While the global burden of inflammatory bowel diseases (IBD) is increasing, the identification of novel therapeutic targets and biomarkers is of significant importance. In particular, blood transcriptomes provide a non-invasive source for biomarker discovery. Therefore, this study aimed to identify potential blood markers for IBD.

By employing an integrated transcriptomics approach, four datasets obtained from blood specimens of patients with IBD were analyzed (GSE119600, GSE94648, GSE86434, and GSE71730). After determining differentially expressed genes (DEGs) in IBD, a protein-protein interaction (PPI) network was constructed, and regulatory miRNAs targeting hub genes were identified. Weighted gene co-expression network analysis (WGCNA) was carried out to determine IBD-specific modules. Subsequently, converging results from differential expression analysis and WGCNA were subjected to random forest (RF) decision tree-based and LASSO regression methods. Lastly, the diagnostic efficacy of genes highlighted by both machine learning methods was measured using receiver operating characteristic (ROC) analysis in the integrated dataset, in each individual dataset separately, and in external datasets (GSE276395, GSE169568, GSE112057, GSE100833, GSE33943, and GSE3365).

Downregulated TNF was identified as the central hub gene of the PPI network, and PRF1 was the only gene identified as a hub gene in a co-expressed gene module enriched in IBD. Following the identification of FEZ1 and NLRC5 among the top 10 genes by both RF and LASSO, ROC analysis demonstrated their acceptable diagnostic efficacy in the integrated data. However, only FEZ1 was considered a potential biomarker based on replication of the results in the external datasets.

The results of the present study suggest FEZ1 as a potential blood biomarker for IBD. While autophagy is currently the most convincing explanation for the involvement of FEZ1 in IBD, further investigations are required to elucidate its immunological role.

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.

Observational studies have shown a link between autoimmune diseases and schizophrenia, with conflicting conclusions. Due to the existence of confounding factors, the causal link between autoimmune diseases and schizophrenia is still unknown.

We conducted a comprehensive Mendelian randomization (MR) analysis of schizophrenia and ten common autoimmune diseases in individuals of European descent using genome-wide association studies (GWASs). To evaluate the relationships between autoimmune diseases and schizophrenia, inverse variance weighted, MR-RAPS, Bayesian weighted MR, constrained maximum likelihood, debiased IVW, MR-Egger, and weighted median were utilized. Several sensitivity analyses were performed to ensure the reliability of the study's results.

Our findings reveal that genetically predicted ankylosing spondylitis is related to an increased risk of schizophrenia, whereas celiac disease, type 1 diabetes, and systemic lupus erythematosus are associated with a lower risk of schizophrenia. In the reverse MR analysis, our study indicated that genetically predicted schizophrenia is linked to higher risks of ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and psoriasis. Neither multiple sclerosis nor rheumatoid arthritis have been linked to schizophrenia, and vice versa.

Despite contradicting some other observational reports, this study showed support for a causal link between autoimmune diseases and schizophrenia. To gain a better understanding of the mechanisms underlying the development of immune-mediated schizophrenia, additional research is required to identify potential mechanisms identified in observational studies.

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.

The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear.

Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms.

The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes.

These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.

The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear.

By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders.

SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07–1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06–1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04–1.18, p = 1.84 × 10−3).

We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

Previous observational studies have suggested an association between tryptophan (TRP)-kynurenine (KYN) pathway and inflammatory bowel disease (IBD). However, whether there is a causal relationship among them remains unclear. Therefore, a two-sample Mendelian randomization (MR) study was conducted to explore the potential causal effects of crucial metabolites in TRP-KYN pathway on IBD and its subtypes. Using summary data from genome-wide association studies, a two-sample MR was employed to evaluate the genetic associations between TRP and KYN as exposures and IBD as an outcome. The inverse variance weighted method was used as the primary MR analysis, with MR-Egger, weighted mode, simple mode, and weighted median methods as complementary analyses. The odds ratios (OR) and 95% confidence intervals (CI) were determined for TRP-IBD (OR 0.739, 95% CI [0.697; 0.783]), TRP-UC (OR 0.875, 95% CI [0.814; 0.942]), TRP-CD (OR 0.685, 95% CI [0.613; 0.765]), KYN-IBD (OR 4.406, 95% CI [2.247; 8.641]), KYN-UC (OR 2.578, 95% CI [1.368; 4.858], and KYN-CD (OR 13.516, 95% CI [4.919; 37.134]). Collectively, the MR analysis demonstrated a significant protective association between TRP and IBD, whereas KYN was identified as a risk factor for IBD.

