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AICAR improves depression-like behaviors and is associated with hippocampal AMPK activation and modulation of neurogenesis and neuroinflammation in a microbiota disruption model.
Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions.
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Preclinical and clinical evidence of the association of colibactin-producing Escherichia coli with anxiety and depression in colon cancer.
BACKGROUND: The association between the intestinal microbiota and psychiatric disorders is becoming increasingly apparent. The gut microbiota contributes to colorectal carcinogenesis (CRC), as demonstrated with colibactin-producing Escherichia coli (CoPEC). AIM: To evaluate the association between CoPEC prevalence and anxiety- and depressive-like behaviors with both preclinical and clinical approaches. METHODS: Patients followed after a CRC surgery and for whom the prevalence of CoPEC has been investigated underwent a psychiatric interview. Results were compared according to the CoPEC colonization. In parallel C57BL6/J wild type mice and mice with a CRC susceptibility were chronically infected with a CoPEC strain. Their behavior was assessed using the Elevated Plus Maze test, the Forced Swimming Test and the Behavior recognition system PhenoTyper®. RESULTS: In a limited cohort, all patients with CoPEC colonization presented with psychiatric disorders several years before cancer diagnosis, whereas only one patient (17%) without CoPEC did. This result was confirmed in C57BL6/J wild-type mice and in a CRC susceptibility mouse model (adenomatous polyposis colimultiple intestinal neoplasia/+). Mice exhibited a significant increase in anxiety- and depressive-like behaviors after chronic infection with a CoPEC strain. CONCLUSION: This finding provides the first evidence that CoPEC infection can induce microbiota-gut-brain axis disturbances in addition to its procarcinogenic properties.
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Polygalae Radix Oligosaccharide Esters May Relieve Depressive-like Behavior in Rats with Chronic Unpredictable Mild Stress via Modulation of Gut Microbiota.
Polygalae radix (PR) is a well-known traditional Chinese medicine that is used to treat depression, and polygalae radix oligosaccharide esters (PROEs) are the main active ingredient. Although gut microbiota are now believed to play key role in depression, the effects of PROEs on depression via modulation of gut microbiota remain unknown. In this article, we investigate the effect of PROEs on the gut microbiota of a depression rat and the possible mechanism responsible. The depression rat model was induced by solitary rearing combined with chronic unpredictable mild stress (CUMS). The depression-like behavior, the influence on the hypothalamic-pituitary-adrenal (HPA) axis, the contents of monoamine neurotransmitter in the hippocampus, and the quantity of short-chain fatty acids (SCFAs) in the feces were each assessed, and the serum levels of lipopolysaccharide (LPS) and interleukin-6 (IL-6) were measured by ELISA. Additionally, ultrastructural changes of the duodenal and colonic epithelium were observed under transmission electron microscope, and the gut microbiota were profiled by using 16S rRNA sequencing. The results show that PROEs alleviated the depression-like behavior of the depression model rats, increased the level of monoamine neurotransmitters in the brain, and reduced the hyperfunction of the HPA axis. Furthermore, PROEs regulated the imbalance of the gut microbiota in the rats, relieving intestinal mucosal damage by increasing the relative abundance of gut microbiota with intestinal barrier protective functions, and adjusting the level of SCFAs in the feces, as well as the serum levels of LPS and IL-6. Thus, we find that PROEs had an antidepressant effect through the restructuring of gut microbiota that restored the function of the intestinal barrier, reduced the release of intestinal endotoxin, and constrained the inflammatory response.
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Activation of Sirt6 by icariside Ⅱ alleviates depressive behaviors in mice with poststroke depression by modulating microbiota-gut-brain axis.
BACKGROUND: Sirt6-mediated gut microbiota plays a vital role in poststroke depression (PSD). Icariside Ⅱ (ICS Ⅱ) is a naturally-occurring neuroprotectant with Sirt6 induction potency. However, it is unknown whether ICS Ⅱ protects against PSD through modulation of gut microbiota. OBJECTIVE: This study aimed to reveal the effect and potential mechanisms of ICS Ⅱ on PSD, and the role of the microbiota-gut-brain axis was investigated. METHODS: Using middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) to establish post-stroke depression (PSD) mice, we assessed anti-depressant effects of ICS Ⅱ via behavioral tests, immunohistochemistry, and western blot. Transcriptome profiling, molecular docking, and surface plasmon resonance were used to identify key targets. 16S rDNA genomic-derived taxonomic profiling and fecal microbiota transplantation (FMT) were conducted to figure out the mechanistic role of the gut microbiota and short-chain fatty acids (SCFAs). RESULTS: ICS Ⅱ ameliorated depressive-like behaviors in PSD mice as evidenced by sucrose preference test, forced swimming test and tail suspension test. ICS Ⅱ restored mitochondrial function, reduced oxidative damage and pro-inflammatory cytokines both in brain and intestine through regulation of Sirt6/NF-κB pathway. ICS Ⅱ significantly increased the abundance of gut microbiota (such asAkkermansia and Ligilactobacillus), enhanced SCFAs concentrations, repaired intestinal barrier integrity and upreglated the tight junction protein expression. FMT from ICS II-treated mice replicated these benefits, confirming gut microbiota's role. Mechanistically, ICS Ⅱ directly bound to Sirt6 and enhanced its activity. However, ICS Ⅱ-mediated neuroprotection was neutralized in PSD mice or hydrogen peroxide-induced enteric glial cells when Sirt6 was absent. CONCLUSION: Our findings expand the pharmacological properties of ICS II by demonstrating its ability to ameliorate PSD through modulation of the microbiota-gut-brain axis. ICS Ⅱ, as a novel Sirt6 activator, could be translated into an alternative microbiota-targeted avenue for coping with PSD.
