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The host genetics affects gut microbiome diversity in Chinese depressed patients.
The gut microbiome and host genetics are both associated with major depressive disorder (MDD); however, the molecular mechanisms among the associations are poorly understood, especially in the Asian, Chinese group. Our study applied linear discriminant analysis (LDA) effect size (LEfSe) and genome-wide association analysis in the cohort with both gut sequencing data and genomics data. We reported the different gut microbiota characteristics between MDD and control groups in the Chinese group and further constructed the association between host genetics and the gut microbiome. Actinobacteria and Pseudomonades were found more in the MDD group. We found significant differences in the ACE and Chao indexes of alpha diversity while no discrepancy in beta diversity. We found three associations between host genetics with microbiome features: beta diversity and rs6108 (p = 8.65 × 10-9), Actinobacteria and rs77379751 (p = 8.56 × 10-9), and PWY-5913 and rs1775633082 (p = 4.54 × 10-8). A species of the Romboutsia genus was co-associated with the species of Ruminococcus gnavus in an internetwork through four genes: METTL8, ITGB2, OTULIN, and PROSER3, with a strict threshold (p < 5 × 10-4). Furthermore, our findings suggested that the gut microbiome diversity might affect microRNA expression in the brain and influenced SERPINA5 and other spatially close genes afterward. These findings suggest new linkages between depression and gut microbiome in Asian, Chinese people, which might be mediated by genes and microRNA regulation in space distance.
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Exploring gender differences in the relationship between gut microbiome and depression - a scoping review.
BACKGROUND: Major depressive disorder (MDD) exhibits gender disparities, and emerging evidence suggests the involvement of the gut microbiome, necessitating exploration of sex-specific differences. METHODS: A review was conducted, encompassing a thorough examination of relevant studies available in Medline via Ovid, Embase via OvidSP, CINAHL, and PsycINFO databases from their inception to June 2023. The search strategy employed specific keywords and Medical Subject Headings (MeSH) terms tailored to major depressive disorder in women, encompassing unipolar depression, depressive symptoms, and dysbiosis. RESULTS: Five studies were included. Among the four studies, alterations in alpha (n=1) and beta diversity (n=3) in the gut microbiome of individuals with MDD were revealed compared to controls. Gender-specific differences were observed in four studies, demonstrating the abundance of specific bacterial taxa and highlighting potential sex-specific implications in MDD pathophysiology. Correlation analyses (n=4) indicated associations between certain bacterial taxa and the severity of depressive symptoms, with varying patterns between males and females. Studies (n=3) also highlighted promising findings regarding the potential utility of microbial markers in diagnosing MDD, emphasizing the crucial role of sex stratification in understanding the disease pathophysiology. CONCLUSIONS: The findings underscore the importance of recognizing gender-specific differences in the composition of the gut microbiome and its relationship with MDD. Further comprehensive robust studies are required to unravel the intricate mechanisms underlying these disparities.
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Sex-specific difference on anxiety- and depressive-like behavior in neuronal growth regulator 1-knockout mice.
BACKGROUND: Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut-brain communication. Negr1, a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear. METHODS: Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1-/- mice, and molecular assays were performed to evaluate endoplasmic reticulum (ER) stress and apoptosis in the brain, liver, and colon. Behavioral test data were analyzed using a three-way mixed repeated-measures analysis of variance (RM-ANOVA), and molecular data were analyzed using two-way or three-way ANOVA. RESULT: Negr1-/- mice exhibited sex-dependent phenotypes in both central and peripheral systems. Baseline analyses revealed increased intestinal permeability in Negr1-/- mice and sex-specific patterns of brain-derived neurotrophic factor (Bdnf) mRNA expression across multiple time points. Behaviorally, Negr1-/- mice showed increased anxiety-like behavior, decreased social interaction, and impaired spatial learning in the Morris water maze, regardless of sex. Female Negr1-/- mice displayed impaired fear learning and increased depression-like behavior, while male Negr1-/- mice exhibited heightened anxiety-like responses. At the molecular level, ER stress marker spliced X-box binding protein 1 (Xbp1s) mRNA was upregulated in peripheral tissues of males but downregulated in females. Apoptosis analysis revealed enhanced caspase-3 activation in peripheral tissues of female Negr1-/- mice, while males showed no significant changes. Brain tissue showed no significant apoptotic alterations in either sex. CONCLUSIONS: This study demonstrates that, in Negr1-/- mice, both sexes show general behavioral alterations. However, female Negr1-/- mice exhibit greater vulnerability to fear learning impairments and depression-like behavior, whereas males Negr1-/- mice show heightened anxiety responses. These behavioral differences were associated with opposing ER stress responses and differential apoptotic signaling between the sexes in peripheral tissues. Our findings highlight the importance of considering sex as a biological variable in depression research and suggest that Negr1 plays a crucial role in the sex-specific pathophysiology of psychiatric disorders through complex mechanisms spanning central and peripheral systems.
