Linum usitatissimum L., commonly known as flaxseed, is a perennial herb in the Lineaceae family that has been traditionally used to manage gastrointestinal disorders and diarrhea. The health benefits and medicinal applications of flaxseed can be attributed to the presence of some beneficial compounds, such as omega-3 fatty acids, tocopherol, cyclic peptides, alkaloids, mucilage, and phenylpropanoids.

This investigation explored the potential anti-inflammatory and antioxidant properties of the total alkaloid extract of Linum usitatissimum L. seeds (ALU) in a model of Crohn's disease induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in BALB/c mice.

ALU fraction was chemically characterized by liquid chromatography combined with electrospray ionization mass spectrometry (LC-ESI-MS/MS). Six groups of mice (n=6) were divided as follow: healthy group, colitic control, Dexamethasone treated-group (2.4 mg/kg) and three group for ALU treatment (50, 100 and 200 mg/kg). Intrarectal instillation of DNBS (250 mg/kg) induced colonic inflammation accompanied by body weight loss, colonic architecture modification, inflammatory cells infiltration and excessive inflammatory markers production. Tissues sample were used to assess the histological damages and eventual goblet cells loss (H & E and PAS staining) and to evaluate inflammatory and oxidative statute (MPO, NO, H2O2, MDA, CAT and GSH).

The phytochemical analysis of total alkaloid fraction of LU revealed the presence of 10 compounds. Oral administration of ALU (50, 100, and 200 mg/kg) significantly ameliorated DNBS-induced colitis in mice in a dose-dependent manner. ALU treatment mitigated body weight loss, reduced the weight/length (W/L) ratio, and improved clinical outcomes, including diarrhea and food intake. Histological analyses revealed preserved colonic architecture, enhanced goblet cell numbers, reduced neutrophil infiltration, and minimal mucosal damage, comparable to dexamethasone treatment. ALU also promoted mucosal healing and neutral mucin retention. Furthermore, ALU exerted potent anti-inflammatory and antioxidant effects by modulating key markers such as MPO, NO, H2O2, MDA, CAT, and GSH, supporting its protective role against colonic inflammation.

These findings indicate that alkaloid fraction extracted from Linum usitatissimum L. have strong anti- inflammatory and antioxidant properties in a DNBS-induced colitis model in BALB/c mice.

The purpose of this study was to investigate the function of the NLRP3-Caspase 1 signaling pathway in the colon during fecal microbiota transplantation (FMT) in colitis induced by acetic acid. Additionally, the study aimed to determine the impact of FMT on anxiety behaviors by analyzing the function of the NLRP3-Caspase 1 signaling pathway in the hippocampus. A total of twenty-four rats were selected randomly for the study and divided into two groups, a control group, and an acid acetic-induced colitis group. The acid acetic-induced colitis group further consisted of three subgroups: untreated acid acetic-induced colitis group, mesalazine 0.3 gr/kg group, and FMT group. After 6 days, the colon was evaluated for macroscopic and microscopic damage, and the signaling pathway NLRP3-Caspase1-related genes in the colon and hippocampus were analyzed. Additionally, anxiety-related behaviors of the rats were observed. FMT decreased colonic mRNA expression levels of NLRP3, NF-кB, and Caspase1 and pro-inflammatory cytokines (IL-1β and IL-18). Also, FMT reduced the expression of NLRP3, NF-κB, and Caspase1 protein levels as well as pro-inflammatory cytokines IL-1β and IL-18 in the hippocampus, resulting in a reduction of anxiety behaviors in the open field and elevated plus maze tests in the colitis model. FMT may improve acetic acid-induced colitis by regulating the NLRP3-Caspase1 signaling pathway in the colon. It also reduced colitis-induced anxiety behavior by regulating the expression of proteins related to the NLRP3-Caspase 1 pathway in the hippocampus.

Patients with inflammatory bowel disease (IBD) often report symptoms of anxiety and depression as well as impaired quality of life (QoL). To date, there are few studies on the effect of psychotherapy on psychological functioning and clinical outcome in patients with IBD. The aim of this prospective, randomized, controlled study was to investigate the effect of a brief psychotherapeutic intervention on psychological distress, QoL, sexual functioning, and inflammation and disease activity indices in patients with IBD.

Participants were randomized to receive either group cognitive behavioral therapy or treatment as usual (controls) and were assessed at baseline and after 6 months using psychometric instruments to assess psychological distress, QoL, and sexual functioning. In addition, laboratory measurements, including levels of C-reactive protein (CRP), cytokines, and calprotectin, and calculations of disease activity indices were performed during the 2 study periods.

A total of 80 participants took part in the study. Patients who received psychotherapy reported a significant decrease in anxiety and depression symptoms; a significant improvement in physical functioning, general health, vitality, social functioning, and mental health; and a decrease in physical pain and role limitations caused by emotional problems. CRP levels and the Crohn's Disease Activity Index (CDAI) also decreased significantly at follow-up compared to controls.

Group cognitive behavioral therapy is proving to be an important component of holistic care for IBD patients, as it can significantly improve not only patients' psychosocial functioning but also their clinical course by inhibiting inflammation and reducing disease activity.

clinicaltrials.gov: NCT03667586.

