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Anxiety and Depression in Pancreatitis: Mechanisms, Assessment, and Treatment.
BACKGROUND: Numerous studies have detailed that patients with pancreatitis frequently experience comorbid anxiety and depression, which may arise from physiological factors or psychosocial influences, and these conditions adversely affect daily functioning and quality of life. However, there is still a lack of reviews on epidemiological and mechanistic studies of anxiety and depression in patients with pancreatitis. SUMMARY: Patients with pancreatitis commonly present with comorbid anxiety and depression, with chronic pancreatitis patients being more susceptible than those with acute pancreatitis. The mechanisms underlying this comorbidity are complex and likely multifactorial. Biological factors encompass inflammation-driven cytokine signaling to the brain, hypothalamic-pituitary-adrenal axis hyperactivity, gut microbiome dysbiosis, and altered central nervous system plasticity. Psychosocial factors include the emotional burden of pancreatitis, persistent sleep disturbances, substance abuse, and diminished family and social support. Assessment primarily relies on various types of scales, while treatment encompasses a comprehensive approach involving medication, psychological interventions, and family and social support. KEY MESSAGES: This paper reviews the epidemiological characteristics of anxiety and depression in patients with pancreatitis, explores their biological and psychosocial mechanisms, and summarizes key points for the assessment and treatment of this comorbidity.
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Si-Ni-San alleviates depression-like behavior via regulating the gut microbiota-tryptophan metabolism-AhR/NF-κB pathway axis.
BACKGROUND: Si-Ni-San (SNS), a classic herbal formula from the Treatise on Cold Damage Diseases, is used to treat depression by relieving "liver qi stagnation". However, the underlying mechanism remains unclear. PURPOSE OF THE RESEARCH: This study aimed to investigate the mechanism by which SNS alleviates depression-like behavior, specifically focusing on its role in modulating gut microbiota and host tryptophan metabolism. METHODS: A depression model was induced in mice by chronic unpredictable mild stress (CUMS). The antidepressant effects of SNS were evaluated through behavioral tests. Integrated untargeted and targeted metabolomics, alongside 16S rRNA sequencing, were utilized to identify potential gut-brain signaling molecules. Molecular interactions between the gut-brain signaling molecule and its target were validated by surface plasmon resonance (SPR) and molecular docking. Key protein expression was measured via Western blot and ELISA. Finally, the function of gut microbiome-derived indole-3-acetic acid (IAA) as a key gut-brain signaling molecule was confirmed by oral supplementation experiments. RESULTS: SNS significantly alleviated CUMS-induced depression-like behaviors. Multi-omics analysis revealed that SNS reversed tryptophan metabolic disorders and elevated gut microbiome-derived IAA levels in both the colon and prefrontal cortex, which was attributed to the enrichment of Lactobacillus. Further investigations confirmed that IAA directly binds to and activates the aryl hydrocarbon receptor (AhR), thereby inhibiting NF-κB pathway-mediated neuroinflammation. Moreover, oral supplementation with IAA replicated the antidepressant effects of SNS and suppressed CUMS-induced neuroinflammation via the AhR/NF-κB signaling pathway. CONCLUSION: SNS alleviates depression-like behavior by modulating gut microbiota-mediated tryptophan metabolism to enhance IAA production, thereby activating central AhR signaling and suppressing NF-κB-mediated neuroinflammation.
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Resilience and the Gut Microbiome: Insights from Chronically Socially Stressed Wild-Type Mice.
The microbiome is an important player within physiological homeostasis of the body but also in pathophysiological derailments. Chronic social stress is a challenge to the organism, which results in psychological illnesses such as depression in some individuals and can be counterbalanced by others, namely resilient individuals. In this study, we wanted to elucidate the potential contribution of the microbiome to promote resilience. Male mice were subjected to the classical chronic social defeat paradigm. Defeated or undefeated mice were either controls (receiving normal drinking water) or pre-treated with antibiotics or probiotics. Following social defeat, resilient behavior was assessed by means of the social interaction test. Neither depletion nor probiotic-shifted alteration of the microbiome influenced stress-associated behavioral outcomes. Nevertheless, clear changes in microbiota composition due to the defeat stress were observed such as elevated Bacteroides spp. This stress-induced increase in Bacteroides in male mice could be confirmed in a related social stress paradigm (instable social hierarchy) in females. This indicates that while manipulation of the microbiome via the antibiotics- and probiotics-treatment regime used here has no direct impact on modulating individual stress susceptibility in rodents, it clearly affects the microbiome in the second line and in a sex-independent manner regarding Bacteroides.