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NLRP3 inflammatory pathway. Can we unlock depression?
Depression holds the title of the largest contributor to worldwide disability, with the numbers expected to continue growing. Currently, there are neither reliable biomarkers for the diagnosis of the disease nor are the current medications sufficient for a lasting response in nearly half of patients. In this comprehensive review, we analyze the previously established pathophysiological models of the disease and how the interplay between NLRP3 inflammasome activation and depression might offer a unifying perspective. Adopting this inflammatory theory, we explain how NLRP3 inflammasome activation emerges as a pivotal contributor to depressive inflammation, substantiated by compelling evidence from both human studies and animal models. This inflammation is found in the central nervous system (CNS) neurons, astrocytes, and microglial cells. Remarkably, dysregulation of the NLRP3 inflammasome extends beyond the CNS boundaries and permeates into the enteric and peripheral immune systems, thereby altering the microbiota-gut-brain axis. The integrity of the brain blood barrier (BBB) and intestinal epithelial barrier (IEB) is also compromised by this inflammation. By emphasizing the central role of NLRP3 inflammasome activation in depression and its far-reaching implications, we go over each area with potential modulating mechanisms within the inflammasome pathway in hopes of finding new targets for more effective management of this debilitating condition.
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Dietary values of macroalgae Porphyra haitanensis in Litopenaeus vannamei under normal rearing and WSSV challenge conditions: Effect on growth, immune response and intestinal microbiota.
Two trials were conducted to determine the effects of dietary macroalgae Porphyra haitanensis on growth, immunity and intestinal microbiota of Litopenaeus vannamei. In trial 1, shrimp (mean initial wet weight about 0.64 g) were fed with seven diets (P0, P1, P2, P3, P4, P5 and P6) containing 0% (basal diet), 1%, 2%, 3%, 4%, 5% and 6% P. haitanensis in triplicate for 60 days. Growth performance (weight gain, WG; specific growth rate, SGR) of shrimp fed the P4 diet were significantly higher than that of shrimp fed P0, P5 and P6 diets (P < 0.05) but without significant differences with shrimp fed P1-P3 diets (P > 0.05). Hepatopancreas phenoloxidase (PO) activity of shrimp fed the P. haitanensis containing diets was significantly higher than that of shrimp fed the basal diet (P0) (P < 0.05). Total haemocyte count (THC) of shrimp fed basal diet (P0) was significantly lower than that of shrimp fed diets containing P. haitanensis. Our results declared that dietary P. haitanensis supplementation increases the abundance of beneficial bacterials such as Nitrosopumilus, Marinobacter or Bifidobacterium and reduces the abundance of harmful bacterias such as Vibrio, and especially pronounced in P4 diet treatment. In trial 2, a WSSV injection challenge test was conducted for 7-day after the rearing trial and shrimp survival was also compared among treatments. A sudden shrimp death was found from the 4th day, and values of survival of shrimp fed the P3-P4 diets were higher than that of shrimp fed other diets during 4-7 days challenge test. The immune response in trial 2 were characterized by higher superoxide dismutase activity (SOD) and PO activities, lower THC and higher HCT compared to levels found in trial 1. In conclusion, suitable dietary P. haitanensis could enhance the growth performance, antioxidant capacity and alter total bacterial numbers or microbial diversity of L. vannamei and furthermore reduce oxidative stress and immune depression challenged by WSSV injection stress, and the level of P. haitanensis supplemented in the diet should be between 2.51% and 3.14%.
