Low-Dose Ketone Monoester Administration in Adults with Cystic Fibrosis: A Pilot and Feasibility Study

Introduction: Cystic fibrosis transmembrane conductance regulator () modulators have greatly improved outcomes in persons with CF (pwCF); however, there is still significant heterogeneity in clinical responses, particularly with regard to respiratory infection and inflammation. Exogenous administration of ketones has profound systemic anti-inflammatory effects and produces several nutrient-signaling and metabolic effects that may benefit multiple organ systems affected in pwCF. This pilot study was designed to determine the feasibility of administration of a ketone monoester (KME) to increase circulating D-beta hydroxybutyrate concentrations (D-βHB) and to improve subjective measures of CF-specific quality of life and markers of inflammation in serum and sputum in adults with CF.

Methods: Fourteen participants receiving modulator therapy were randomized to receive either KME (n = 9) or placebo control (PC, n = 5) for 5-7 days during hospitalization for treatment of acute pulmonary exacerbation or as outpatients under standard care.

Results: The KME was well tolerated, with only mild reports of gastrointestinal distress. D-βHB concentrations increased from 0.2 ± 0.1 mM to 1.6 ± 0.6 mM in the KME group compared to 0.2 ± 0.0 to 0.3 ± 0.1 in the PC group ( = 0.011) within 15 min following consumption and remained elevated, relative to baseline, for over 2 h. Pulmonary function was not altered after single- or short-term KME administration, but participants in the KME group self-reported higher subjective respiratory scores compared to PC in both cases ( = 0.031). Plasma inflammatory markers were not statistically different between groups following the short-term (5-7 d) intervention ( > 0.05). However, an exploratory analysis of plasma pre- and post-IL-6 concentrations was significant ( = 0.028) in the KME group but not PC. Sputum IFNγ ( = 0.057), IL-12p70 ( = 0.057), IL-1β ( = 0.100), IL-15 ( = 0.057), IL-1α ( = 0.114), and MPO ( = 0.133) were lower in the KME group compared to PC but did not achieve statistical significance.

Conclusions: With the emerging role of exogenous ketones as nutrient signaling molecules and mediators of metabolism, we showed that KME is well tolerated, increases circulating D-βHB concentrations, and produces outcomes that justify the need for large-scale clinical trials to investigate the role of KME on whole-body and tissue lipid accumulation and inflammation in pwCF.