (UC-CRCC), and the National Cancer Institute’s Diversity Supplement.