Cell Metabolism｜Bacteria + diet-induced high proline levels may be the killer of depression

Author | 617 Depression is a common mental disorder
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According to WHO data, depression affects more than 300 million people worldwide and is one of the main causes of disability [1]
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However, at present, we still do not know the pathogenic mechanism of depression, and there is a lack of effective intervention and treatment methods [2]
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In recent years, research in the field of the microbiome has revealed the important role of the gut-brain axis in psychiatric disorders, and several studies have shown that depression is closely related to changes in the microbiome [3]
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However, due to the limitations of most studies in terms of sample size and research methods (such as the use of 16S rRNA sequencing), the results of different studies vary greatly
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Moreover, there is currently a serious lack of longitudinal studies on depression-microbiome
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In addition, most studies ignore the influence of factors such as diet and drugs on the microbiome of patients with depression, which may interfere with the analysis results
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On May 3, 2022, Josep Trueta Hospital Jose ́ Manuel Ferna ́ ndez-Real, Jordi Mayneris-Perxachs team and Pompeu Fabra University Rafael Maldonado team published in the journal Cell Metabolism entitled Microbiota alterations in proline Article on metabolism impact depression
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Using data from three cohorts, combined with multi-omics analysis and experiments in mice and Drosophila, the researchers deeply explored the relationship between the microbiome and depression, revealing the role of microbiome-dependent changes in proline metabolism in depression.
influence
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We first analyzed the microbiome composition and function of the IRONMET cohort, which included non-depressed, moderately depressive, and major depressive patients
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After excluding the influence of factors such as BMI, gender, age, educational age, and drugs, the results showed that the depression screening scale score PHQ-9 was positively correlated with Parabacteroides, Acidaminococcus, and with Bifidobacterium pseudolongum and Lachnospiraceae butyrate-producing The bacterial species of salt was negatively correlated
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In addition, the study also showed that lower levels of Actinomycetes (Bifidobacterium and Collins) and Lachnospiraceae and higher levels of Prevotella and Enterobacter were associated with higher PHQ-9 after 1 year related to the score
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In terms of function, the results showed that arginine, proline and histidine metabolism, glutamate metabolism, glutamatergic synapses, GABAergic synapses and other functions were significantly correlated with PHQ-9 scores
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In addition, the neurotransmitter transporter solute carrier 6 (SLC6) was also significantly negatively correlated with PHQ-9
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Next, the researchers analyzed blood and fecal metabolomic data, which showed significant changes in metabolites involved in the TCA cycle, histidine metabolism, proline and glutamate metabolism
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To further validate these changes, the researchers analyzed metabolomic data from another large depression cohort, IMAGEOMICS
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The results showed that circulating proline exhibited a strong positive correlation with depression scores
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Because diet can have an impact on the gut microbiome, the researchers further explored the effect of diet
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The researchers divided the subjects into 4 groups based on dietary proline intake and blood proline levels: HPD-HPP (high dietary proline-high blood proline), LPD -HPP (Low Dietary Proline Level - High Blood Proline Level), HPD-LPP, LPD-LPP
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The results showed that the order of PHQ-9 from high to low was HPD-HPP, LPD-HPP, HPD-LPP, and LPD-LPP
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Next, the authors explored the relationship between the microbiome and blood proline levels and found that Parabacteroides and Prevotella were positively correlated with proline levels, while Actinobacteria and Lachnospira SCFA-producing bacteria were negatively correlated
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Moreover, there were significant differences in the gut microbiome between the HPD-LPP group and the HPD-HPP group, and the abundance of bacterial genes related to proline metabolism and transport was higher in the HPD-LPP group
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The above results indicate that the intestinal flora of the HPD-LPP group may help the host metabolize and transport proline, reduce the level of proline in the blood, and then relieve depression
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To determine the relationship between proline and depression, the researchers used a mouse model for validation
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By giving mice a standard diet and a diet supplemented with proline, the researchers found that proline supplementation accelerated depression-like behavior in the mice, and that this behavioral change may be related to microbial translocation
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Therefore, the above evidences indicate that elevated blood proline is significantly associated with depression severity
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In addition, the researchers used the INTESTINE cohort to explore the relationship between the host itself and proline metabolism
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Using RNA-seq analysis of 28 small intestine samples, the researchers found that high proline intake is associated with small intestinal genes involved in glutamatergic synapses, GABAergic synapses, and extracellular matrix homeostasis
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Since metagenomic, metabolomic, and transcriptomic data all consistently demonstrated changes in the glutamatergic and GABAergic systems, we further explored the role of iron in glutamatergic and GABA homeostasis
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The researchers used MRI to assess brain iron deposition in IRONMET patients, and the results showed that brain iron deposition was positively correlated with depression
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In addition, the researchers analyzed resting-state fMRI data of the brain to study the relationship between brain-wide functional dynamics and depression
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The results showed that multiple regions of the brain, especially those associated with rich-club, were associated with depression and proline levels
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To further confirm the causal link between the gut microbiome and depression, the researchers transplanted microbiota from 20 people with different PHQ-9 scores into 20 antibiotic-treated mice
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Fear-induced freezing experiments showed that the donor PHQ-9 score was significantly correlated with the duration of the freezing state in recipient mice
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The researchers then performed RNA-seq analysis on samples of the medial prefrontal cortex of the mice, and the results showed that 59 genes were significantly associated with the donor's PHQ-9, of which 44 were also significantly associated with the duration of the freezing state in the mice, Including the genes encoding GABA or proline transporters slc6a12, slc6a13 and slc6a20a
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In order to determine the role of the above-mentioned transporters in depression, the researchers established a Drosophila model and found that after knocking down the slc6a20 homolog CG43066 in Drosophila neuron cells, the stress group and the non-stress group had better ability to cross gaps, exercise ability There was no significant difference in isobehavioral experiments, that is, the stress group no longer exhibited obvious depression-like behaviors
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In addition, knockdown of the homologous gene Gat of slc6a12 and slc6a13 can also improve the depressive behavior of Drosophila to a certain extent
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The above results suggest that low expression of proline/GABA transporter in Drosophila neurons can counteract mechanical stress-induced depressive states
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Finally, to determine the importance of microbially-produced GABA, the researchers performed single-microbe colonization experiments on germ-free fruit flies
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Since the previously identified enterobacteria closely associated with human depression were not present in the Drosophila gut microbiome, the authors selected Lactobacillus plantarum (a highly efficient GABA producer) and sulcus, which are themselves present in the Drosophila gut microbiome.
Enterobacteriaceae (GABA inefficient producers) for colonization
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Behavioral experiments showed that Lactobacillus plantarum was protective against depression in Drosophila
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Taken together, this study reveals the importance of proline-glutamate-GABA-microbiome interaction in depression through multi-omics data, mouse and Drosophila experiments
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At the same time, this study suggests that reducing dietary proline may be effective in improving depression
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Original link: https://doi.
org/10.
1016/j.
cmet.
2022.
04.
001 Publisher: Eleven References 1.
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, Furukawa, TA, Weisz, JR, Li, X.
, Cuijpers, P.
, Coghill, D.
, Xiang, Y.
, et al.
(2020).
Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a sys- tematic review and network meta-analysis.
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Simpson, CA, Diaz-Artche, C.
, Eliby , D.
, Schwartz, OS, Simmons, JG, and Cowan, CSM (2021).
The gut microbiota in anxiety and depression—a systematic review.
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