A common neuropsychiatric complication of advanced liver disease, hepatic encephalopathy (HE), impacts the quality of life and length of hospital stays. There is new evidence that gut microbiota plays a significant role in brain development and cerebral homeostasis. Microbiota metabolites are providing a new avenue of therapeutic options for several neurological-related disorders. For instance, the gut microbiota composition and blood-brain barrier (BBB) integrity are altered in HE in a variety of clinical and experimental studies. Furthermore, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have been shown to positively affect BBB integrity in disease models that are potentially extendable to HE by targeting gut microbiota. However, the mechanisms that underlie microbiota dysbiosis and its effects on the BBB are still unclear in HE. To this end, the aim of this review was to summarize the clinical and experimental evidence of gut dysbiosis and BBB disruption in HE and a possible mechanism.

Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.

Background: There are no data available on the levels of genetic networks between obsessive–compulsive disorder (OCD) and multiple sclerosis (MS). To this point, we aimed to investigate common mechanisms and pathways using bioinformatics approaches to find novel genes that may be involved in the pathogenesis of OCD in MS. Methods: To obtain gene–gene interactions for MS and OCD, the STRING database was used. Cytoscape was then used to reconstruct and visualize graphs. Then, ToppGene and Enrichr were used to identify the main pathological processes and pathways involved in MS-OCD novel genes. Additionally, to predict transcription factors and microRNAs (miRNAs), the Enrichr database and miRDB database were used, respectively. Results: Our bioinformatics analysis showed that the signal transducer and the activator of transcription 3 (STAT3) and neurotrophic receptor tyrosine kinase 2 (NTRK2) genes had connections with 32 shared genes between MS and OCD. Furthermore, STAT3 and NTRK2 had the greatest enrichment parameters (i.e., molecular function, cellular components, and signaling pathways) among ten hub genes. Conclusions: To summarize, data from our bioinformatics analysis showed that there was a significant overlap in the genetic components of MS and OCD. The findings from this study make two contributions to future studies. First, predicted mechanisms related to STAT3 and NTRK2 in the context of MS and OCD can be investigated for pharmacological interventions. Second, predicted miRNAs related to STAT3 and NTRK2 can be tested as biomarkers in MS with OCD comorbidity. However, our study involved bioinformatics research; therefore, considerable experimental work (e.g., postmortem studies, case–control studies, and cohort studies) will need to be conducted to determine the etiology of OCD in MS from a mechanistic view.

Background: Monkeypox (MPOX) is a zoonotic disease caused by the MPOX virus (MPXV). MPOX resurfaced globally in May 2022, spreading throughout six WHO regions, resulting in nearly 87,000 cases and 112 deaths. Clinical symptoms include swollen lymph nodes, fever, joint pain and several neurological complications such as headache, encephalitis, myalgia, fatigue, photophobia and seizures. Despite these manifestations, the precise mechanisms of MPXV’s neurotropism remain elusive. This study aimed to explore the genetic underpinnings of MPOX-related neurological manifestations, including headache, myalgia, fatigue, and photophobia, using advanced bioinformatics tools.Methods: Data were sourced from the GeneCards database, which is an integrated database of human genes. Genes linked to MPOX and its neurological manifestations were identified and cross-referenced to uncover shared genes between these conditions. Network visualization was created using STRING, followed by topological analysis in Cytoscape to identify key genes based on degree and betweenness centrality. Functional enrichment analysis through ToppGene provided insights into molecular functions, biological processes, and cellular components associated with these target genes. Pathway analysis was performed using WikiPathways, and cell-type-specific enrichment was conducted using Enrichr. Additionally, we predicted functional microRNAs using mirTarbase and identified potential drug candidates via the Stitch database. Results: We identified 32 MPOX-associated genes and a large set of neurological manifestation-related genes. Ten hub genes, including CD55, CXCL1, NFKB1, CXCL8, CD4, IL6, MX1, CFH, KLRK1, and CD46 were shared between MPOX and its neurological manifestations. Five novel genes, including CFHR3, C5AR1, C3AR1, IFNA2, and CXCL3 were predicted to be associated with MPOX and its neurological complications. Gene ontology analysis highlighted biological processes such as immune regulation, viral life cycle, and lymphocyte activation, while pathway enrichment identified critical signaling mechanisms like prostaglandin signaling, toll-like receptor 4 (TLR4) signaling, complement activation, and neuroinflammation. Moreover, cell types such as T-helper cells, natural killer cells, and microglia were found to be significantly impacted by MPOX and its frequent neurological complications. We identified 11 key microRNAs associated with MPOX-neurological manifestations and repurposed eight potential drugs, offering promising therapeutic strategies. Conclusion: This study emphasizes the central role of the complement system, immunological responses, and inflammatory pathways in the neurological manifestations of MPOX. The identification of novel genes and predicted therapeutic targets paves the way for future research and therapeutic interventions. Experimental validation is required to confirm these findings and determine the effectiveness of the proposed treatments.

Purpose: Hepatic encephalopathy (HE), one of the more important cerebral complications attributable to acute liver failure and more severe forms, has traditionally been associated with hyperammonemia. However, recent studies implicate gut microbiota-derived metabolites in HE pathogenesis through systemic inflammation and neurotoxicity. Despite this, the integrated molecular mechanisms linking these metabolites to HE remains poorly described. This study addresses this gap by employing a bioinformatics-based systems biology approach to identify interactions between gut metabolites and host genes, thereby identifying novel diagnostic and therapeutic targets. Methods: Differentially expressed genes (DEGs) from peripheral (GSE184200: CD4⁺ T lymphocytes) and central (GSE57193: fusiform gyrus) tissues of HE patients were analyzed using GEO2R. Genes associated with five gut microbiota-derived metabolites including choline metabolites, lipid metabolites, short-chain fatty acids, tryptophan catabolites, and secondary bile acids were extracted from GeneCards. Overlapping genes between HE-related genes and gut-derived metabolites were then subjected to multi-level enrichment analyses (pathway, phenotype, cell type, and cellular component), and miRNA/drug prediction using Enrichr and ToppGene. Results: We identified nine hub genes related to gut-systemic interactions and 29 hub genes associated with gut-brain interactions in the context of HE. The most significantly impaired pathways were signaling by interleukin 24 and TP53, as well as oxidative stress, which were affected by gut metabolites and peripheral HE-related genes. Similarly, mitochondrial fatty acid β-oxidation, neuroinflammation, and glutamate tone were significantly altered by gut metabolites and central HE-related genes. Additionally, we predicted 18 miRNAs and 13 potential drugs that target both gut microbiota metabolites and HE. Conclusion: This study offers the first systems-level framework connecting gut-derived metabolites to HE through gene networks, challenging the ammonia-centric viewpoint. The predicted miRNAs and drugs offer translational potential for precision medicine in HE. Experimental validation of these targets is required to advance therapeutic strategies.