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Esketamine alleviates COPD-depression comorbidity in rats via MAPK/NF-κB inhibition and gut-lung-brain axis modulation.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) and depression frequently co-occur, yet the biological basis of this comorbidity and effective therapeutic strategies remain poorly defined. METHODS: We established a rat model of COPD-depression comorbidity through sequential cigarette-smoke exposure and chronic unpredictable mild stress. Pulmonary function, depression-like behaviors, histopathology, and MAPK/NF-κB signaling in lung and hippocampus were assessed. Esketamine or esketamine plus the TLR1/2 agonist Diprovocim was administered for 14 days. Cytokines, oxidative-stress markers, neuronal apoptosis, and microglial activation were evaluated. Complementary in-vitro studies used NR8383 alveolar macrophages (CSE model) and HAPI microglia (LPS + CSE). Gut and lung microbiota were profiled by 16 S rRNA sequencing and correlated with physiological and inflammatory indices. RESULTS: Comorbid rats displayed airflow limitation, depression-like behaviors, systemic inflammation, oxidative stress, and MAPK/NF-κB activation. Esketamine improved pulmonary function and behavior, reduced neuronal apoptosis and microglial activation, and suppressed MAPK/NF-κB signaling; these effects were partly reversed by Diprovocim. In vitro, esketamine increased macrophage and microglial viability, lowered proinflammatory cytokines and oxidative markers, and inhibited pathway activation. Microbiota profiling showed dysbiosis of gut and lung communities, with loss of beneficial taxa and expansion of conditional pathogens, whereas esketamine partially restored balance by promoting commensals and reducing potential pathogens. CONCLUSIONS: These findings delineate a gut-lung-brain inflammatory-microbial network in COPD-depression comorbidity and identify esketamine as a multi-target intervention capable of modulating signaling pathways, inflammation and oxidative stress, and microbial homeostasis.
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Links Between Gut Dysbiosis and Neurotransmitter Disturbance in Chronic Restraint Stress-Induced Depressive Behaviours: the Role of Inflammation.
Accumulating evidence has shown that inflammation, the gut microbiota, and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test, and elevated plus maze) and analysis. The results showed that CRS significantly increased interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor α (TNFα) levels and decreased brain-derived neurotrophic factor (BDNF) expression, accompanied by the activation of IkappaB-alpha-phosphorylation-nuclear factor kappa-B (IκBα-p-NF-κB) signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and their corresponding metabolites, and gut microbiota faecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours, and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.
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Lactobacillus yogurts alleviate anxious- and depressive-like effects in CUMS mice via multiple pathways and regulating gut-brain axis.
Background: Current researches suggest that the microbiota-gut-brain axis plays a critical role in modulating human cognition and emotion, particularly in the context of psychiatric disorders. Probiotic fermented dairy products have been shown to regulate gut microbiota composition and alleviate depressive symptoms; however, the underlying mechanism and associated metabolic pathways remain unclear.Methods: In this study, we compared the effects of probiotics (Lactobacillus reuteri and Lactobacillus bulgaricus) fermented yogurt on chronic unpredictable mild stress (CUMS)-induced anxious and depressive-like symptoms in mice, as well as discussed potential mechanisms.Results: Behavioral tests revealed that both L. reuteri and L. bulgaricus fermented yogurt significantly alleviated these symptoms. We also observed that Lactobacillus fermented yogurt exerted an overall neuroprotective effect in the hippocampus and helped maintain normal cerebral activity. L. reuteri and L. bulgaricus fermented yogurts were also observed to ameliorate the levels of monoamine neurotransmitters and inflammatory cytokines via inhibiting the activation of the NF-κB pathway accompanied by elevating the CREB-BDNF pathway.Conclusion: Our findings suggest that L. reuteri and L. bulgaricus fermented yogurts may modulate gut microbiota composition and host metabolism, thereby performing neuroprotective effects and ameliorating depressive behaviors in mice by at least partially microbiota-gut-brain axis. These findings have important implications for understanding the antidepressant mechanisms of fermented dairy products that target the intestinal microbiota and provide a promising new way for the development of novel treatments for depression.
