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Objective: Animal studies have demonstrated the extensive interplay between the gut microbiota and immunity. Moreover, in critically ill patients, who almost invariably suffer from a pronounced immune response, a shift in gut microbiota composition is associated with infectious complications and mortality. We examined the relationship between interindividual differences in gut microbiota composition and variation in the in vivo cytokine response induced by bacterial lipopolysaccharide (LPS). Furthermore, we evaluated whether an LPS challenge alters the composition of the gut microbiota., Methods: Healthy male volunteers received an intravenous bolus of 2 ng kg -1 LPS ( n  = 70) or placebo ( n  = 8). Serial plasma concentrations of tumor necrosis factor-α, interleukin (IL)-6, IL-8 and IL-10 were measured, and subjects were divided into high and low cytokine responders. Gut microbiota composition was determined using 16s RNA gene sequencing of faecal samples obtained 1 day before (baseline) and 1 day and 7 days following the LPS challenge., Results: Baseline microbiota composition, analysed by principal coordinate analysis and random forest analysis, did not differ between high and low responders for any of the four measured cytokines. Furthermore, baseline microbiota diversity (Shannon and Chao indices) was similar in high and low responders. No changes in microbiota composition or diversity were observed at 1 and 7 days following the LPS challenge., Conclusion: Our results indicate that existing variation in gut microbiota composition does not explain the observed variability in the LPS-induced innate immune response. These findings strongly argue against the interplay between the gut microbiota composition and the innate immune response in humans., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)