Quinoa, rich in pharmacologically active ingredients, possesses the potential benefit in preventing cognitive impairments induced by hypoxia. In this study, the efficacy of quinoa ethanol extracts (QEE) consumption (200 and 500 mg/kg/d, respectively) against hypobaric hypoxia (HH)-induced cognitive deficits in mice was investigated. QEE significantly ameliorated hypoxic stress induced by HH, as evidenced by improvements in baseline indices and reductions in hypoxia-inducible factor 1α levels. Furthermore, QEE enhanced antioxidant defense mechanisms, alleviated neuroinflammation in brain regions associated with memory, and improved HH-induced cognitive impairments by modulating the cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling pathway. Higher doses generally yielded more effective outcomes than lower doses. QEE also significantly reshaped the gut microbiome structure of HH mice, inhibited gut barrier damage, and reduced lipopolysaccharide migration, thereby increasing short-chain fatty acids (SCFAs) levels. Our findings suggest that QEE may be a promising strategy for preventing hypoxia-induced cognitive impairments by maintaining gut microbiome stability and increasing SCFAs levels.

Inflammatory bowel disease (IBD) is often accompanied by psychiatric disorders. Emerging evidence suggests that neuroinflammation and oxidative stress contribute to the psychiatric symptoms associated with IBD. Umbelliprenin (UMB) possesses several pharmacological properties, including anti-inflammatory and antioxidant effects. This study aimed to investigate the protective effects of UMB on comorbid behavioral disorders in a mouse model of experimental colitis, focusing on its potential anti-neuroinflammatory and antioxidant activities. After inducing colitis with acetic acid, male NMRI mice were treated for 7 consecutive days with UMB, saline, or dexamethasone. Behavioral assessments included the forced swimming test (FST), splash test, open field test (OFT), and elevated plus maze (EPM). Histopathological changes in the colon were evaluated, and total antioxidant capacity (TAC), malondialdehyde (MDA) levels, and the expression of inflammatory genes (TNFα, IL1β, and TLR4) were measured in the hippocampus. Colitis was associated with increased immobility time in the FST, reduced entries and time spent in the open arms of the EPM, decreased grooming behavior in the splash test, and reduced time spent in the central zone of the OFT. Colitis also resulted in a reduction in TAC and an increase in MDA levels and inflammatory gene expression in the hippocampus. UMB treatment mitigated the behavioral disorders associated with colitis, reduced neuroinflammation and oxidative stress in the hippocampus, and alleviated histopathological alterations in the colon. In conclusion, UMB may reduce behavioral disorders induced by colitis by decreasing oxidative stress and neuroinflammation in the hippocampus.

The risk of suicide in patients with major depressive disorder (MDD) poses a major concern, with studies suggesting that genetics may be a contributing factor. Although there are many transcriptomic studies on postmortem brain tissue related to suicidal behavior, the blood transcriptional mechanisms of suicidal ideation (SI) remain unknown. This study utilized a weighted gene coexpression network analysis (WGCNA) approach to investigate the associations between gene coexpression modules and SI in individuals with MDD using peripheral blood RNA-seq data from 75 MDD patients with SI (MDD_SI), 82 MDD patients without SI (MDD_nSI), and 149 healthy controls (HC). An ANCOVA was conducted to assess differences in gene coexpression modules among groups, with age and sex included as covariates. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases were used to annotate module functions. Results indicated that the magenta module (associated with RNA splicing processes) differentiated MDD_SI from MDD_nSI (p = 0.021), while the green module (related to immune and inflammatory responses) distinguished MDD_SI from HC (p = 0.004). Additionally, three modules showed differences between MDD_nSI and HC: magenta (p = 0.009), brown (related to innate immunity and mitochondrial metabolism; p = 0.001), and turquoise (associated with energy metabolism and neurodegeneration; p = 0.005). Our findings highlight that gene expression regulation, immune response, and inflammation may be linked to SI in patients with MDD, while pathways associated with innate immunity, energy metabolism, mitochondrial function, and neurodegeneration appear to be more broadly related to MDD.

Inflammatory bowel disease is a gut-brain axis disorder that comprises chronic inflammatory conditions affecting the gastrointestinal tract, where alterations in the mood of patients are common. Gut-brain axis is a bidirectional communication that link gut and brain. The close association between inflammatory bowel disease and neuroinflammation has far-reaching implications, as is increasingly recognized as a contributing factor to neuropsychiatric and neurodegenerative diseases. The increasing prevalence and high economic cost, together with the loss of life quality of people suffering from these diseases, point to the need to find alternatives to alleviate them. Exploring new therapeutic avenues prompts us to consider the potential benefits of milk fractions, taking advantage of the use of dairy by-products, such as whey and buttermilk. This study examines the impact of cow's whey- and buttermilk-based formulas supplemented with bovine lactoferrin and milk fat globule membrane on the expression of cytokines, as well as on the components of immune and serotonergic system of the brain in a murine model of dextran sodium sulfate-induced colitis. Our results show the potential of these dairy by-products, especially whey, as functional foods in ameliorating neuroinflammation and safeguarding the central nervous system function amid the neurological complications induced or concomitant with intestinal inflammatory processes.

