Beta-Hydroxybutyrate Attenuates Bronchial Smooth Muscle Pro-Inflammatory Cytokine Production

Abstract

Asthma is a common airway condition causing breathing difficulties due to reversible airflow obstruction. It often affects obese individuals, with symptoms triggered by environmental factors that induce immune responses, leading to inflammation and bronchoconstriction. Bronchial smooth muscle (BSM) plays a central role in airway narrowing, driven by type 2 immune responses involving cytokines like IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells. These responses cause structural changes such as fibrosis and airway thickening, while BSM cells worsen asthma by releasing pro-inflammatory cytokines in response to allergens, microbial signals, or inflammatory cytokines from other cells. While current treatments manage asthma in most patients, alternative therapies are needed for difficult-to-treat cases, particularly prevalent in obese, allergic individuals. Emerging research suggests that therapeutic ketosis, induced by dietary changes or ketone supplementation, may reduce airway hyperresponsiveness and inflammation. The primary ketone body, {beta}-hydroxybutyrate (BHB), produced during carbohydrate scarcity, acts via cell-surface receptors and transporters, potentially mitigating asthma symptoms. Weight loss and caloric restriction increase ketone levels, correlating with reduced inflammation and improved asthma outcomes. We hypothesized that {beta}-hydroxybutyrate (BHB) reduces bronchoconstriction and inflammation in asthma by targeting bronchial smooth muscle. Using human bronchial smooth muscle cells (HBSMC) in vitro, we demonstrate herein that BHB suppresses IL-1{beta}-induced pro-inflammatory cytokine production through Free Fatty Acid Receptor 3 (FFAR3) activation. These findings suggest that bronchial smooth muscle is a key target of therapeutic ketosis, supporting BHBs potential benefits in preclinical asthma models.