Butyrate- and Beta-Hydroxybutyrate-Mediated Effects of Interventions with Pro- and Prebiotics, Fasting, and Caloric Restrictions on Depression: A Systematic Review and Meta-Analysis.

To examine the butyrate- and beta-hydroxybutyrate (BHB)-modulated effects of pre- and probiotic interventions, fasting, and caloric restriction interventions, a systematic literature review was carried out with a subsequent meta-analysis. Three pre-and probiotic intervention randomized control trials (RCTs) were included in the meta-analysis. A significant increase in butyrate (standardized mean difference (SMD) [confidence interval (CI)] 0.34; [0.02-0.67]) and an improvement in depression scores (SMD [CI] 0.15, [-0.35-0.70]) through pre- and probiotic interventions were shown in the meta-analysis. The intervention duration of the included studies ranged from three days to four weeks, with the examined population being healthy adults. Butyrate was measured in either plasma or feces, and the depression score was obtained under the Swedish core affect scale, the hospital anxiety and depression scale (HADS), or the depression, anxiety, and stress scale-21 items (DASS-21). In addition to butyrate, the total SCFA concentration also seems to be positively associated with pre- and probiotic administration (SMD [CI] 0.55 [0.15-0.95]). Despite the significant short-chain fatty acid (SCFA) and butyrate concentration changes, no significant correlation between butyrate and depression or between SCFAs and depression could be shown through linear regression models. Nevertheless, the regression coefficient b1 = 1.57 ( p = 0.17) for butyrate suggests a strong, positive connection between butyrate and depression. Additionally, three studies were qualitatively analyzed, examining fasting as an intervention and revealing a connection between fasting, BHB, and depression. The association between fasting, BHB, and depression or mood elevation appeared to be related to BHB concentrations, which may be due to the similar biochemical properties of BHB and butyrate. Furthermore, caloric restrictions as alternatives to fasting were proposed as potential long-term interventions.