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Chaihu-Jia-Longgu-Muli Tang ameliorates chronic restraint stress-induced depressive-like behaviors in association with modulation of the gut microbiota-NLRP3 inflammasome-microglia axis.
Chronic stress-induced neuroinflammation and gut microbiota dysbiosis have been implicated in the pathogenesis of depression. The classic herbal formula Chaihu-Jia-Longgu-Muli Tang (CLM) has been reported to exert antidepressant effects, but the underlying mechanisms remain poorly understood. This study aimed to investigate whether CLM ameliorates depressive-like behavior in chronic restraint stress (CRS)-induced mice and to explore its association with the gut microbiota remodeling, NLRP3 inflammasome signaling, and microglia activation. A mouse model of depression was established through exposure to CRS. Depressive-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Hippocampal neuronal damage was evaluated by HE and Nissl staining. Intestinal barrier integrity was examined by HE staining and immunofluorescence staining for ZO-1 and occludin. Colonic and hippocampal levels of pro-inflammatory cytokines were measured by ELISA. Gut microbiota composition was analyzed by 16 S rRNA gene sequencing. Hippocampal M1 microglial polarization and microglial NLRP3 localization were assessed by Iba-1/CD86 and Iba-1/NLRP3 double immunofluorescence staining, and NLRP3 inflammasome-related protein expression was further evaluated by Western blotting. CLM attenuated CRS-induced depressive-like behaviors and hippocampal neuronal damage, restored gut barrier integrity as indicated by increased ZO-1 and occludin expression and reduced colonic IL-6, TNF-α, and IL-1β levels, and reshaped the gut microbiota by increasing SCFA-producing Muribaculaceae, Alloprevotella, and Bacteroides and decreasing Dubosiella and Lactobacillus spp. Exploratory Spearman analyses identified several nominal associations between microbial taxa and behavioral or inflammatory variables; however, these associations did not remain significant after Benjamini-Hochberg FDR correction and should therefore be interpreted as hypothesis-generating. CLM-H also reduced hippocampal CD86⁺/Iba-1⁺ cells, decreased NLRP3+/Iba-1+ co-localization, and reduced NLRP3, caspase-1 p20, and pro-IL-1β expression. CLM-H ameliorates CRS-induced depressive-like behavior and neuronal damage in association with modulation of the gut microbiota composition, NLRP3 inflammasome-related signaling, and microglial activation. These findings support the potential of CLM as a multi-target intervention for depression-related phenotypes, while further causal validation is still required.
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The gut-brain axis in irritable bowel syndrome and inflammatory bowel disease.
Research increasingly demonstrates the bidirectional communication between gut microbiota and the brain, enhancing the role of gut microbiota modulation in the treatment of central nervous system (CNS) disorders. The first five years of life are extremely important as it affects the development of gut microbiota, immune system and, consequently, the onset of psychometric alterations, particularly in genetically predisposed individuals. In this review, we focus on the link between specific microbial genera, gastrointestinal (GI) disorders, anxiety and depression and on the effects of different therapeutic strategies for mood disorders on gut microbiota.
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Antidepressant Effects of 3-Indolepropionic Acid by Regulating Inflammation Level via Short-Chain Fatty Acids.
BACKGROUND: 3-indolepropionic acid (IPA) is an important gut microbiota-derived metabolite and has anti-inflammatory properties. We have observed the potential antidepressant effects of IPA, and therefore conducted this study to further detect its potential antidepressant effects and search for the possible action mechanisms. METHODS: Chronic restraint stress (CRS) was used to induce depression-like behaviors (DLBs) in mice, and then IPA was administered to mice with DLBs (double-blind manner, 20 mg/kg, once daily for 10 consecutive days, intraperitoneal injection, ten days). The feces and hippocampus samples were collected to detect gut microbiota compositions, short-chain fatty acids (SCFAs), G protein-coupled receptor 43 (GPR43), and inflammation-related factors. RESULTS: Disordered gut microbiota, decreased SCFA levels, decreased GPR43 (SCFA receptors), and increased inflammation levels were observed in CRS-induced depressed mice. After IPA treatment, DLBs in CRS mice were significantly improved, along with the improved gut microbiota and increased SCFA levels, especially acetic acid, propanoic acid, and valeric acid. Meanwhile, we found that IPA could increase the level of GPR43 and decrease the levels of inflammation-related factors in the hippocampus of CRS mice. In addition, close relationships among SCFAs, GPR43, and inflammation-related factors were observed. CONCLUSIONS: These results suggested that IPA might exert antidepressant effects through gut microbiota modulation, which elevated SCFA levels and subsequently alleviated brain inflammation.