SCFAs Impact on Inflammation and Core Executive Functioning in Response to Lipopolysaccharide Challenge

INFLEX is a single-center, randomized, triple-blind, placebo-controlled, parallel-group interventional trial conducted at UZ Leuven / KU Leuven. Its primary aim is to test whether a single acute dose of colon-delivered SCFAs, relative to placebo, attenuates the systemic inflammatory response induced by experimental endotoxemia in healthy adults. Secondary aims are to test whether SCFAs attenuate LPS-induced sickness behaviour and mitigate endotoxemia-induced changes in core executive functioning, and to characterize associations between systemic SCFA uptake, the inflammatory response, and these outcomes. Eligible participants are randomized to receive SCFA colon-delivery capsule or placebo capsules, taken on the morning of the test day with a standardized low-fiber breakfast. One hour after capsule intake, participants receive a single intravenous bolus of purified Escherichia coli lipopolysaccharide (0.4 ng/kg body weight), which serves as a fixed inflammatory challenge applied to all participants. The timing is designed so that peak circulating SCFA concentrations (approximately 3-4 hours after colonic delivery) coincide with the peak of LPS-induced cytokines and sickness behaviour (approximately 2-3 hours post-injection). Participants are monitored for a minimum of 6 hours after the LPS challenge. Vital signs, sickness symptoms, and blood and saliva samples are collected hourly to quantify inflammatory markers (including IL-6 and hs-CRP), serum SCFA, cortisol, and ACTH. Core executive-function tasks are administered before and after the LPS challenge and at a 24-hour follow-up visit. A fecal sample collected at home prior to the test day is used for gut microbiota profiling. To standardize endogenous SCFA production, participants follow a low-fiber diet for three days before the test day and avoid caffeine, alcohol, and strenuous exercise beforehand. The night prior to the test day, participants are instructed to consume a standard dinner that is provided to them. The study comprises three visits: a screening visit (\~1 hour), the laboratory test day (\~8 hours), and a follow-up visit (\~30 minutes) 24 hours after the LPS challenge.