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NMR-based metabonomic analysis of normal rat urine and faeces in response to (±)-venlafaxine treatment.
(±)-Venlafaxine, a bicyclic antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class, is prescribed for the treatment of depression and anxiety disorders. As is the case with other antidepressants, its precise mechanisms of action are still unknown. Pharmacometabonomic approaches allow for the detection of diverse metabolites, unlike classic methods for analysing drug interaction based on single metabolites and linear pathways. This provides a global view of the state of homeostasis during treatment and an insight into the mechanisms of action of a drug. Accordingly, the final outcome of treatment is characterised by the network of reactome pathways derived from the on-target and off-target effects of the drug. Regarding antidepressants, the drug network may be located in the gut-microbiome-brain-liver-kidney-immune-cardiovascular system axis (GMBLKICA), implying that neurotransmitters participate as signalling molecules in bidirectional communication. If their bioavailability is increased, this communication and the state of homeostasis may be disrupted. With a pharmacometabonomic approach using NMR in combination with different chemometric methods, a determination was made of subtle changes in the metabolic profile (metabotype) of urine and faeces in normal Wistar rats following a single administration of pharmacological doses of (±)-venlafaxine hydrochloride. Based on the drug-response metabotypes observed, (±)-venlafaxine had effects on gut microbial co-metabolites and osmolytes. Hence, it can be hypothesized that bidirectional communication in the multiorgan axis was perturbed by this drug, and very likely by its active metabolite, (±)-desvenlafaxine. This disrupted signalling could be related not only to therapeutic and adverse effects, but also to the lag period in treatment response.
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The interplay between microbiota and the gut-brain axis in treatment-resistant depression.
Major depressive disorder (MDD) is a common psychiatric condition, and many patients do not respond to standard antidepressant treatments, developing what is known as treatment-resistant depression (TRD). The microbiota-gut-brain axis (MGBA) encompasses the biological processes underlying MDD and TRD. This two-way communication system connects the gut microbiome, the immune system, the central nervous system, and hormone signaling. Changes in the composition and diversity of gut microorganisms can affect neurotransmitter production, blood-brain barrier (BBB) function, immune function, and metabolic processes. These changes may contribute to the development and persistence of TRD. This review describes how the MGBA may influence TRD through mechanisms including BBB function, changes in the kynurenine pathway, variations in short-chain fatty acid (SCFA) production, immune and inflammatory responses, imbalances in the hypothalamic-pituitary-adrenal (HPA) axis, and disruptions in neurotransmitter signaling. The review discusses treatment strategies, focusing on the gut microbiome, including modifications, probiotics, and other approaches.
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Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms.
The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active microbial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antidepressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhRΔIEC). Additionally, this study examined whether the antidepressant effects of dietary DIM and DHNA is mediated by intestinal AhR. AhRΔIEC and WT female mice were fed daily with vehicle, 20 mg/kg DIM or DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for weight gain, anhedonia-like behavior (sucrose preference test), anxiety levels (open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests), and spatial learning (Morris water maze). UCMS reduced weight gain in AhRΔIECs, but not WTs. Moreover, UCMS initially reduced sucrose preference in both AhRΔIECs and WTs, but over 4 weeks of UCMS, AhRΔIECs develop resilience to UCMS-induced anhedonia. Additionally, AhRΔIECs exhibit slightly reduced anxiety in certain tests and faster spatial learning. DIM and DHNA acted as antidepressants in both AhRΔIECs and WTs. Thus, this study suggests that intestinal AhR plays differential roles, mitigating stress effects on weight gain, and increasing stress effects on mood. However, the site of antidepressant action of SAhRMs, such as DIM and DHNA, is not dependent on the expression of intestinal AhR.
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The safety and efficacy of fecal microbiota transplantation in a population with bipolar disorder during depressive episodes: study protocol for a pilot randomized controlled trial.