Inflammatory bowel disease (IBD) is accompanied by psychiatric disorders, including Schizophrenic-like manifestations. Although incompletely illustrated, intestinal mucosal membrane damage and blood-brain barrier (BBB) penetrability may have significant roles in psychiatric symptoms of IBD. This study aimed to investigate role of the Claudin-5 (CLDN5) (a regulator of the permeability of BBB) and neuroinflammatory response in the comorbid behavioral disorders in experimental colitis in mice. Acetic acid was used to induce colitis in mice. 7 days after induction of colitis, behaviors including social interaction and locomotor activity as well as anxiety-like behaviors were evaluated. Then, the colon was extracted for gross and microscopic evaluations. The expression of CLDN5, TNF-α, IL1β and IL23 was measured by RT-PCR in the colon and hippocampus. Histopathologic evaluations demonstrated mucosal, submucosal, and crypt-related damages in the colon. The negative and positive number of social interactions significantly increased in the colitis group. A considerable increase in locomotor activities (horizontal and vertical components) shown in the colitis group. Mice in colitis group spent less time in the central zone in the open field apparatus. Gene expressions of TNF-α, IL1β, and IL23 increased and CLDN5 decreased in the colitis group. The barrier function of the intestine and brain would be impaired, partially at least, following colitis (as we observed decrease in CLDN5 gene expression). Furthermore, we found that beside inflammatory response in the colon, a neuro-immune response triggered in the hippocampus following colitis. These alterations probably, mediated comorbid behavioral disorders in acetic acid-induced colitis in mice.

Treatments targeting the gut-brain axis (GBA) are effective at reducing symptom burden in irritable bowel syndrome (IBS). The prevalence of common mental disorders and IBS-type symptom reporting is significantly higher in inflammatory bowel disease (IBD) than would be expected, suggesting potential GBA effects in this setting. Manipulation of the GBA may offer novel treatment strategies in selected patients with IBD. We present a narrative review of the bi-directional effects of the GBA in IBD and explore the potential for GBA-targeted therapies in this setting.

We searched MEDLINE, EMBASE, EMBASE Classic, PsychINFO, and the Cochrane Central Register of Controlled Trials for relevant articles published by March 2024.

The bi-directional relationship between psychological well-being and adverse longitudinal disease activity outcomes, and the high prevalence of IBS-type symptom reporting highlight the presence of GBA-mediated effects in IBD. Treatments targeting gut-brain interactions including brain-gut behavioural treatments, neuromodulators, and dietary interventions appear to be useful adjunctive treatments in a subset of patients.

Psychological morbidity is prevalent in patients with IBD. The relationship between longitudinal disease activity outcomes, IBS-type symptom reporting, and poor psychological health is mediated via the GBA. Proactive management of psychological health should be integrated into routine care. Further clinical trials of GBA-targeted therapies, conducted in selected groups of patients with co-existent common mental disorders, or those who report IBS-type symptoms, are required to inform effective integrated models of care in the future.

Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.

A significant percentage of patients with an inflammatory bowel disease (IBD) encounter fatigue which can profoundly diminish patients' quality of life, particularly during periods of disease remission when gastrointestinal symptoms have receded. Various contributing risk factors have been identified including active inflammation, anemia, psychological, lifestyle and drug-related factors. While addressing these risk factors has been suggested as the initial approach to managing fatigue, a considerable number of patients still experience persisting symptoms, the primary causes of which remain incompletely understood. Recent insights suggest that dysfunction of the gut-brain axis may play a pathogenic role. This review provides an overview of established risk factors for fatigue, alongside emerging perspectives on the role of the gut-brain axis, and potential treatment strategies.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder. Oxidative stress and inflammatory responses have a vital role in the pathophysiology of IBD as well as seizure. IBD is associated with extraintestinal manifestations. This study aimed to explore the relationship between colitis and susceptibility to seizures, with a focus on the roles of neuroinflammation and oxidative stress in acetic acid-induced colitis in mice. Forty male Naval Medical Research Institute mice were divided into four groups: control, colitis, pentylenetetrazole (PTZ), and colitis + PTZ. Colitis was induced by intrarectal administration of acetic acid, and seizures were induced by intravenous injection of PTZ 7 days postcolitis induction. Following the measurement of latency to seizure, the mice were killed, and their colons and prefrontal cortex (PFC) were dissected. Gene expression of inflammatory markers including interleukin-1β, tumor necrosis factor-alpha, NOD-like receptor protein 3, and toll-like receptor 4, as well as total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels were measured in the colon and PFC. Histopathological evaluations were performed on the colon samples. Data were analyzed by t-test or one-way variance analysis. Colitis decreased latency to seizure, increased gene expression of inflammatory markers, and altered levels of MDA, nitrite, and TAC in both the colon and PFC. Simultaneous induction of colitis and seizure exacerbated the neuroimmune response and oxidative stress in the PFC and colon. Results concluded that neuroinflammation and oxidative stress in the PFC at least partially mediate the comorbid decrease in seizure latency in mice with colitis.

Postpartum depression and cognitive impairment are the common complications of prenatal obesity. Stevioside is a non-nutritive natural sweetener with antioxidant and anti-inflammatory. However, its effects on depression behaviors and cognitive impairment induced by a high-fat diet (HFD) remain unclear.

An 8-week HFD is used to establish a prenatal obesity model in female C57BL/6J mice to explore the improvement effects of stevioside (0.5 mg mL-1 in drinking water) on maternal depression and cognitive dysfunction after weaning. The results demonstrated that stevioside improves behavioral performance of obese maternal mice, and inhibits neuronal damage and 5-hydroxytryptamine (5-HT) abnormality induced by HFD. In addition, stevioside inhibits oxidative stress by reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) and glutathione (GSH) activities in the brains of obese maternal mice. Additionally, stevioside improves gut barrier integrity and prevented lipopolysaccharide (LPS) extravasation, and alleviates neuroinflammation. Correlation analysis shows that gut barrier and serum LPS are closely related to behavioral performance and brain biochemical indicators.

