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Antibiotic-induced gut microbe dysbiosis alters neurobehavior in mice through modulation of BDNF and gut integrity.
Gut microbiota is essential for intestinal integrity and brain functions. Herein we aimed to investigate the effects of alteration of gut microbiome using broad-spectrum antibiotics on CD 1 male mice (germ-modified group (GM). Moreover, we co-administrated probiotics with or without antibiotics for four weeks and evaluated if probiotics could reverse these behavioral and intestinal effects. GM, co-administered antibiotics and probiotics, and probiotics-only groups were compared to control mice of the same sex, age, and weight that did not receive either drug (n=12 in all groups). Cultivation of aerobic and anaerobic bacteria was evaluated by fecal culture of all groups. We tested exploratory behavior, anxiety, memory, depression-like behavior, and hippocampal and frontal lobe BDNF protein level alterations in response to antibiotics and its downstream effect on the PI3K/Akt1/Bcl2 pathway. Intestinal integrity was evaluated using gene expression analysis of ZO-1, claudin, and occludin genes. Additionally, the inflammatory TLR4 and p-p38 MAPK pathways in the intestines were investigated. Twice-daily administration of oral antibiotics for four weeks significantly reduced total bacterial count and upregulated TLR4 and p-p38.GM mice showed a significant reduction in BDNF(P =0.04), impaired spatial memory, and long-term memory as evidenced by decreased T maze correct alternation trails and shortened retention time in the passive avoidance test in GM(P =0.01). Passive avoidance showed significantly increased latency after probiotics intake. Depressive-like behavior was more pronounced in GM mice as assessed by the tail suspension test (P =0.01). GM showed significant upregulation(p<0.001) of the TLR4 and p-p38 MAPK pathway. Co-administration of probiotics with antibiotics showed an increase in BDNF levels, and upregulation of the cell survival PI3K/Akt1/Bcl2 pathway, significantly higher relative abundance in the firmucutes members, a significant decrease in the Firmicutes/Bacteroidetes ratio and downregulation of TLR4 and p-p38 MAPK. The tight junction proteins ZO-1, claudin and occludin were downregulated by antibiotic administration for four weeks and restored by probiotics. Collectively, the data suggest that long-term use of antibiotics appears to disrupt the intestinal epithelial barrier and alter neurobehavioral qualities specifically, long-term memory and exploratory drive, possibly through the reduction of BDNF, and probiotics partially reverse these effects. Our study emphasizes the effect of prolonged intake of antibiotics on production of dysbiosis as well as the impact of the antibiotic induced intestinal inflammation on neurobehavioral aspects in mice as the memory and anxiety-like behavior. We also reveal that co-administration of probiotics can reverse these changes.
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Gut microbiome-derived tryptophan metabolites predict relapse in alcohol use disorder.
Relapse is common in alcohol use disorder (AUD), a condition that affects nearly 11 % of adults in the US. Excessive alcohol consumption causes gut dysbiosis, which may in turn alter the production of bacterial-derived tryptophan metabolites. These metabolites impact the intestinal enteroendocrine environment and modulate neuroinflammation. This can ultimately affect behavior. However, the role of bacterial-derived tryptophan metabolites in AUD is not well-understood. Thus, in this study, we enrolled 40 patients admitted for severe AUD (26 males, 14 females) to investigate whether bacterial-derived indoles could predict AUD relapse. Upon enrollment, alcohol use as well as depression and anxiety symptoms were assessed. Peripheral blood samples were collected and analyzed for cytokines, bacterial-derived as well as endogenous tryptophan metabolites, and hematological factors. At three months after discharge, 25 patients completed follow-up and were re-assessed for clinical symptoms to identify AUD relapse. Ten patients relapsed and 15 patients were in early remission. Two bacterial tryptophan metabolites, indole-3-carboxaldehyde (IAld) and indole-3-acetic acid (IAA), significantly predicted relapse versus remission using logistic regression models (p = 0.019, SGPV = 0, and p = 0.035, SGPV = 0 respectively). These findings remained significant after adjustment for age, sex, BMI, and when additionally adjusting for nicotine use and depression severity. Moreover, higher IAld levels correlated with increased serotonin levels (Pearson's R; 0.592, p < 0.001) and fewer white blood cells (Pearson's R; -0.318, p < 0.05) in all 40 patients. Our data indicate significant interactions between microbiome-derived metabolites and host metabolism, and that IAld specifically may have a protective role in AUD, potentially through serotonin modulation.
