ObjectivesShort-chain fatty acids (SCFA) are considered beneficial for overall health and daily functioning but large human trials investigating the relationship between SCFA concentrations and peripheral parameters are scarce. We now tested in a large scale study whether SCFA concentrations correlate to cognitive function, psychological well-being, muscle function, and body composition. MethodsWe selected 232 participants > 50 y from the MEDIT database consisting of healthy adults and adults with ≥1 stable chronic disease. We measured postabsorptive plasma SCFA concentrations (acetate (C2), propionate (C3), butyrate (C4), valerate (C5), isovalerate (Ci5)) by GC-MS and body composition (DXA), respiratory muscle strength (mouth pressure device), handgrip and leg muscle strength and endurance (dynamometry). We assessed cognitive function and severity of depressive symptoms by questionnaires and performed stats by ANCOVA (covariates age, sex, BMI, presence of comorbidity) with significance level P < 0.05. ResultsC2 was the main SCFA correlating with cognitive function tests. A higher C2 concentration was associated with a lower depression score (P = 0.040) and emotional distress (P = 0.018), higher semantic (P = 0.002) and phonemic (P < 0.0001) fluencies, as well as higher mental flexibility (P = 0.054) and selective attention (P = 0.012). In contrast, an elevated C3 concentration was related to higher emotional distress (P = 0.045) and reduced phonemic fluency (P = 0.015), and a higher Ci5 concentration correlated with a lower categorical fluency (P = 0.045). Low C2 (P = 0.027) and high Ci5 (P = 0.004) and C5 (P = 0.008) concentrations correlated with high visceral adipose tissue mass and high C5 concentration with high total fat mass. None of the SCFA concentrations were associated with lean mass, bone mineral density, or muscle function parameters (all P > 0.05). ConclusionsAs the dominant SCFA in the systemic circulation, acetate appears to be crucial for cognitive functioning and emotional well-being. In contrast, high isovalerate and valerate concentrations (products of colonic bacterial amino acid fermentation) are negatively associated with health. Hence, the role of the different SCFA on health is diverse and should be considered separately. Funding SourcesNone