Stevioside is capable to prevent prenatal obesity-induced cognitive and mood disorders by restoring intestinal barrier damage and inhibiting inflammation.

Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well-established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP).

We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open-field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)-1β, tumor necrosis factor (TNF), and toll-like receptor 4 (TLR4) in the HIP, were measured.

The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL-1β, TLR4, and TNF, along with a reduction in nitrite levels following resocialization.

These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), often have concomitant mental disorders such as depression and anxiety. Therefore, a bidirectional approach involving the gut and brain axes is necessary for the prevention and treatment thereof. In this study, we explored the potential of Poncirus trifoliata extract (PT), traditionally known for its neuroprotective effects against gastrointestinal diseases, as a natural treatment agent for IBD in a dextran sulfate sodium (DSS)-induced colitis model. Oral administration of PT ameliorated weight loss and inflammatory responses in mice with DSS-induced colitis. Furthermore, PT treatment effectively restored the colon length and ameliorated enterocyte death by inhibiting DSS-induced reactive oxygen species (ROS)-mediated necroptosis. The main bioactive components of PT, poncirin and naringin, confirmed using ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-qTOF), can be utilized to regulate necroptosis. The antidepressant-like effects of PT were confirmed using open field test (OFT) and tail suspension test (TST). PT treatment also restored vascular endothelial cell integrity in the hippocampus. In the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) regions of the hippocampus, PT controlled the neuroinflammatory responses of proliferated microglia. In conclusion, PT, which contains high levels of poncirin and naringin, has potential as a bidirectional therapeutic agent that can simultaneously improve IBD-associated intestinal and mental disorders.

Autism spectrum disorder (ASD) is a neurodegenerative disease with increasing incidence in the world. The maternal separation (MS) stress at early life with its own neuroendocrine and neurostructural changes can provide the basis for development of ASD. Previously it has been reported neuroprotective characteristics for anethole. The PI3K/AKT/mTOR signaling pathway has pivotal role in the function of central nervous system (CNS). This study aimed to evaluate the possible effects of anethole on the autistic-like behaviors in the maternally separated (MS) mice focusing on the potential role of the PI3K/AKT/mTOR pathway. Forty male Naval Medical Research Institute (NMRI) mice were assigned to five groups (n = 8) comprising a control group (treated with normal saline) and four groups subjected to MS and treated with normal saline and or anethole at doses of 31.25, 62.5 and 125 mg/kg, respectively. All gents were administrated via intraperitoneal (i.p.) route for 14 constant days. Behavioral tests were conducted, including the three-chamber test, shuttle box and resident-intruder test. The gene expression of the PI3K, AKT and mTOR assessed in the hippocampus by qRT-PCR. Findings indicated that MS is associated with autistic-like behaviors. Anethole increased the sociability and social preference indexes in the three-chamber test, increased duration of secondary latency in the shuttle box test and decreased aggressive behaviors in the resident-intruder test. Also, anethole increased the gene expression of PI3K, AKT and mTOR in the hippocampus of MS mice. We concluded that anethole through increase in the gene expression of PI3K/ AKT/mTOR mitigated autistic-like behaviors induced by MS in mice.

The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Inflammatory cytokines and the kynurenine pathway (KP) play important roles in IBD and associated depression. Aripiprazole (ARP), an atypical antipsychotic, shows various anti-inflammatory properties and may be useful in treating major depressive disorder. This study aimed to evaluate the protective effects of ARP on TNBS-induced colitis and subsequent depression in rats, highlighting the role of the KP.

Fifty-six male Wistar rats were used, and all groups except for the normal and sham groups received a single dose of intra-rectal TNBS. Three different doses of ARP and dexamethasone were injected intraperitoneally for two weeks in treatment groups. On the 15th day, behavioral tests were performed to evaluate depressive-like behaviors. Colon ulcer index and histological changes were assessed. The tissue levels of inflammatory cytokines, KP markers, lipopolysaccharide (LPS), nuclear factor-kappa-B (NF-κB), and zonula occludens (ZO-1) were evaluated in the colon and hippocampus.

TNBS effectively induced intestinal damages and subsequent depressive-like symptoms in rats. TNBS treatment significantly elevated the intestinal content of inflammatory cytokines and NF-κB expression, dysregulated the KP markers balance in both colon and hippocampus tissues, and increased the serum levels of LPS. However, treatment with ARP for 14 days successfully reversed these alterations, particularly at higher doses.

ARP could alleviate IBD-induced colon damage and associated depressive-like behaviors mainly via suppressing inflammatory cytokines activity, serum LPS concentration, and affecting the NF-κB/kynurenine pathway.

With the proposal of the "biological-psychological-social" model, clinical decision-makers and researchers have paid more attention to the bidirectional interactive effects between psychological factors and diseases. The brain-gut-microbiota axis, as an important pathway for communication between the brain and the gut, plays an important role in the occurrence and development of inflammatory bowel disease. This article reviews the mechanism by which psychological disorders mediate inflammatory bowel disease by affecting the brain-gut-microbiota axis. Research progress on inflammatory bowel disease causing "comorbidities of mind and body" through the microbiota-gut-brain axis is also described. In addition, to meet the needs of individualized treatment, this article describes some nontraditional and easily overlooked treatment strategies that have led to new ideas for "psychosomatic treatment".