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Sex-specific microbial and tryptophan signatures of depression implicate archaeal methanogens and indole-3-acetic acid only in women.
Sex differences in mental health are often overlooked, yet gut microbiota-host metabolite interactions may contribute to sexual dimorphism in depression. In a population-based cohort, we investigated sex-specific links among plasma tryptophan metabolites, depressive symptoms (PHQ-9), and the gut microbiome, controlling for smoking, diet, alcohol, and physical activity. Women (N = 419) exhibited higher plasma indole-3-acetic acid (IAA) and picolinic acid (PA) concentrations, but lower trigonelline (TRIG) than men (N = 383). Machine learning models with SHAP explanations revealed that IAA and TRIG were positively associated, whereas PA was negatively associated with depression severity in women, whereas only kynurenic acid (KA) was inversely associated in men. In women, depression severity strongly correlated with methanogenic archaea, including Methanobrevibacter smithii, and microbial methane-production pathways. Methanobrevibacter and specifically M. smithii were negatively linked to genes for tryptophan, PA, and KA biosynthesis, but positively to genes for IAA and nicotinate/nicotinamide metabolism. Most microbial species associated with depression severity in women were predicted to produce IAA. These findings reveal pronounced sex-specific microbiome-metabolite interactions, highlighting potentially distinct microbial mechanisms shaping depression in men and women.
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Prebiotic and Probiotic Modulation of the Microbiota-Gut-Brain Axis in Depression.
Emerging evidence demonstrates that alterations to the gut microbiota can affect mood, suggesting that the microbiota-gut-brain (MGB) axis contributes to the pathogenesis of depression. Many of these pathways overlap with the way in which the gut microbiota are thought to contribute to metabolic disease progression and obesity. In rodents, prebiotics and probiotics have been shown to modulate the composition and function of the gut microbiota. Together with germ-free rodent models, probiotics have provided compelling evidence for a causal relationship between microbes, microbial metabolites, and altered neurochemical signalling and inflammatory pathways in the brain. In humans, probiotic supplementation has demonstrated modest antidepressant effects in individuals with depressive symptoms, though more studies in clinically relevant populations are needed. This review critically discusses the role of the MGB axis in depression pathophysiology, integrating preclinical and clinical evidence, as well as the putative routes of communication between the microbiota-gut interface and the brain. A critical overview of the current approaches to investigating microbiome changes in depression is provided. To effectively translate preclinical breakthroughs in MGB axis research into novel therapies, rigorous placebo-controlled trials alongside a mechanistic and biochemical understanding of prebiotic and probiotic action are required from future research.
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Gut microbiota-derived trimethylamine N-oxide involved in methamphetamine-induced depression-like behaviors of male mice.
Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.
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Randomised control trial indicates micronutrient supplementation may support a more robust maternal microbiome for women with antenatal depression during pregnancy.
BACKGROUND AND AIMS: We investigated the effects of high dose dietary micronutrient supplementation or placebo on the human gut microbiome in pregnant women who had moderate symptoms of antenatal depression. There is a significant absence of well-controlled clinical studies that have investigated the dynamic changes of the microbiome during pregnancy and the relationship among diet, microbiome and antenatal depression. This research is among the first to provide an insight into this area of research. METHODS: This 12 - week study followed a standard double blinded randomised placebo-controlled trial (RCT) design with either high dose micronutrients or active placebo. Matching stool microbiome samples and mood data were obtained at baseline and post-treatment, from participants between 12 and 24 weeks gestation. Stool microbiome samples from 33 participants (17 in the placebo and 16 in the treatment group) were assessed using 16s rRNA sequencing. Data preparation and statistical analysis was predominantly performed using the QIIME2 bioinformatic software tools for 16s rRNA analysis. RESULTS: Microbiome community structure became increasingly heterogenous with decreased diversity during the course of the study, which was represented by significant changes in alpha and beta diversity. This effect appeared to be mitigated by micronutrient administration. There were less substantial changes at the genus level, where Coprococcus decreased in relative abundance in response to micronutrient administration. We also observed that a higher abundance of Coprococcus and higher alpha diversity correlated with higher antenatal depression scores. CONCLUSIONS: Micronutrient treatment appeared to support a more diverse (alpha diversity) and stable (beta diversity) microbiome during pregnancy. This may aid in maintaining a more resilient or adaptable microbial community, which would help protect against decreases or fluctuations that are observed during pregnancy.
