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Antidepression of Xingpijieyu formula targets gut microbiota derived from depressive disorder.
OBJECTIVE: This investigation aims to determine the antidepressant role of Xingpijieyu formula (XPJYF) mediated via gut microbiota (GM)-brain axis. METHODS: We collected fecal microbiota from patients with depressive disorder (DD) and cultured microbiota in vitro. Some of microbiota were transplanted into germ-free rats with the intragastric administration of XPJYF grain at the dose of 1.533 g/kg/day. The behaviors were studied by forced swimming test, open field test, sucrose preference test, and body weight. Products of hypothalamus-pituitary-adrenocortical (HPA) axis, neurotransmitter, and serum cytokines were investigated by enzyme linked immunosorbent assay. Glial fibrillary acidic protein (GFAP), a biomarker of astrocyte, was quantified using immunofluorescence. Microbiota culturing in vitro after XPJYF treatment was analyze by 16 s RNA sequencing technology. We used lipopolysaccharide (LPS) to mimic activated rat primary astrocyte in vitro. Brain-derived neurotrophic factor (BDNF), cytokines, and oxidative stress factors were determined by western blotting, and glycometabolism in astrocyte was investigated by 2-deoxy-D-glucose (2-DG) uptake, adenosine triphosphate (ATP), and glucose-1-phosphate (G1P) kits. RESULTS: Microbiota composition during 8 mg/ml of XPJYF (H12-8) for 12 h showed the more consistency. Lactococcus is enriched in DD-derived microbiota composition, and Biffdobacterium and Lactobacillus in H12-8 group. GLUCOSE1PMETAB-PWY and PWY-7328 of which biofunctions were dominantly encoded by Biffdobacterium were the top two of altered pathways. XPJYF improved behaviors and repressed astrocyte activation in depression rats. XPJYF elevated 2-DG uptake, ATP, glucose-1-phosphate, and brain-derived neurotrophic factor (BDNF), and inhibited cytokines and oxidative stress in LPS-induced astrocyte. CONCLUSION: XPJYF treatment targets inflammation, activation, and glycometabolim in astrocyte via gut microbiota modulation, thereby improve animal behaviors, HPA axis dysfunction, and neurotransmitter synthesis in depression rats.
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Targeting astrocytic Nrf2 by Trilobatin alleviates lipopolysaccharide-induced depressive-like behaviors and cognitive impairment in mice: Mechanistic insights into gut microbiota and metabolites modulation.
BACKGROUND: Clinical and preclinical evidence links major depressive disorder (MDD) and Alzheimer's disease (AD), suggesting MDD treatment could prevent some AD. Dysfunction within the microbiota-gut-brain axis contributes to MDD and AD pathogenesis via dysregulated microbial metabolites. Trilobatin (TLB) functions as a neuroprotective agent modulating gut microbiota. However, its capacity to alleviate depressive-like behavior and cognitive deficits through restoration of gut microbial ecology and metabolite profiles requires clarification. OBJECTIVE: The present research was designed to examine the impact of TLB on depressive-like behavior and cognitive impairments, and the role of the gut microbiota and metabolites. METHODS: Neuroprotective effects of TLB on MDD and AD were evaluated using an LPS mouse model exhibiting depressive-like behavior and memory impairment. The principal molecular target of TLB was identified through a combination of single-cell sequencing, surface plasmon resonance, and gene knockout approaches. Mechanistic insights into gut microbiota and metabolites were gained through 16S rRNA sequencing and fecal microbiota transplantation (FMT). RESULTS: TLB attenuated LPS-induced depressive-like behaviors manifested as lowered sucrose preference, extended immobility, and improved cognitive deficits as reflected by Y-maze and novel object recognition. Mechanistically, TLB directly bound Nrf2, enhanced Nrf2-ARE activity, and suppressed neuroinflammation and oxidative stress. TLB restored gut microbiota homeostasis, elevated Akkermansia muciniphila (AKK) abundance and short-chain fatty acids, and strengthened intestinal tight junction proteins. FMT from TLB-treated mice replicated these benefits in wild-type but not Nrf2-knockout mice. AKK supplementation similarly ameliorated behavioral and cognitive deficits via Nrf2 activation. CONCLUSION: Our findings reveal that TLB mitigates neuropsychiatric deficits by activating Nrf2, remodeling restructuring gut microbiota and fortifying intestinal barrier function. The Nrf2-mediated microbiota-gut-brain axis is suggested as a potential therapeutic target for MDD and AD, positioning TLB as a promising natural Nrf2 activator.
