Short Term Intrarectal Administration of Sodium Propionate Induces Antidepressant-Like Effects in Rats Exposed to Chronic Unpredictable Mild Stress

Abstract

Depression has been correlated with metabolic disorders, and the gut microbiota and its metabolites have been reported to be key factors affecting metabolic disorders. Several metabolites generated by the gut microbiota have been reported to exert antidepressant-like effects, including the short chain fatty acid (SCFA) butyrate. However, recent work has suggested that the abundance of butyrate is not significantly changed in neither human nor experimental animals with depression, and butyrate has been reported to decrease upon the administration of prebiotics with antidepressant-like effects. Supplementation of endogenous metabolites that are unchanged in depression may induce additional metabolic disorders and may lead to poorer clinical outcomes. However, the endogenous metabolites that are imbalanced in depression may include several antidepressant candidates that could circumvent these problems. In this study, we used GC-MS spectrometry to study the fecal metabolome of rats under Chronic Unpredictable Mild Stress (CUMS). We carried out static and dynamic metabolomics analyses to identify the differential metabolites between the CUMS rats and control rats. We identified propionic acid, rather than butyric acid, as a differential metabolite of the CUMS rats. Consistent with this, a 1-week intrarectal administration of sodium propionate (NaP, the salt form of propionic acid) induced antidepressant-like effects and partially rebalanced the plasma metabolome. The antidepressant-like effects of NaP were correlated with differential rescue of neurotransmitters in the prefrontal cortex, which may be achieved through the reduction of catabolism of noradrenaline, tryptophan and dopamine, rather than serotonin. These findings support NaP as a potential candidate in fighting depression by administering an endogenous metabolite.

Gut microbial metabolites in depression: understanding the biochemical mechanisms

“…The SCFA propionate also acts as a HDAC inhibitor [104], and intrarectal administration of sodium propionate was shown to improve despair behavior in rats [105]. The antidepressant effect of propionate was accompanied by an increase in norepinephrine, dopamine, tryptophan, 5-HIAA and 3-hydroxyanthranilic acid (3-HAA) in the prefrontal cortex, although no change was detected in 5-HT and 3-hydroxykynurenine (3-HK).…”

“…Both butyrate and propionate may also contribute to dopaminergic function by inhibiting the expression of dopamine-β-hydroxylase, which catalyzes the conversion of dopamine into norepinephrine. Thus, the opposite effects of SCFAs on behavior may be explained by their action via independent mechanisms: for example, Li et al [105] found that while butyrate modulated the expression of 5-HT (with slow-onset but long-term antidepressant action), propionate altered the expression of norepinephrine (with fast-acting, but short-term antidepressant action). However, propionate is also able to modulate serotonergic function by increasing the expression of tryptophan hydroxylase (TPH) [101], responsible for the conversion of tryptophan to 5-HT.…”

“…However, propionate is also able to modulate serotonergic function by increasing the expression of tryptophan hydroxylase (TPH) [101], responsible for the conversion of tryptophan to 5-HT. This finding is significant for unveiling the link between neuroinflammation and neurotransmitter production, as an increased TPH turnover induces an accumulation of kynurenine and neurotoxic metabolites like 3-HK [105]. Since altered tryptophan–kynurenine metabolism is characteristic of depression [106], this observation suggests that serotonergic function may be linked to anti-inflammatory mechanisms.…”

“…Despite this evidence ( Table 3 ), results supporting the antidepressant potential of SCFAs are not consistent enough to be translated into medical practice. For example, cecal isobutyrate is reduced in response to administration of probiotics with antidepressant efficacy [115], and some studies have failed to detect significant abnormalities in the abundance of butyrate in MDD patients [116, 117] or animal models of depression [105] compared to controls. Such discrepancies may be partly due to the highly volatile nature of SCFA and to their sensitivity to the conditions of storage and tissue extraction [118], which can affect quantification and hinder comparable results across studies.…”

“…Although the ideal control for this experimental model should be sodium matched, some behavioral and/or physiological effects cannot be excluded [63], especially in the light of recent findings showing that a diet high in salt alters gut microbiota composition and reduces butyrate production [119]. As for propionate, its dysregulation in animal models of depression has been consistently demonstrated [64, 105], but its neurotoxic effects and the behavioral deficits elicited at excessive doses imply that more in-depth knowledge of the underlying mechanisms are required before a targeted intervention can be developed.…”