Ulcerative colitis (UC), an ongoing inflammatory disorder of the colon, is marked by persistent mucosal surface irritation extending from the rectum to the near-proximal colon. Tiron is a synthetic analogue of vitamin E which is known to have antioxidant and anti-inflammatory effects in various animal models, so the goal of this study was to find out whether Tiron had any preventive impacts on UC inflicted by acetic acid (A.A) exposure in rats.

Tiron (235 and 470 mg/kg) was administered intra-peritoneally for 2 weeks, and A.A (2 ml, 3 % v/v) was injected intra-rectally to cause colitis. Colon tissues and blood samples were then collected for measurement of various inflammatory and oxidative stress biomarkers.

Tiron administration significantly diminished lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon as compared to A.A-injected rats. Additionally, Tiron attenuated oxidative stress biomarkers. Tiron also enforced the levels of Glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3), while it greatly lowered the expression of nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interferon-γ (IFN-γ), and transforming growth factor-1(TGF-β1), phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic cellular structures. Furthermore, colonichistopathologic damages, revealed by hematoxylin and eosin (H&E) and Alcian Blue stain, were significantly decreased upon Tiron administration.

Tiron prevented A.A-induced colitis in rats via modulating inflammatory pathway TGF-β1/P-EGFR/PI3K/AKT/NF-κB, alongside managing the oxidant/antioxidant equilibrium, and boosting the reliability of the intestinal barrier.

Chronic restraint stress (CRS) is a widely used stimulus to induce anxiety- and depression-like behaviors, linked to alterations in tryptophan-kynurenine (TRP-KYN) metabolism in animals. This study assessed the effects of different CRS periods on anxiety- or depression-like behaviors and TRP-KYN metabolism along brain-gut axis in C57BL/6N mice. Results showed that one-week CRS decreased the open arm entries of mice in elevated plus maze and delayed latency of feeding in novelty suppressed feeding test. Four-week CRS reduced sucrose preference, increases forced swimming immobility time, and also induced anxiety-like behaviors of mice. UPLC-MS/MS analysis revealed decreased levels of the neurotoxic 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), and an increase in the neuroprotective kynurenic acid (KA) in the hippocampus of one-week CRS mice; meanwhile, four-week CRS mice displayed a reduction in KA and increases in 3-HK and QA. In the colon, both one-week and four-week CRS mice exhibited significant reductions in 3-HK and QA, with a marked increase of KA exclusively in four-week CRS mice. Briefly, one-week CRS only induced anxiety-like behaviors with hippocampal neuroprotection in TRP-KYN metabolism, whereas four-week CRS caused anxiety- and depression-like behaviors with neurotoxicity. In the colon, during both CRS periods, KYN was metabolized in the direction of NAD+ production. However, four-week CRS triggered intestinal inflammation risk with increased KA. Summarily, slightly short-term stress has beneficial effects on mice, while prolonged chronic stress can lead to pathological changes. This study offers valuable insights into stress-induced emotional disturbances.

Depression is a prevalent psychiatric disorder with high long-term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular and molecular mechanisms of depression remain largely unknown. What's more, about one third of patients do not have effective anti-depressant therapies, so there is an urgent need to uncover more mechanisms to guide the development of novel therapeutic strategies. Adenosine triphosphate (ATP) plays an important role in maintaining ion gradients essential for neuronal activities, as well as in the transport and release of neurotransmitters. Additionally, ATP could also participate in signaling pathways following the activation of postsynaptic receptors. By searching the website PubMed for articles about "ATP and depression" especially focusing on the role of extracellular ATP (eATP) in depression in the last 5 years, we found that numerous studies have implied that the insufficient ATP release from astrocytes could lead to depression and exogenous supply of eATP or endogenously stimulating the release of ATP from astrocytes could alleviate depression, highlighting the potential therapeutic role of eATP in alleviating depression.

Currently, there are few reviews discussing the relationship between eATP and depression. Therefore, the aim of our review is to conclude the role of eATP in depression, especially focusing on the evidence and mechanisms of eATP in alleviating depression.

We will provide insights into the prospects of leveraging eATP as a novel avenue for the treatment of depression.

Mitochondria are key cellular organelles whose main function is maintaining cell bioenergetics by producing ATP through oxidative phosphorylation. However, mitochondria are involved in a much higher number of cellular processes. Mitochondria are the home of key metabolic pathways like the tricarboxylic acid cycle and β-oxidation of fatty acids, as well as biosynthetic pathways of key products like nucleotides and amino acids, the control of the redox balance of the cell and detoxifying the cell from H2S and NH3. This plethora of critical functions within the cell is the reason mitochondrial function is involved in several complex disorders (apart from pure mitochondrial disorders), among them inflammatory bowel diseases (IBD). IBD are a group of chronic, inflammatory disorders of the gut, mainly composed of ulcerative colitis and Crohn's disease. In this review, we present the current knowledge regarding the impact of mitochondrial dysfunction in the context of IBD. The role of mitochondria in both intestinal mucosa and immune cell populations are discussed, as well as the role of mitochondrial function in mechanisms like mucosal repair, the microbiota- and brain-gut axes and the development of colitis-associated colorectal cancer.

Anxiety is common in patients with inflammatory bowel disease (IBD), including those with ulcerative colitis (UC) and Crohn's disease (CD); however, the causal relationship between IBD and anxiety remains unknown.

To investigate the causal relationship between IBD and anxiety by using bidirectional Mendelian randomization analysis.