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Balancing the mind: Toward a complete picture of the interplay between gut microbiota, inflammation and major depressive disorder.
The intricate interplay existing between gut microbiota and homeostasis extends to the realm of the brain, where emerging research underscores the significant impact of the microbiota on mood regulation and overall neurological well-being and vice-versa, with inflammation playing a pivotal role in mediating these complex interactions. This comprehensive review explores the complex interplay between inflammation, alterations in gut microbiota, and their impact on major depressive disorder (MDD). It provides a cohesive framework for the puzzle pieces of this triad, emphasizing recent advancements in understanding the gut microbiota and inflammatory states' contribution to the depressive features. Two directions of communication between the gut and the brain in depression are discussed, with inflammation serving as a potential modulator. Therapeutic implications were discussed as well, drawing insights from interventional studies on the effects of probiotics on gut bacterial composition and depressive symptoms. Ultimately, this review will attempt to provide a complete and valuable framework for future research and therapeutic interventions in MDD.
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Shared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder.
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease with symptoms that go beyond the domain of glucose metabolism. In fact, research has shown that T2DM is accompanied by neurodegeneration and neuroinflammation. Interestingly, Major Depressive Disorder (MDD), a mood disorder characterized mainly by depressed mood and anhedonia is a key feature of T2DM. A body of evidence demonstrates that there are many shared neuroimmune mechanisms underlying the pathophysiology of T2DM and MDD. Therefore, here we review the state-of-art regarding the underlying factors common to both T2DM and MDD. Furthermore, we briefly discuss how depressive symptoms in diabetic patients could be tackled by using novel therapeutic approaches uncovered by these shared mechanisms. Understanding the comorbidity of depression in diabetic patients is essential to fully address T2DM pathophysiology and treatment.
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Linking the Gut Microbiota to a Brain Neurotransmitter.
The past decade has yielded substantial evidence that the gut microbiome modulates brain function, including for instance behaviors relevant to anxiety and depression, pointing to a need to identify the biological pathways involved. In 2013 Clarke and colleagues reported that the early-life microbiome regulates the hippocampal serotonergic system in a sex-dependent manner, findings that opened up numerous lines of inquiry on the effects of the microbiome on neurodevelopment and behavior.
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Probiotic treatment improves post-traumatic stress disorder outcomes in mice.
Post-traumatic stress disorder (PTSD) is a mental disorder resulting from traumatic events which are characterized primarily by anxiety and depressive disorder. In this study, we determine the role of gut bacteria in PTSD. PTSD-like symptoms were produced by single prolonged stress (SPS). SPS animals showed increased levels of anxiety as measured by the elevated plus maze test, while depressive behaviour was confirmed using sucrose preference, force swim, and tail suspension tests. Gut dysbiosis was confirmed in PTSD animals by next-generation sequencing of 16 s RNA of faecal samples, while these animals also showed increased intestinal permeability and altered intestinal ultrastructure. Probiotic treatment increases beneficial microbiota, improves intestinal health and reduces PTSD-associated anxiety and depression. We also found a decrease in cortical BDNF levels in PTSD animals, which was reversed after probiotic administration. Here, we establish the link between gut dysbiosis and PTSD and show that probiotic treatment may improve the outcome of PTSD like symptoms in mice.
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Do probiotics modulate dietary intake? Pilot data from a randomized controlled sub-study of the ProBioHRV clinical trial in patients with depression and healthy controls.
BACKGROUND: The gut microbiome plays a central role in human health and is strongly influenced by diet. Probiotics can beneficially modulate the microbiome and, through the gut-brain axis, may affect mood, appetite, and food preferences. This randomized controlled trial examined whether three months of probiotic supplementation could alter dietary intake in individuals with major depression (MD) and healthy controls (HC). METHODS: In this double-blind, placebo-controlled trial, 53 participants (23 with MD, 30 HC) received either a multi-strain probiotic or placebo twice daily for three months. Dietary intake was assessed at baseline and three follow-ups using the Vienna Food Record (VFR). Nutritional data were analyzed with nut.s® software and evaluated using mixed ANOVAs for repeated measures. These analyses represent additional data collected within the framework of the ProBioHRV study. RESULTS: Changes across dietary measures were generally small, with only a limited number reaching statistical significance. Significant three-way interactions (time × intervention × diagnosis) emerged for vitamin D intake, dietary variety, folic acid, and diversity. In HC, probiotic supplementation was associated with higher vitamin D intake after one week, while in MD, a similar increase was observed after three months (trend level, p = .058). Conversely, participants receiving probiotics showed lower dietary variety and diversity scores at several time points. Across all time points, folic acid intake was lower in MD compared to HC, independent of intervention. CONCLUSION: Probiotic supplementation did not produce consistent changes in nutrient intake but showed exploratory, time- and group-dependent patterns for selected measures, including vitamin D intake and dietary variety and diversity. Given the pilot nature of the study, these findings are descriptive and hypothesis- generating. Larger, well-powered studies with objective nutritional and microbiome measures are required.
