Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options and poor survival. This study explores how a medically supervised ketogenic diet (MSKD) impacts the gut microbiome and treatment response in patients with newly diagnosed metastatic PDAC receiving gemcitabine, nab-paclitaxel, and cisplatin chemotherapy. Methods: As part of a randomized Phase II trial, 32 evaluable patients (median age 65. 9 years; 53% male), 16 were randomized to either MSKD or standard diet (SD) combined with chemotherapy. Stool samples were collected from 4 patients in the MSKD group (13 samples) and 8 patients in the SD group (23 samples). Deep shotgun metagenomic sequencing was conducted using NovaSeq (Illumina). Taxonomical and functional microbiome characterization was performed using MetaPhlAn 4. 0 and HUMAnN 3. 6 (The Huttenhower Lab, Harvard). Comprehensive bioinformatics analyses, using QIIME2, were performed to analyze microbiome composition and function over time. Results: Patients in the MSKD group showed better treatment responses overall. Microbiome profiles between the two groups remained distinct throughout therapy. Though not statistically significant due to sample size, MSKD patients showed lower alpha diversity (Shannon diversity; p-value=0. 1339), likely reflecting reduced intake of fermentable fiber. Differential abundance analysis using the ANCOM-BC method revealed a significant enrichment of beneficial taxa in the MSKD group compared to the SD group (p0. 05, log-fold change lfc≥2), including Akkermansia muciniphila (linked to improved response to immune checkpoint inhibitors; p=0. 017931, q=1), Intestinimonas butyriciproducens (a short-chain fatty acid SCFA and butyrate producer; p=3. 09E-05, q=0. 017), and Streptococcus thermophilus (a supporter of gut mucosal health; p=1. 15E-05, q=0. 006). During the course of the study, only MSKD patients showed sustained increases in Roseburia hominis (SFCA/butyrate producer; p=3. 94E-05, q=0. 021) and Lacticaseibacillus rhamnosus (with anti-inflammatory and immune-modulating properties; p=7. 28E-19, q=3. 98E-16), along with a marked reduction in potentially pro-inflammatory Actinomyces spp. (p≤4. 47E-05, q≤0. 024). Functional profiling showed increased abundance of cancer-relevant microbial pathways in MSKD patients, including phosphatidate metabolism (PWY-7039; involved in lipid signaling and immune regulation; p=4. 36E-04, q=0. 20) and allantoin degradation (PWY-5705; linked to redox balance; p=9. 16E-06, q=0. 004). Conversely, L-ascorbate biosynthesis V (PWY-6415) was reduced (p=3. 80E-04, q=0. 17), likely due to decreased D-galacturonate substrate availability from fiber restriction. Conclusion: These findings suggest that an MSKD may beneficially modulate the gut microbiome in ways that support and enhance therapeutic response in patients with PDAC. Further validation in a larger cohort is warranted to confirm these results and improve analytical resolution. Citation Format: Keehoon Lee, Derek Cridebring, Gayle S. Jameson, Denis J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G. P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela T. Alistar, Alan M. Miller, J. Erin Wiedmeier-Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Drew W. Rasco, Daniel D. Von Hoff. Ketogenic Diet Modulates Gut Microbiome Composition and Enhances Treatment Response in Patients with Advanced Pancreatic Cancer: A Phase II Study abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B094.
Lee et al. (Sun,) studied this question.