Single nucleotide polymorphisms retrieved from genome-wide association studies (GWAS) of the European population were identified as genetic instrument variants. GWAS statistics for individuals with UC (6968 patients and 20464 controls; adults) and CD (5956 patients and 14927 controls; adults) were obtained from the International IBD Genetics Consortium. GWAS statistics for individuals with anxiety were obtained from the Psychiatric Genomics Consortium (2565 patients and 14745 controls; adults) and FinnGen project (20992 patients and 197800 controls; adults), respectively. Inverse-variance weighted was applied to assess the causal relationship, and the results were strengthened by heterogeneity, pleiotropy and leave-one-out analyses.

Genetic susceptibility to UC was associated with an increased risk of anxiety [odds ratio: 1.071 (95% confidence interval: 1.009-1.135), P = 0.023], while genetic susceptibility to CD was not associated with anxiety. Genetic susceptibility to anxiety was not associated with UC or CD. No heterogeneity or pleiotropy was observed, and the leave-one-out analysis excluded the potential influence of a particular variant.

This study revealed that genetic susceptibility to UC was significantly associated with anxiety and highlighted the importance of early screening for anxiety in patients with UC.

A growing body of evidence from neuroimaging studies suggests that inflammatory bowel disease (IBD) is associated with functional and structural alterations in the central nervous system and that it has a potential link to emotional symptoms, such as anxiety and depression. However, the neurochemical underpinnings of depression symptoms in IBD remain unclear. We hypothesized that changes in cortical gamma-aminobutyric acid (GABA+) and glutamine (Glx) concentrations are related to cortical thickness and resting-state functional connectivity in IBD as compared to healthy controls. To test this, we measured whole-brain cortical thickness and functional connectivity within the medial prefrontal cortex (mPFC), as well as the concentrations of neurotransmitters in the same brain region. We used the edited magnetic resonance spectroscopy (MRS) with the MEGA-PRESS sequence at a 3 T scanner to quantitate the neurotransmitter levels in the mPFC. Subjects with IBD (N = 37) and healthy control subjects (N = 32) were enrolled in the study. Compared with healthy controls, there were significantly decreased GABA+ and Glx concentrations in the mPFC of patients with IBD. The cortical thickness of patients with IBD was thin in two clusters that included the right medial orbitofrontal cortex and the right posterior cingulate cortex. A seed-based functional connectivity analysis indicated that there was higher connectivity of the mPFC with the left precuneus cortex (PC) and the posterior cingulate cortex, and conversely, lower connectivity in the left frontal pole was observed. The functional connectivity between the mPFC and the left PC was negatively correlated with the IBD questionnaire score (r = -0.388, p = 0.018). GABA+ concentrations had a negative correlation with the Hamilton Depression Scale (HAMD) score (r = -0.497, p = 0.002). Glx concentration was negatively correlated with the HAMD score (r = -0.496, p = 0.002) and positively correlated with the Short-Form McGill Pain Questionnaire score (r = 0.330, p = 0.046, uncorrected). There was a significant positive correlation between the ratio of Glx to GABA+ and the HAMD score (r = 0.428, p = 0.008). Mediation analysis revealed that GABA+ significantly mediated the main effect of the relationship between the structural and functional alterations and the severity of depression in patients with IBD. Our study provides initial evidence of neurochemistry that can be used to identify potential mechanisms underlying the modulatory effects of GABA+ on the development of depression in patients with IBD.

Depression is one of the common neurological comorbidities in patients with inflammatory bowel disease (IBD). The current study aimed to investigate the potential impact of niacin on colitis-induced depressive-like behavior in rats.

Animals were given 5 % dextran sulfate sodium (DSS) in drinking water for one week to induce colitis. Niacin (80 mg/kg), with or without mepenzolate bromide (GPR109A blocker), was administered once per day throughout the experimental period. Rats were tested for behavioral changes using open field and forced swimming tests.

Niacin significantly ameliorated DSS-induced behavioral deficits and alleviated macroscopic and microscopic colonic inflammatory changes. It also augmented the hippocampal levels of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the blood-brain barrier (BBB) integrity. Moreover, niacin decreased hippocampal IL-1ꞵ and NF-ĸB contents but increased GSH, Sirt-1, Nrf-2, HO-1 concentrations. All these beneficial effects were partially abolished by the co-administration of mepenzolate bromide.

The neuroprotective effect of niacin against DSS-induced depressive-like behavior was partially mediated through GPR109A-mediated mechanisms. Such mechanisms are also involved in modulating neuronal oxidative stress and inflammation via Sirt-1/Nrf-2/HO-1 signaling pathways.

One of the key features of major depressive disorder (MDD, depression) is increased oxidative stress manifested by elevated levels of mtROS, a hallmark of mitochondrial dysfunction, which can arise from mitochondrial DNA (mtDNA) damage. Thus, the current study explores possibility that the single-nucleotide polymorphisms (SNPs) of genes encoding the three enzymes that are thought to be implicated in the replication, repair or degradation of mtDNA, i.e., POLG, ENDOG and EXOG, have an impact on the occurrence, onset, severity and treatment of MDD. Five SNPs were selected: EXOG c.-188T > G (rs9838614), EXOG c.*627G > A (rs1065800), POLG c.-1370T > A (rs1054875), ENDOG c.-394T > C (rs2977998) and ENDOG c.-220C > T (rs2997922), while genotyping was performed on 538 DNA samples (277 cases and 261 controls) using TaqMan probes. All SNPs of EXOG and ENDOG modulated the risk of depression, but the strongest effect was observed for rs1065800, while rs9838614 and rs2977998 indicate that they might influence the severity of symptoms, and, to a lesser extent, treatment effectiveness. Although the SNP located in POLG did not affect occurrence of the disease, the result suggests that it may influence the onset and treatment outcome. These findings further support the hypothesis that mtDNA damage and impairment in its metabolism play a crucial role not only in the development, but also in the treatment of depression.