BACKGROUND: Bipolar disorder (BD) is a chronic, debilitating illness with significant medical morbidity, often secondary to current treatments, and a high recurrence rate. This burden of disease reflects limitations in the tolerability and efficacy of current treatments. There is a compelling body of evidence linking the gut microbiota to mental illness, and while microbial manipulation via probiotic use has been studied as a therapeutic in BD, targeted trials of fecal microbiota transplantation (FMT) have not been conducted in this population. METHODS AND DESIGN: We describe a pilot randomized controlled trial of FMT in participants with BD depression to assess the feasibility, efficacy, safety, and tolerability of this intervention. Individuals between 18 and 65 years of age will be enrolled in the study if they meet diagnostic criteria for a major depressive episode of at least moderate severity in the context of a BD diagnosis and have not responded to treatment for BD. Participants will be randomized 1:1 to receive either screened and processed donor stool (allogenic FMT) or their own stool (autologous FMT) via colonoscopy and monitored for 24 weeks post intervention. Depressive and manic symptoms, treatment acceptability, and gastrointestinal and other side effects are assessed at baseline (prior to randomization) and weekly. Stool samples to assess microbiome composition are obtained at baseline and 3 and 6 months. DISCUSSION: Currently, FMT represents a novel therapeutic option for treating BD depression. This protocol allows for the assessment of the feasibility, efficacy, acceptability, and safety of an intervention aimed at changing the microbiome in those with BD. Results from this pilot study will guide the development of larger trials of FMT for BD depression and may give more insight into how the gut microbiome are altered in those with BD depression. TRIAL REGISTRATION: Clinical Trials Gov NCT03279224.
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Reduced-fat dried distillers grains with solubles reduces the risk for milk fat depression and supports milk production and ruminal fermentation in dairy cows.
Twenty Holstein cows, 12 primiparous and 8 multiparous, with (mean ± SD) 91 ± 19 d in milk and 595 ± 81 kg were used in replicated 4 × 4 Latin squares to compare the effects of feeding conventional dried distillers grains with solubles (DDGS) and reduced-fat DDGS (RFDDGS) in combination with rumen-inert fat (RIF) on milk production and rumen fermentation; one square contained rumen cannulated animals for rumen measurements. In each 21-d period, cows were randomly assigned to 1 of 4 dietary treatments (values on a dry matter basis): (1) control (CON) that contained 0% DDGS; (2) DG contained 30% DDGS; (3) RFDG contained 30% RFDDGS in substitution of DDGS; and (4) RFDG+RIF was similar to RFDG with the addition of 1.9% RIF. Unlike most practical diets in the dairy field, our diets had <22% forage neutral detergent fiber and >18.0% crude protein. Dry matter intake was similar across treatments with any form of DDGS averaging 26.0 ± 0.6 kg/d, whereas the CON diet resulted in less dry matter intake, 21.6 ± 0.6 kg/d. Milk yield tended to be 1.7 kg/d greater for diets with either type of DDGS. Concentration of milk protein was greatest for the DG and RFDG diets, intermediate for the RFDG+RIF diet, and least for the CON diet, namely 3.22, 3.21, 3.12, and 3.07 ± 0.05%. Reduced milk fat percentage and yield were observed when cows consumed the DG diet, 3.27 ± 0.10% and 1.11 ± 0.04 kg/d, respectively, whereas these responses were similar among CON, RFDG, and RFDG+RIF, which averaged 3.68 ± 0.10% and 1.22 ± 0.04 kg/d. The presence of trans-10,cis-12 conjugated linoleic acid was only detected in milk from cows consuming the DG diet; similarly, concentration and yield of trans-10 18:1 were greater for cows consuming this diet. Rumen ammonia was similar across treatments averaging 27.0 ± 2.1mg/dL. The CON and RFDG+RIF diets had similar mean pH, 6.1 ± 0.11, whereas DG and RFDG resulted in lower pH averaging 5.79 ± 0.11. No effect on total concentration of volatile fatty acids was observed; the overall mean was 121 ± 4.11 mM; molar proportion of acetate was affected by treatment resulting in 67.3, 63.2, 61.4, and 60.9 ± 0.93 mol/100 mol for CON, RFDG+RIF, RFDG, and DG, respectively. Results from DNA sequencing showed that rumen bacterial community structure was relatively stable with minor changes at the family and genus levels; these changes may be associated with low starch diets, and hence reduced amylolytic bacteria populations. Feeding high proportions of RFDDGS resulted in greater dry matter intake with low risk for milk fat depression while supporting ruminal fermentation.