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Gut Bacteria Improve Depressive Symptoms by Degrading Cortisol into Androgen.
Gut microbiota may play a role in regulating the stress hormone cortisol. However, the mechanisms underlying the regulation of cortisol by gut microbiota are poorly understood. Here, it is found that gut microbiota degraded cortisol, and this ability is heterogeneous among individuals. Mice gavaged with gut microbiota having a low ability to degrade cortisol may be prone to developing depressive-like behavior. The cortisol-degrading strain Pseudomonas aeruginosa Tongji is isolated from faecal microbiota. The des-like enzyme expressed by P. aeruginosa Tongji converts cortisol into androgen. Bacterial des-like enzyme protects mice against depressive-like behavior via degrading cortisol and producing androgen. The probiotic Bacillus subtilis expressing the des-like enzyme is constructed, which protects the host against cortisol elevation. These findings suggest that bacterial des-like enzyme may regulate cortisol and improve depression by converting cortisol into androgen.
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Esketamine alleviates depressive-like behavior in mice via modulation of the microbiota-gut-brain axis and amino acid metabolism.
BACKGROUND: The microbiota‒gut‒brain axis is increasingly recognized as a critical pathway in the pathogenesis of depression and the response to antidepressant treatments. Esketamine(S-Ket), a noncompetitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, has shown a rapid and long-lasting antidepressant effects. However, the precise mechanisms underlying the antidepressant actions of S-Ket remain unclear. METHODS: In this study, we explore the role of gut microbiota and metabolites in the antidepressant effects of esketamine in lipopolysaccharide (LPS)-induced mouse model of depression. Behavioral tests, including the open-field test, forced swimming test, tail suspension test, and sucrose preference test, were conducted to evaluate the antidepressant efficacy of S-Ket. Additionally,16S rRNA sequencing and untargeted metabolomics were performed to characterize the gut microbiota and metabolome profiles in fecal and hippocampal tissues of LPS-induced mice treated with S-Ket. Bioinformatics analysis was employed to identify key changes. Spearman's rank correlation analyses were used to explore associations between depression-like behaviors (DLBs), differential gut microbes, and metabolites. RESULTS: S-Ket significantly alleviated DLBs in LPS-induced mice, partially restored the disrupted gut microbiota composition (β-diversity), and improved metabolic dysfunction. Pathway analysis revealed that four key amino acid metabolism pathways were significantly altered in both fecal and hippocampal samples, including ‘Glutathione metabolism’. ‘Alanine, aspartate, and glutamate metabolism’, ‘Arginine biosynthesis’, and ‘Arginine and proline metabolism’. Further analysis indicated that the genus Rikenella was significantly correlated with DLBs and host amino acids (e.g., glutamic acid and pyro glutamic acid). CONCLUSIONS: This study demonstrates that a single dose of S-Ket rapidly alleviates depression-like behaviors in LPS-induced mice, and its mechanisms are associated with regulating both the composition of gut microbiota and associated metabolites in fecal and hippocampal tissues, particularly the alteration of host amino acid metabolism. These results highlight the potential role of the gut–microbiome–amino acid metabolism axis in esketamine’s antidepressant effects and suggest that targeting this axis may offer therapeutic benefits for depression. Further research is needed to fully elucidate these mechanisms.
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Insulin resistance: The role in comorbid type 2 diabetes mellitus and depression.
