Gut short-chain fatty acids are decreased in cutaneous T-cell lymphoma patients

Summary: Abstract Body: Short-chain fatty acids (SCFAs) are critical metabolites produced by gut microbiota that play a key role in modulating inflammation and regulating systemic immunity, including against cancer. Decreases in SCFAs can foster a permissive tumor immune environment. Recent studies have shown that cutaneous T-cell lymphoma (CTCL) patients exhibit increasing gut dysbiosis and loss of bacteria predicted to produce SCFAs with increasing disease severity. To investigate this functional connection, we collected stool swab samples from 8 mycosis fungoides (MF) patients and 7 closely-matched healthy controls (HC) and quantified concentrations of four SCFAs (acetate, propionate, isovalerate, butyrate) via liquid chromatography-mass spectrometry. Only MF patients not yet on systemic CTCL medications were selected to prevent confounding. Diet and other concurrent systemic medications did not differ between cohorts. Our results demonstrated significantly reduced total measured SCFA concentrations (1226 µg/g in the MF group versus 2759 µg/g in HC; p=0.048), including significantly reduced acetate (671.3 µg/g in the MF group versus 1807.2 µg/g in HC; p=0.024) and propionate (156.3 µg/g in the MF group versus 544.4 µg/g in HC; p=0.030) concentrations in MF patients when compared to HC. Both propionate and acetate have been previously demonstrated to promote tumor apoptosis, inhibit tumor proliferation, and enhance antitumor immunity. These also align with our prior CTCL gut microbiome studies showing reductions in Lactobacillaceae, Ruminococcaceae, and Lachnospiracae, which are linked to these SCFA levels. Thus, optimizing SCFA levels may enhance concurrent CTCL therapy by creating a less permissive tumor environment. Our pilot findings add to the growing body of knowledge implicating the gut microbiota-SCFA axis in CTCL pathogenesis and offer potential new avenues for therapeutic intervention. Zachary Thomas¹, JoJo Holm¹, Morgan McCarthy¹, William Nguyen¹, Yanzhen Pang¹, Lauren Chrisman¹, Joan Guitart¹, Michael Burns², Alan Zhou¹ 1. Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States. 2. Biology, Loyola University Chicago, Chicago, IL, United States. Translational Studies: Cell and Molecular Biology