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Functional shotgun metagenomic insights into gut microbial pathway and enzyme disruptions linking metabolism, affect, cognition, and suicidal ideation in major depressive disorder.
BACKGROUND: Major depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune–metabolic processes. AIMS: To identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune–metabolic biomarkers of MDD. METHODS: Shotgun metagenomics with taxonomic profiling was performed in MDD versus controls using MetaPhlAn v4.0.6, and functional profiling was conducted using HUMAnN v3.9, aligning microbial reads to species-specific pangenomes (Bowtie2 v2.5.4) followed by alignment to the UniRef90 v201901 protein database (DIAMOND v2.1.9). RESULTS: Gut microbiome diversity, both species richness and evenness, is quite similar between MDD and controls. The top enriched taxa in the multivariate discriminant profile of MDD reflect gut dysbiosis associated with leaky gut and NIMETOX mechanisms, that is, Ruminococcus gnavus, Veillonella rogosaem, and Anaerobutyricum hallii. The top four protective taxa enriched in controls indicate an anti-inflammatory ecosystem and microbiome resilience, that is, Vescimonas coprocola, Coprococcus, Faecalibacterium prausnitzii, and Faecalibacterium parasitized. Pathway analysis indicates loss of barrier protection, antioxidants, and short-chain fatty acids, and activation of NIMETOX pathways. The differential abundance of gene families suggests that there are metabolic distinctions between both groups, indicating aberrations in purine, sugar, and protein metabolism. The gene and pathway scores explain a larger part of the variance in suicidal ideation, recurrence of illness, neurocognitive impairments, immune functions, and atherogenicity. CONCLUSION: The gut microbiome changes might contribute to activated peripheral NIMETOX pathways in MDD.
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Exploring the mechanisms of action of the antidepressant effect of the ketogenic diet.
The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.
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Gut microbiota and inflammatory factor characteristics in major depressive disorder patients with anorexia.
BACKGROUND: This study aimed to explore the gut microbiota and inflammatory factor characteristics in major depressive disorder (MDD) patients with anorexia and to analyze the correlation between gut microbiota and inflammatory factors, anorexia, and HAMD scores. METHODS: 46 MDD patients and 46 healthy controls (HC) were included in the study. The 46 MDD patients were divided into two groups according to whether they had anorexia:20 MDD without anorexia (MDA0 group) and 26 MDD with anorexia (MDA1 group). We used the Hamilton Depression Scale-24 (HAMD-24) to evaluate the depression status of all participants and 16 S ribosomal RNA (16 S rRNA)sequencing to evaluate the composition of the gut microbiota. Inflammatory factors in peripheral blood such as C-reactive protein (CRP) were detected using enzyme-linked immunosorbent assay (ELISA). Spearman's correlation analysis was used to evaluate the correlation between gut microbiota and inflammatory factors, HAMD scores, and anorexia. RESULTS: 1). CRP was significantly higher in the MDA0, MDA1, than HC. 2). An analysis of α-diversity shows: the Simpson and Pielou indices of the HC group are higher than the MDA1 group (P < 0.05). 3). The β-diversity analysis shows differences in the composition of microbial communities between the MDA0, MDA1, and HC group. 4). A correlation analysis showed that Blautia positively correlated with anorexia, HAMD scores, and CRP level, whereas Faecalibacterium, Bacteroides, Roseburia, and Parabacteroides negatively correlated with anorexia, HAMD scores, and CRP level. 5). The receiver operating characteristic (ROC) curve was drawn using the differential bacterial genera between MDD patients with or without anorexia as biomarkers to identify whether MDD patients were accompanied with anorexia, and its area under curve (AUC) was 0.85. The ROC curve was drawn using the differential bacterial genera between MDD patients with anorexia and healthy controls as biomarkers to diagnose MDD patients with anorexia, with its AUC was 0.97. CONCLUSION: This study suggested that MDD patients with anorexia had a distinct gut microbiota compared to healthy individuals, with higher level of CRP. Blautia was more abundant in MDD patients with anorexia and positively correlated with CRP, HAMD scores, and anorexia. The gut microbiota might have influenced MDD and anorexia through the inflammatory factor CRP.