Comorbidities associated with psychiatric disorders often occur in patients with cancer. A causal effect of schizophrenia on cancer was observed using Mendelian randomization (MR) analysis. However, the causal effect of colorectal cancer on schizophrenia has not been studied using MR analysis. Therefore, we performed MR analysis to investigate the causal effects of colorectal cancer on schizophrenia. We performed "two-sample summary-data Mendelian randomization" using publicly available genome-wide association studies data to investigate the causal relationship between colorectal cancer (as exposure) and schizophrenia (as outcome). The inverse variance weighted method was used to calculate causal estimates. In 2 TSMR analyses, we reported that the odds ratios for schizophrenia per log odds increase in colorectal cancer risk were 6.48 (95% confidential interval [CI] of OR 1.75-24.03; P = .005) and 9.62 × 106 (95% CI of OR 1.13-8.22 × 1013; P = .048). Pleiotropic tests and sensitivity analysis demonstrated minimal horizontal pleiotropy and robustness of the causal relationship. We provide evidence for a causal relationship between the incidence of colorectal cancer and the development of schizophrenia through TSMR analysis.

Co-occurrence of diseases decreases patient quality of life, complicates treatment choices, and increases mortality. Analyses of electronic health records present a complex scenario of comorbidity relationships that vary by age, sex, and cohort under study. The study of similarities between diseases using 'omics data, such as genes altered in diseases, gene expression, proteome, and microbiome, are fundamental to uncovering the origin of, and potential treatment for, comorbidities. Recent studies have produced a first generation of genetic interpretations for as much as 46% of the comorbidities described in large cohorts. Integrating different sources of molecular information and using artificial intelligence (AI) methods are promising approaches for the study of comorbidities. They may help to improve the treatment of comorbidities, including the potential repositioning of drugs.

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.

Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, the degree to which the shared genetic determinants are involved in these associations underlying the GBA is unclear.

To investigate the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways.

This genome-wide pleiotropic association study using genome-wide association summary statistics from publicly available data sources was performed with various statistical genetic approaches to sequentially investigate the pleiotropic associations from genome-wide single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]), and gene levels and biological pathways to disentangle the underlying shared genetic etiology between 4 gastrointestinal tract diseases (inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and gastroesophageal reflux disease) and 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and anorexia nervosa). Data were collected from March 10, 2021, to August 25, 2021, and analysis was performed from January 8 through May 30, 2022.

The primary outcomes consisted of a list of genetic loci, genes, and pathways shared between gastrointestinal tract diseases and psychiatric disorders.

Extensive genetic correlations and genetic overlaps were found among 22 of 24 trait pairs. Pleiotropic analysis under a composite null hypothesis identified 2910 significant potential pleiotropic SNVs in 19 trait pairs, with 83 pleiotropic loci and 24 colocalized loci detected. Gene-based analysis found 158 unique candidate pleiotropic genes, which were highly enriched in certain GBA-related phenotypes and tissues, whereas pathway enrichment analysis further highlighted biological pathways primarily involving cell adhesion, synaptic structure and function, and immune cell differentiation. Several identified pleiotropic loci also shared causal variants with gut microbiomes. Mendelian randomization analysis further illustrated vertical pleiotropy across 8 pairwise traits. Notably, many pleiotropic loci were identified for multiple pairwise traits, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2 (NCAM1), and 1p32.3 (LRP8).

These findings suggest that the pleiotropic genetic determinants between gastrointestinal tract diseases and psychiatric disorders are extensively distributed across the genome. These findings not only support the shared genetic basis underlying the GBA but also have important implications for intervention and treatment targets of these diseases simultaneously.

Schizophrenia is a severe mental illness which can have a devastating impact on an individual's quality of life. Comorbidities are high amongst patients and life expectancy is approximately 15 years less than the general population. Despite the well-known increased mortality, little is known about the impact of gastrointestinal and liver disease on patients with schizophrenia. We aimed to review the literature and to make recommendations regarding future care. Literature searches were performed on PubMed to identify studies related to gastrointestinal and liver disease in patients with schizophrenia. High rates of chronic liver disease were reported, with Non-Alcoholic Fatty Liver Disease being of particular concern; antipsychotics and metabolic syndrome were contributing factors. Rates of acute liver failure were low but have been associated with antipsychotic use and paracetamol overdose. Coeliac disease has historically been linked to schizophrenia; however, recent research suggests that a causal link is yet to be proven. Evidence is emerging regarding the relationships between schizophrenia and peptic ulcer disease, inflammatory bowel disease and irritable bowel syndrome; clinical vigilance regarding these conditions should be high. Patients with schizophrenia poorly engage with bowel cancer screening programmes, leading to late diagnosis and increased mortality. Clozapine induced constipation is a significant issue for many patients and requires close monitoring. There is a significant burden of gastrointestinal and liver disease amongst patients with schizophrenia. Better levels of support from all members of the medical team are essential to ensure that appropriate, timely care is provided.