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Food & mood: a review of supplementary prebiotic and probiotic interventions in the treatment of anxiety and depression in adults.
BACKGROUND: A bidirectional relationship exists between the brain and the gastrointestinal tract. Foods containing bacteria that positively influence the gastrointestinal microbiome are termed, probiotics; compounds that promote the flourishing of these bacteria are termed, prebiotics. Whether microbiome influencing therapies could treat psychiatric conditions, including depression and anxiety, is an area of interest. Presently, no established consensus for such treatment exists. METHODS: This systematic review analyses databases and grey literature sites to investigate pre and/or probiotics as treatments for depression and/or anxiety disorders. Articles included are from within 15 years. Pre-determined inclusion exclusion criteria were applied, and articles were appraised for their quality using a modified-CASP checklist. This review focuses specifically on quantitative measures from patients with clinical diagnoses of depression and/or anxiety disorders. RESULTS: 7 studies were identified. All demonstrated significant improvements in one or more of the outcomes measuring the of effect taking pre/probiotics compared with no treatment/placebo, or when compared to baseline measurements. DISCUSSION: Our review suggests utilising pre/probiotic may be a potentially useful adjunctive treatment. Furthermore, patients with certain co-morbidities, such as IBS, might experience greater benefits from such treatments, given that pre/probiotic are useful treatments for other conditions that were not the primary focus of this discourse. Our results are limited by several factors: sample sizes (adequate, though not robust); short study durations, long-term effects and propensity for remission undetermined. CONCLUSION: Our results affirm that pre/probiotic therapy warrants further investigation. Efforts should aim to elucidate whether the perceived efficacy of pre/probiotic therapy in depression and/or anxiety disorders can be replicated in larger test populations, and whether such effects are maintained through continued treatment, or post cessation. Interventions should also be investigated in isolation, not combination, to ascertain where the observed effects are attributable to. Efforts to produce mechanistic explanations for such effect should be a priority.
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Nutrient-Synbiotic Complex Ameliorates LPS-Induced Depressive-Like Behavior via Modulation of Gut Microbiota and Tryptophan Metabolism in Mice.
The conventional antidepressant treatments are ineffective, having undesirable side effects and relapse susceptibility. Nutrient and probiotics supplementation may have adjuvant antidepressant effects. This study aims to develop and assess the antidepressant properties of a nutrient-synbiotic complex and investigate the underlying mechanisms. We randomly divided into control, model, and four complex groups (nutrient, prebiotic, probiotic and united all components, respectively). We used lipopolysaccharide (LPS) to establish the depression model and assessed depressive-like behaviors using various behavioral tests, neuroplasticity, tryptophan pathway metabolites, and brain-derived neurotrophic factor (BDNF) in serum and prefrontal cortex (PFC). Intestinal microbiome analysis was performed using 16S rRNA gene sequencing. The nutrient-synbiotic complex presented beneficial effects against the depression-like behaviors induced by LPS, mitigated the increased level of kynurenine, and decreased levels of 5-hydroxytryptamine and BDNF both in serum and PFC (p < 0.05). It also reduced neuronal damage in PFC after LPS exposure (p < 0.05). Additionally, the nutrient-synbiotic complex effectively prevented the disturbance in abundance and diversity of the intestinal flora induced by LPS (Chao1: p = 0.013, ACE: p = 0.006, PCoA: R 2 = 0.25, p = 0.003). A total of nine bacterial genera were negatively associated with depression, while eight were positively associated with depression. Among them, g__Family_XIII_UCG_001, g__Clostridia_vadinBB60_group, and g__Lactobacillus showed significant intergroup differences (p < 0.05). This is the first study to demonstrate that a combined nutrient-synbiotic complex can prevent depressive-like behavioral changes induced by LPS. The underlying mechanisms may be associated with modifying the composition of the gut microbial community and improving the tryptophan metabolic homeostasis.
