The gut microbiota has been increasingly correlated with depressive disorder. It was recently shown that the transplantation of the gut microbiota from depressed patients to animals can produce depressive-like behaviors, suggesting that the gut microbiota plays a causal role in the development of depression. In addition, metabolic disorder, which is strongly associated with depression, is exacerbated by changes in the composition of the gut microbiota and is alleviated by treatment with antidepressants. However, the key players and pathways that link the gut microbiota to the pathogenesis of depression remain largely unknown. To evaluate the relationships between depression and metabolic disorders in feces and plasma, we monitored changes in fecal and plasma metabolomes during the development of depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS). In these animals, the fecal metabolome was altered first and subjected to changes in the plasma metabolome. Changes in the abundance of fecal metabolites were associated with depressive-like behaviors and with altered levels of neurotransmitters in the hippocampus. Furthermore, the analysis of the fecal metabolome and the fecal microbiota in CUMS rats demonstrated consistent changes in the levels of several amino acids, including L-threonine, isoleucine, alanine, serine, tyrosine, and oxidized proline. Finally, we observed significant correlations between these amino acids and the altered fecal microbiota. The results of this study suggest that changes in amino acid metabolism by the gut microbiota contribute to changes in circulating amino acids and are associated with the behavior indices of depression.

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.

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.

Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (IEMs). Maternal hyperglycemia exerts epigenetic effects on genes that encode IEM-associated enzymes, resulting in changes in the neonatal blood metabolome. However, the relationship between maternal gut microbiota and the neonatal blood metabolome remains poorly understood. This study aimed at understanding the connections between maternal gut microbiota and the neonatal blood metabolome in GDM. 1H-NMR-based untargeted metabolomics was performed on maternal fecal samples and targeted metabolomics on the matched neonatal dry blood spots from a cohort of 40 pregnant women, including 22 with GDM and 18 controls. Multi-omic association methods (including Co-Inertia Analysis and Procrustes Analysis) were applied to investigate the relationship between maternal fecal metabolome and the neonatal blood metabolome. Both maternal fecal metabolome and the matched neonatal blood metabolome could be separated along the vector of maternal hyperglycemia. A close relationship between the maternal and neonatal metabolomes was observed by multi-omic association approaches. Twelve out of thirty-two maternal fecal metabolites with altered abundances from 872 1H- NMR features (Bonferroni-adjusted P < 0.05) in women with GDM and the controls were identified, among which 8 metabolites contribute (P < 0.05 in a 999-step permutation test) to the close connection between maternal and the neonatal metabolomes in GDM. Four of these eight maternal fecal metabolites, including lysine, putrescine, guanidinoacetate, and hexadecanedioate, were negatively associated (Spearman rank correlation, coefficient value < −0.6, P < 0.05) with maternal hyperglycemia. Biotin metabolism was enriched (Bonferroni-adjusted P < 0.05 in the hypergeometric test) with the four-hyperglycemia associated fecal metabolites. The results of this study suggested that maternal fecal metabolites contribute to the connections between maternal fecal metabolome and the neonatal blood metabolome and may further affect the risk of IEMs.

Gestational diabetes mellitus (GDM) has been associated with circulating metabolic disorders and alterations in gut microbiota, respectively. Although changes in gut microbiota contribute to metabolic diseases, the connections between gut microbiota and the circulating metabolic state in GDM remain largely undetermined. To investigate the associations between gut microbiota and the circulating metabolome of GDM, we enrolled 40 pregnant women (20 with GDM and 20 non-diabetic control), and performed multi-omics association (MOA) study on 16s rRNA sequencing of fecal microbiota and ¹H-NMR profiling of the plasma metabolome. The results suggested that both fecal microbiota and the plasma metabolome of the enrolled pregnant women could be separated along the vector of hyperglycemia. A close correlation between fecal microbiota and the plasma metabolome of GDM was observed by MOA approaches. Redundancy Analysis identified five plasma metabolites (glycerol, lactic acid, proline, galactitol and methylmalonic acid) and 98 members of fecal microbiota contributing to the close correlation between the plasma metabolome and fecal microbiota. Further spearman rank correlation analysis revealed that four out of five of the identified plasma metabolites (except galactitol) were correlated with hyperglycemia. Co-occurring network analysis suggested that 15 out of 98 of the members of fecal microbiota were positively correlated with each other, forming a co-occurring cohort (mainly consisted of the phylum Firmicutes). The results of this study demonstrated that alterations in fecal microbiota were associated with hyperglycemia related changes of the plasma metabolome of women with GDM, suggesting novel therapies against gut microbiota to alleviate GDM.