Scatter-hoarding animals store food in multiple locations within their home range and rely on spatial memory for subsequent localization and retrieval. The relationship between memory and scatter-hoarding behavior has been widely demonstrated, but the association of gut microbiota with spatial memory and seed-hoarding behavior of animals remains unclear.

In this study, by using enclosure behavior tests, memory tests including an object location test (OLT) and a novel object recognition test (NORT), and fecal microbiota transplantation (FMT) experiment, we evaluated the role of gut microbiota in affecting the memory and seed-hoarding behavior of rodents. According to their scatter-hoarding intensity, South China field mice (Apodemus draco) were divided into scatter-hoarding group (SG) and non-scatter-hoarding group (NG).

We found that the SG performed better than the NG in the NORT. FMT from SG donor mice altered the NG recipient mice's gut microbiota structure. Further tests demonstrated FMT from SG donor mice increased memory of NG recipient mice in laboratory tests and seed larder hoarding intensity of NG recipient mice in enclosures.

Our results suggest gut microbiota could modulate the memory and seed-hoarding behavior of animals.

In this study, the therapeutic effect of quinic acid (QA), which has anti-inflammatory activity, was investigated on acetic acid-induced colitis in male Wistar rats.

Ulcerative colitis (UC) was induced in rats by acetic acid intrarectally, and the protective effects of QA in 10, 30, 60, and 100 mg/kg doses were investigated. Rats were treated for 5 days and their colon tissues were dissected out at the end. Macroscopic and histopathological examinations were performed in colon tissues. Also, the expression of inflammatory and apoptotic genes, including TLR4, IL-1β, INOS, IL-6, TNF-α, NF-κB, Caspase-3, Caspase-8, Bax, and Bcl-2, was measured. Biochemistry indices, such as malondialdehyde (MDA) and nitrite oxide (NO) content, in addition to, total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), and enzymes activities were also assessed.

Colitis increased the levels of MDA and NO, and enhanced the inflammatory and apoptotic gene expressions, while reducing the SOD and CAT enzymes activity, and TAC levels in the colitis rats. Also, results showed that colitis was associated with the infiltration of inflammatory cells, epithelium damage, and edema in colon tissue. QA significantly ameliorated histopathological indices, oxidative stress, inflammation, and apoptosis in colitis rats.

QA ameliorated UC through the inhibition of two TLR4-NF-κB and NF-κB-INOS-NO signaling pathways, which results in the reduction of colitis complications, including oxidative stress, inflammation, apoptosis and histopathological injuries in rats. Therefore it can be concluded, that QA exerts its therapeutic effects through antiapoptotic, antioxidant, and anti-inflammatory properties.

While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce.

We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients.

In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally.

Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants' positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1-6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model.

Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms (p < 0.05). A higher percentage of variability in positive emotions was explained by pain (36%) and depressive symptoms (13%) than by epidemiological characteristics (0.3%), or characteristics of IBD and its treatment (2.4%). Patients with higher levels of positive emotions (score > 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p < 0.05).

The absence of pain and depressive symptoms were the strongest drivers for high positive affect. Higher scores of positive affect were associated with longer disease-free survival in IBD patients.

Inflammatory bowel disease (IBD) is a chronic condition with a high recurrence rate. To date, the clinical treatment of IBD mainly focuses on inflammation and gastrointestinal symptoms while ignoring the accompanying visceral pain, anxiety, depression, and other emotional symptoms. Evidence is accumulating that bi-directional communication between the gut and the brain is indispensable in the pathophysiology of IBD and its comorbidities. Increasing efforts have been focused on elucidating the central immune mechanisms in visceral hypersensitivity and depression following colitis. The triggering receptors expressed on myeloid cells-1/2 (TREM-1/2) are newly identified receptors that can be expressed on microglia. In particular, TREM-1 acts as an immune and inflammatory response amplifier, while TREM-2 may function as a molecule with a putative antagonist role to TREM-1. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we found that peripheral inflammation induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex (ACC). Microglial ablation mitigated visceral hypersensitivity in the inflammation phase rather than in the remission phase, subsequently preventing the emergence of depressive-like behaviors in the remission phase. Moreover, a further mechanistic study revealed that overexpression of TREM-1 and TREM-2 remarkably aggravated DSS-induced neuropathology. The improved outcome was achieved by modifying the balance of TREM-1 and TREM-2 via genetic and pharmacological means. Specifically, a deficiency of TREM-1 attenuated visceral hyperpathia in the inflammatory phase, and a TREM-2 deficiency improved depression-like symptoms in the remission phase. Taken together, our findings provide insights into mechanism-based therapy for inflammatory disorders and establish that microglial innate immune receptors TREM-1 and TREM-2 may represent a therapeutic target for the treatment of pain and psychological comorbidities associated with chronic inflammatory diseases by modulating neuroinflammatory responses.

Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.

