Human Gut Microbiota for Diagnosis and Treatment of Depression.

Nowadays, depressive disorder is spreading rapidly all over the world. Therefore, attention to the studies of the pathogenesis of the disease in order to find novel ways of early diagnosis and treatment is increasing among the scientific and medical communities. Special attention is drawn to a biomarker and therapeutic strategy through the microbiota-gut-brain axis. It is known that the symbiotic interactions between the gut microbes and the host can affect mental health. The review analyzes the mechanisms and ways of action of the gut microbiota on the pathophysiology of depression. The possibility of using knowledge about the taxonomic composition and metabolic profile of the microbiota of patients with depression to select gene compositions (metagenomic signature) as biomarkers of the disease is evaluated. The use of in silico technologies (machine learning) for the diagnosis of depression based on the biomarkers of the gut microbiota is given. Alternative approaches to the treatment of depression are being considered by balancing the microbial composition through dietary modifications and the use of additives, namely probiotics, postbiotics (including vesicles) and prebiotics as psychobiotics, and fecal transplantation. The bacterium Faecalibacterium prausnitzii is under consideration as a promising new-generation probiotic and auxiliary diagnostic biomarker of depression. The analysis conducted in this review may be useful for clinical practice and pharmacology.

GC-MS with Headspace Extraction for Non-Invasive Diagnostics of IBD Dynamics in a Model of DSS-Induced Colitis in Rats.

Inflammatory bowel diseases are extremely common throughout the world. However, in most cases, it is asymptomatic at the initial stage. Therefore, it is important to develop non-invasive diagnostic methods that allow identification of the IBD risks in a timely manner. It is well known that gastrointestinal microbiota secrete volatile compounds (VOCs) and their composition may change in IBD. We propose a non-invasive method to identify the dynamics of IBD development in the acute and remission stage at the level of VOCs in model of dextran sulfate sodium (DSS) with chemically induced colitis measured by headspace GC/MS (HS GC/MS). Methods: VOCs profile was identified using a headspace GC/MS (HS GC/MS). GC/MS data were processed using MetaboAnalyst 5.0 and GraphPad Prism 8.0.1 software. The disease activity index (DAI) and histological method were used to assess intestinal inflammation. The peak of intestinal inflammation activity was reached on day 7, according to the disease activity index. Histological examination data showed changes in the intestine due to different stages of inflammation. As the acute inflammation stage was reached, the metabolomic profile also underwent changes, especially at the short-fatty acids level. A higher relative amounts of acetic acid (p value < 0.025) and lower relative amounts of propanoic acid (p value < 0.0005), butanoic acid (p value < 0.005) and phenol 4-methyl- (p value = 0.053) were observed in DSS7 group on day 7 compared to the control group. In remission stage, disease activity indexes decreased, and the histological picture also improved. But metabolome changes continued despite the withdrawal of the DSS examination. A lower relative amounts of propanoic acid (p value < 0.025), butanoic acid (p value < 0.0005), pentanoic acid (p value < 0.0005), and a significant de-crease of hexanoic acid (p value < 0.0005) relative amounts were observed in the DSS14 group compared to the control group on day 14. A model of DSS-induced colitis in rats was successfully implemented for metabolomic assessment of different stages of inflammation. We demonstrated that the ratios of volatile compounds change in response to DSS before the appearance of standard signs of inflammation, determined by DAI and histological examination. Changes in the volatile metabolome persisted even after visual intestine repair and it confirms the high sensitivity of the microbiota to the damaging effects of DSS. The use of HS GC/MS may be an important addition to existing methods for assessing inflammation at early stages.

Dysregulation of Long Intergenic Non-Coding RNA Expression in the Schizophrenia Brain.

BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions. AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions. METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold. RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways. CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.

Alterations of the Composition and Neurometabolic Profile of Human Gut Microbiota in Major Depressive Disorder.

Major depressive disorder (MDD) is among the most prevalent mental disorders worldwide. Factors causing the pathogenesis of MDD include gut microbiota (GM), which interacts with the host through the gut-brain axis. In previous studies of GM in MDD patients, 16S rRNA sequencing was used, which provided information about composition but not about function. In our study, we analyzed whole metagenome sequencing data to assess changes in both the composition and functional profile of GM. We looked at the GM of 36 MDD patients, compared with that of 38 healthy volunteers. Comparative taxonomic analysis showed decreased abundances of Faecalibacterium prausnitzii, Roseburia hominis, and Roseburia intestinalis, and elevated abundances of Escherichia coli and Ruthenibacterium lactatiformans in the GM of MDD patients. We observed decreased levels of bacterial genes encoding key enzymes involved in the production of arginine, asparagine, glutamate, glutamine, melatonin, acetic, butyric and conjugated linoleic acids, and spermidine in MDD patients. These genes produced signature pairs with Faecalibacterium prausntizii and correlated with decreased levels of this species in the GM of MDD patients. These results show the potential impact of the identified biomarker bacteria and their metabolites on the pathogenesis of MDD, and should be confirmed in future metabolomic studies.

Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression.

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.

Bacterial Metabolites of Human Gut Microbiota Correlating with Depression.

Depression is a global threat to mental health that affects around 264 million people worldwide. Despite the considerable evolution in our understanding of the pathophysiology of depression, no reliable biomarkers that have contributed to objective diagnoses and clinical therapy currently exist. The discovery of the microbiota-gut-brain axis induced scientists to study the role of gut microbiota (GM) in the pathogenesis of depression. Over the last decade, many of studies were conducted in this field. The productions of metabolites and compounds with neuroactive and immunomodulatory properties among mechanisms such as the mediating effects of the GM on the brain, have been identified. This comprehensive review was focused on low molecular weight compounds implicated in depression as potential products of the GM. The other possible mechanisms of GM involvement in depression were presented, as well as changes in the composition of the microbiota of patients with depression. In conclusion, the therapeutic potential of functional foods and psychobiotics in relieving depression were considered. The described biomarkers associated with GM could potentially enhance the diagnostic criteria for depressive disorders in clinical practice and represent a potential future diagnostic tool based on metagenomic technologies for assessing the development of depressive disorders.

The Comparison of a New Ultrasound-Induced Depression Model to the Chronic Mild Stress Paradigm.

Willner's "chronic mild stress" (CMS) model is a globally recognized and most commonly used depression model. A depression model induced by ultrasonic exposure of variable frequencies has been created in our laboratory. This article compares two models of the depressive-like state according to three validity criteria. Face validity has been demonstrated in sucrose preference test, Porsolt test, social interest, open field and the Morris water maze. Rats after ultrasound impact have more pronounced anhedonia and social isolation. The construct validity has been proven due to increased levels of corticosterone, epinephrine and norepinephrine and reduced levels of dopamine and some of its metabolites in rat plasma after ultrasound exposure. Predictive validity has been described previously, where the therapeutic effects of various classes of antidepressants have been shown. Our study has demonstrated that the ultrasound-induced depression model is suitable, such as the generally accepted CMS protocol, and meets all required validity criteria. The model presented in this article might help to study pathogenetic mechanisms of depressive disorders, as well as to test promising methods of depression treatment.

Prenatal exposure to brain-specific anion transporter-1-specific monoclonal antibodies impairs cognitive function in post-natal life.

Subclinical hypothyroidism is caused by thyroid hormone deficit and can lead to impairments in mood and cognition. In brain, supply with thyroxine (T4) is mediated by thyroid hormone transporters including the brain-specific anion transporter-1 (BSAT-1). In humans and rodents, BSAT-1 is expressed in brain microvessels and astrocytes. In this study, we tested whether exposure in utero with BSAT-1-specific monoclonal antibodies (MabBSAT) will affect the cognitive function of the progeny. On gestation day 16th, females were intravenously treated with MabBSAT, non-specific antibodies (control 1), and saline (control 2). 72h after injection, MabBSAT were still detectable in the rat brain while non-specific antibodies were found. Immunocytochemistry showed that MabBSAT can bind to cultured primary cerebrovascular rat cells. At the age of 1month, the progeny was subjected to the Y-maze test, novel object recognition test, passive avoidance test, and Morris water maze, which revealed significant impairments in the cognitive function in the MabBSAT-exposed progeny compared to both control progeny groups. Therefore, prenatal exposure to MabBSAT blocks brain BSAT-1 and limits T4 influx to the brain. This impairs the cognitive function in exposed progeny in the post-natal life.

Changes in Gene Expression Profiles in Adult Rat Brain Structures after Neonatal Action of Dipeptidyl Peptidase-IV Inhibitors.

BACKGROUND: Previous studies have shown the development of emotional and motivational disorders, such as anxiety-depression-like disorders with increased aggression in adolescent and adult Wistar rats, occurs after neonatal exposure to the dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) inhibitors diprotin A and sitagliptin (postnatal days 5-18). METHODS: In this study, using real-time PCR, we evaluated changes in the gene expression of serine protease DPP-IV and prolyl endopeptidase (PREP, EC 3.4.21.26; dpp4 and prep genes), monoamine oxidase А (maoA) and B (maoB), and serotonin transporter (SERT; sert) in the brain structures from 3-month-old rats after postnatal action of DPP-IV inhibitors diprotin A and sitagliptin. RESULTS: Dpp4, sert, and maoB gene expression increased and maoA gene expression changed with a tendency to increase in the striatum of rats with neonatal sitagliptin action. The increase of maoA gene expression was also shown in the amygdala. An increase in prep gene expression was found in the striatum of rats with the neonatal action of diprotin A, and a decrease in maoB gene expression was observed in the amygdala. We detected a significant downward trend in sert gene expression in the frontal cortex and amygdala, as well as a tendency to increase in maoA gene expression in the hypothalamus. DISCUSSION: These findings suggest that changes in the expression of the abovementioned genes are associated with the development of anxiety and depression, with increased aggression caused by the neonatal action of diprotin A and sitagliptin.