Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner

Abstract

Propionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.

A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia

“…Species within these genera metabolise lactate to the SCFAs propionate and acetate while producing hydrogen [ 136 ]. Whilst propionate has been hypothesised to have antidepressant effects, excess propionate has been associated with increased depressive-like behaviours in animal studies [ 137 ] and elevated levels of propionate have been reported in Alzheimer’s disease [ 138 ]. In addition, it has been hypothesised that a by-product of lactate metabolism—hydrogen—may also influence host physiology [ 130 , 139 ].…”

Long-term Pu-erh tea consumption improves blue light-induced depression-like behaviors

“…55 Acetate and propionate have been reported to exert antidepressant effects and anti-inflammatory effects through the activation of G-protein coupled receptors (GPR)41 and GPR43. [56][57][58] Meanwhile, SCFAs can directly cross the BBB and affect brain function. 59 In germ-free mice, the BBB permeability is primarily associated with reduced expression of tight junction proteins, such as Occludin and claudin-5.…”

The Effects of Synbiotics Administration on Stress-Related Parameters in Thai Subjects—A Preliminary Study

“…A connection between stress regulation and gut commensal microbial metabolites has been suggested [ 51 , 52 ]. SCFAs such as propionate and butyrate play a role in neuroprotective and psychiatric disorder treatment [ 53 , 54 ]. According to the preclinical study of Maltz et al (2019), low levels of acetate and butyrate were observed in stressed mice [ 55 ].…”