Background and aims: Inflammatory bowel diseases (IBD) are chronic disorders associated with a reduced quality of life, and patients often also suffer from psychiatric comorbidities. Overall, both mood and cognitive disorders are prevalent in chronic organic diseases, especially in the case of a strong immune component, such as rheumatoid arthritis, multiple sclerosis, and cancer. Divergent data regarding the true incidence and prevalence of mental disorders in patients with IBD are available. We aimed to review the current evidence on the topic and the burden of mental illness in IBD patients, the role of the brain-gut axis in their co-existence, and its implication in an integrated clinical management. Methods: PubMed was searched to identify relevant studies investigating the gut-brain interactions and the incidence and prevalence of psychiatric disorders, especially of depression, anxiety, and cognitive dysfunction in the IBD population. Results: Among IBD patients, there is a high prevalence of psychiatric comorbidities, especially of anxiety and depression. Approximately 20-30% of IBD patients are affected by mood disorders and/or present with anxiety symptoms. Furthermore, it has been observed that the prevalence of mental illnesses increases in patients with active intestinal disease. Psychiatric comorbidities continue to be under-diagnosed in IBD patients and remain an unresolved issue in the management of these patients. Conclusions: Psychiatric illnesses co-occurring in IBD patients deserve acknowledgment from IBD specialists. These comorbidities highly impact the management of IBD patients and should be studied as an adjunctive therapeutic target.

Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines.

Male and female C57BL/6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1β, IL-1β; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA; and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice.

These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.

Early life stress (ELS) is defined as a period of severe and/or chronic trauma, as well as environmental/social deprivation or neglect in the prenatal/early postnatal stage. Presently, the impact of ELS on the retina in the adult stage is unknown. The long-term consequences of ELS at retinal level were analyzed in an animal model of maternal separation with early weaning (MSEW), which mimics early life maternal neglect. For this purpose, mice were separated from the dams for 2 h at postnatal days (PNDs) 4-6, for 3 h at PNDs 7-9, for 4 h at PNDs 10-12, for 6 h at PNDs 13-16, and weaned at PND17. At the end of each separation period, mothers were subjected to movement restriction for 10 min. Control pups were left undisturbed from PND0, and weaned at PND21. Electroretinograms, visual evoked potentials, vision-guided behavioral tests, retinal anterograde transport, and retinal histopathology were examined at PNDs 60-80. MSEW induced long-lasting functional and histological effects at retinal level, including decreased retinal ganglion cell function and alterations in vision-guided behaviors, likely associated to decreased synaptophysin content, retina-superior colliculus communication deficit, increased microglial phagocytic activity, and retinal ganglion cell loss through a corticoid-dependent mechanism. A treatment with mifepristone, injected every 3 days between PNDs 4 and16, prevented functional and structural alterations induced by MSEW. These results suggest that retinal alterations might be included among the childhood adversity-induced threats to life quality, and that an early intervention with mifepristone avoided ELS-induced retinal disturbances.

Due to the high side effects of commonly used drugs and according to the pharmacological properties reported for coumaric acid (CA), this study was designed to determine the impact of CA on acetic acid-induced colitis in rats, considering its possible anti-inflammatory, antioxidant, and anti-apoptotic properties.

Forty-eight male Wistar rats were divided into 6 equal groups (n = 8). Colitis was induced by acetic acid intrarectally. CA in three different doses (50, 100, and 150 mg/kg) was administrated for 5 days. Finally, the macroscopic and histopathological changes in the colon tissue were examined. The expression of inflammatory and apoptotic genes, including NF-κB, TNF-α, INOS, IL-1β, IL-6, TLR4, Caspase-3, Caspase-8, Bax, Bcl-2 was assessed. In addition, changes in the levels of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), nitrite, and total antioxidant capacity (TAC) were measured in the colon tissue.

Colitis led to a decrease in TAC and the activity levels of CAT and SOD and an increase in the expression of inflammatory and apoptotic genes, MDA, and nitrite levels in the colon. Colitis was also associated with edema and severe damage to the epithelium, infiltration of inflammatory cells, and the presence of ulcers and necrosis in the colon tissue. CA significantly improved the inflammation, oxidative stress, apoptosis, and histopathological indices caused by acetic acid-induced colitis on the colon.

It is concluded that CA probably exerts its positive effects in the management of colitis, through its anti-inflammatory, antioxidant, and anti-apoptotic properties.

Depression is a worldwide disease causing severe disability, morbidity, and mortality. Despite abundant studies, the precise mechanisms underlying the pathophysiology of depression remain elusive. Recently, cumulate research suggests that a disturbance of microbiota-gut-brain axis may play a vital role in the etiology of depression while correcting this disturbance could alleviate depression symptoms. The vagus nerve, linking brain and gut through its afferent and efferent branches, is a critical route in the bidirectional communication of this axis. Directly or indirectly, the vagus afferent fibers can sense and relay gut microbiota signals to the brain and induce brain disorders including depression. Also, brain changes in response to stress may result in gut hyperpermeability and inflammation mediating by the vagal efferents, which may be detrimental to depression. Notably, vagus nerve stimulation owns an anti-inflammatory effect and was proved for depression treatment. Nevertheless, depression was accompanied by a low vagal tone, which may derive from response to stress and contribute to pathogenesis of depression. In this review, we aim to explore the role of the vagus nerve in depression from the perspective of the microbiota-gut-brain axis, highlighting the relationship among the vagal tone, the gut hyperpermeability, inflammation, and depression.

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.