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Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.
Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.
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Neuropsychological Symptoms and Intrusive Thoughts Are Associated With Worse Trajectories of Chemotherapy-Induced Nausea.
CONTEXT: Although chemotherapy-induced vomiting is well controlled with evidence-based antiemetic regimens, chemotherapy-induced nausea (CIN) remains a significant clinical problem. OBJECTIVES: Study purposes, in a sample of outpatients with breast, gastrointestinal, gynecological, or lung cancer who received two cycles of chemotherapy (CTX, n = 1251), were to evaluate for interindividual differences in the severity of CIN and to determine which demographic, clinical, symptom, and stress characteristics are associated with higher initial levels as well as with the trajectories of CIN. METHODS: Patients were recruited during their first or second cycle of CTX. Patients completed self-report questionnaires a total of six times over two cycles of CTX. Hierarchical linear modeling was used to evaluate for interindividual differences in and characteristics associated with the severity of CIN. RESULTS: Across the two cycles of CTX, higher levels of sleep disturbance, depression, and morning fatigue, as well as higher levels of intrusive thoughts, were associated with higher initial levels of CIN. In addition, lower functional status scores and shorter cycle lengths were associated with higher initial levels of CIN, and younger age and higher emetogenicity of the CTX regimen were associated with both higher initial levels as well as worse trajectories of CIN severity. CONCLUSION: These findings suggest that common symptoms associated with cancer and its treatment are associated with increased severity of CIN. Targeted interventions for these symptoms may reduce the burden of unrelieved CIN.
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Microbiome and Vocalization Biomarkers of Infant Distress, Maternal Depression and Parenting Styles.
INTRODUCTION: Psychiatric disorders have their genesis in early life. Standard screening approaches during well child visits for pathological infant distress, maternal depression, and dysfunctional parenting behaviors are likely inadequate. Microbiome measures and infant vocalizations have promise as scalable psychiatric biomarkers for infants. The purpose of this study was to examine associations among infant gut colonization based on microbiome measurements with maternal distress and maternal depressive symptoms in a sample of infants. METHODS: This study sought to examine infant microbiome correlates of infant distress, parent-infant interactions, maternal distress, and maternal depressive symptoms. We collected (N = 31) microbiome samples, infant vocalizations during vaccination, and behavioral measures during a 4 month well child visit (WCV) and did a battery of clinical assessments to assess for maternal depression, parent-child interactions, family characteristics and family stress. Whole-genome SHOTGUN sequencing was utilized to identify three types of associations: alpha-diversity using Shannon and Inverse-Simpson indexes, beta-diversity using Bray-Curtis and Jaccard distances, and differential abundance using LinDA. Spectral measures of infant cries were also modeled to assess potential relationships with clinical assessments and the microbiome. RESULTS: There were 19 phyla, 417 genera, and 1246 species identified with taxonomic classification. Maternal distress as measured by PHQ-9 scores obtained when infants were 2 months old were associated with 4 bacterial species (Actinomyces johnsonii, Bilophila wadsworthia, Clostridium dakarense and Ruminococcus flavefaciens; FDR < 0.1) and beta-diversity (p = 0.006-BC; p = 0.005-Jaccard). Infant cries with greater high frequency band power (p < 0.03) and a greater high-to-mid frequency ratio-metrics (p < 0.05) were associated with altered α-diversity of the microbiome. No correlations were present between maternal PHQ-9 at 4 months, PSI-IV and microbiome diversity. CONCLUSION: The present findings suggest that an infant stress (assessed by quality of crying) is associated with lower microbiome diversity. Decreased diversity reflects an unhealthy microbiome. Parental depressive symptoms may also influence infant microbiome. Future interventional studies focused on the quality of the infant-caregiver relationship should examine related changes in intestinal microbiota.
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Molecular mediators of the association between child obesity and mental health.
Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.
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The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline.
Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood-brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.