Insulin resistance (IR) plays a significant role in the pathophysiology of comorbid type 2 diabetes mellitus (T2DM) and depression (CDD) through multifaceted mechanisms, including dysregulation of insulin signaling (both central and peripheral), neuroendocrine disturbances (hypothalamic-pituitary-adrenal axis dysfunction and monoaminergic neurotransmission impairment), chronic inflammation, oxidative stress, disruption of the microbiota-gut-brain axis, reduced brain-derived neurotrophic factor levels, and altered synaptic plasticity. These IR-related pathways may predispose individuals to depressive symptoms or exacerbate existing mood disorders. A comprehensive understanding of these mechanisms is critical for developing integrated therapeutic strategies that concurrently target metabolic and psychiatric dysfunction. Antidepressant medications exhibit divergent effects on glucose metabolism. Tricyclic antidepressants, particularly amitriptyline and nortriptyline, worsen metabolic profiles by exacerbating IR, promoting weight gain, and inducing hyperglycemia, thereby increasing diabetes risk with prolonged use. Consequently, tricyclic antidepressants should be avoided in metabolically vulnerable populations unless alternatives are unavailable. Mirtazapine presents a paradoxical profile-while its appetite-stimulating effects often lead to weight gain (a known IR risk factor), some evidence suggests potential β-cell function preservation, necessitating cautious use of mirtazapine in individuals with metabolic syndrome. Among selective serotonin reuptake inhibitors, fluoxetine and escitalopram demonstrate favorable metabolic effects, including improved insulin sensitivity and glycemic control, though hypoglycemia risk (particularly with concomitant sulfonylureas) warrants monitoring. Bupropion, a norepinephrine-dopamine reuptake inhibitor, uniquely promotes weight loss and enhances glycemic control, making it a preferred option for depression comorbid with obesity or T2DM. Agomelatine, with its neutral metabolic profile and circadian rhythm-modulating properties, represents a safer alternative for patients with metabolic concerns. Concurrently, certain antidiabetic agents show promise in managing depression. Metformin and sodium-glucose cotransporter-2 inhibitors may be prioritized for diabetic patients at risk for depression, while glucagon-like peptide-1 receptor agonists appear particularly beneficial for obesity-related mood disturbances. Thiazolidinediones offer value in treatment-resistant cases, whereas insulin secretagogues should be used cautiously in psychiatrically vulnerable individuals. Future research should prioritize three key directions: (1) Mechanistic investigations using advanced neuroimaging to elucidate the contribution of IR to depressive phenotypes and evaluate novel interventions (such as intranasal insulin); (2) Precision medicine approaches incorporating biomarkers, including genetic polymorphisms, inflammatory markers, and gut microbiome signatures, to optimize antidepressant selection and develop personalized treatment algorithms; and (3) Therapeutic innovation, including dual GLP-1/GIP agonists and anti-inflammatory-antidepressant combinations, as well as integrating digital health technologies (e.g., continuous glucose monitoring coupled with mood tracking), will enable real-time, data-driven management. These advances will be instrumental in establishing integrated care paradigms for this comorbidity, which intertwines metabolic and psychiatric conditions.
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Dietary fiber and its associations with depression and inflammation.
Dietary fiber is a crucial component of a healthy diet, with benefits that can be attributed to processes in the gut microbiota and the resulting by-products. Observational studies support associations between dietary fiber intake and depression and inflammation, but the potential mechanisms are poorly understood. This review examines evidence of the effects of dietary fiber on depression and inflammation and considers plausible mechanisms linking dietary fiber and depression, including microbiota-driven modification of gene expression and increased production of neurotransmitters. Additionally, inflammation may mediate the relationship between dietary fiber intake and depression. A high-fiber diet potentially lowers inflammation by modifying both the pH and the permeability of the gut. The resultant reduction in inflammatory compounds may alter neurotransmitter concentrations to reduce symptoms of depression. Further research into the link between dietary fiber intake and inflammation and depression is essential, as findings could potentially provide guidance for improvement in or prevention of inflammatory and depressive disorders.