Short-term dietary changes can result in mucosal and systemic immune depression.

Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4+ T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.

Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis.

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.

Immune-Microbiota Interplay and Colonization Resistance in Infection.

Commensal microbial communities inhabit biological niches in the mammalian host, where they impact the host's physiology through induction of "colonization resistance" against infections by a multitude of molecular mechanisms. These colonization-regulating activities involve microbe-microbe and microbe-host interactions, which induce, through utilization of complex bacterial networks, competition over nutrients, inhibition by antimicrobial peptides, stimulation of the host immune system, and promotion of mucus and intestinal epithelial barrier integrity. Distinct virulent pathogens overcome this colonization resistance and host immunity as part of a hostile takeover of the host niche, leading to clinically overt infection. The following review provides a mechanistic overview of the role of commensal microbes in modulating colonization resistance and pathogenic infections and means by which infectious agents may overcome such inhibition. Last, we outline evidence, unknowns, and challenges in developing strategies to harness this knowledge to treat infections by microbiota transfer, phage therapy, or supplementation by rationally defined bacterial consortia.

The microbiome and cytosolic innate immune receptors.

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)-like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: Experience from the European Liver Transplant Registry.

Knowledge of living donor liver transplantation (LDLT) for autoimmune liver diseases (AILDs) is scarce. This study analyzed survival in LDLT recipients registered in the European Liver Transplant Registry with autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC) and the non-autoimmune disorder alcohol-related cirrhosis. In total, 29 902 individuals enrolled between 1998 and 2017 were analyzed, including 1003 with LDLT. Survival from >90 days after LDLT for AILDs in adults was 85.5%, 74.2%, and 58.0% after 5, 10, and 15 years. Adjusted for recipient age, sex, and liver transplantation era, adult PSC patients receiving LDLT showed increased mortality compared to donation after brain death (DBD) (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.36-2.80, p < .001). Pediatric PSC patients showed also increased mortality >90 days after LDLT compared to DBD (HR = 3.00, 95% CI 1.04-8.70, p = .043). Multivariate analysis identified several risk factors for death in adult PSC patients receiving LDLT including a male donor (HR = 2.49, p = .025). Adult PSC patients with LDLT versus DBD conferred increased mortality from disease recurrence (subdistribution hazard ratio [subHR] = 5.36, p = .001) and biliary complications (subHR = 4.40, p = .006) in multivariate analysis. While long-term outcome following LDLT for AILD is generally favorable, PSC patients with LDLT compared to DBD might be at increased risk of death.

Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). METHODS: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. RESULTS: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. CONCLUSIONS: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.

SEAweb: the small RNA Expression Atlas web application.

We present the Small RNA Expression Atlas (SEAweb), a web application that allows for the interactive querying, visualization and analysis of known and novel small RNAs across 10 organisms. It contains sRNA and pathogen expression information for over 4200 published samples with standardized search terms and ontologies. In addition, SEAweb allows for the interactive visualization and re-analysis of 879 differential expression and 514 classification comparisons. SEAweb's user model enables sRNA researchers to compare and re-analyze user-specific and published datasets, highlighting common and distinct sRNA expression patterns. We provide evidence for SEAweb's fidelity by (i) generating a set of 591 tissue specific miRNAs across 29 tissues, (ii) finding known and novel bacterial and viral infections across diseases and (iii) determining a Parkinson's disease-specific blood biomarker signature using novel data. We believe that SEAweb's simple semantic search interface, the flexible interactive reports and the user model with rich analysis capabilities will enable researchers to better understand the potential function and diagnostic value of sRNAs or pathogens across tissues, diseases and organisms.

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis.

BACKGROUND & AIMS: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver. METHODS: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs. RESULTS: We identified a population of intrahepatic naive-like CD4+ T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (TH17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards TH17 cells. CONCLUSION: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4+ T cells in PSC harbour the propensity to develop into TH17 cells. LAY SUMMARY: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4+ T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.

Alterations of the bile microbiome in primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC. METHODS: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20). RESULTS: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10-5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021). CONCLUSION: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.

Harnessing the microbiota for therapeutic purposes.

The myriads of microorganisms colonizing the human host (microbiome) affect virtually every aspect of its physiology in health and disease. The past decade witnessed unprecedented advances in microbiome research. The field rapidly transitioned from descriptive studies to deep mechanistic insights into host-microbiome interactions. This offers the opportunity for microbiome-targeted therapeutic manipulation. Currently, several strategies of microbiome-targeted interventions are intensively explored. Best evidence from human randomized clinical trials is available for fecal microbiota transplantation (FMT). However, patient eligibility as well as long-term efficacy and safety are not sufficiently defined. Therefore, there is currently no officially approved indication for FMT. Probiotics (live microorganisms) have long been discussed as a means to aid human health but have yielded varying results. Emerging techniques utilizing microbiota-targeted diets, small microbial molecules, recombinant bacteriophages, and precise control of strain abundance recently yielded promising results but require further investigation. The rapid technological progress of "omics" tools spurs advances in personalized medicine. Understanding and integration of interindividual microbiome variability holds potential to promote personalized preventive and therapeutic approaches. Emerging evidence points towards the microbiome as an important player having an impact on transplantation outcomes. Microbiome-targeted interventions have potential to aid against the many challenges faced by transplant recipients.

Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury.

AIMS: Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical courses of DILI cases due to metamizole at our tertiary care centre in Hamburg, Germany. METHODS: Consecutive patients with DILI who presented to our clinic were analysed retrospectively. Causes of acute hepatitis other than DILI were excluded. RESULTS: In total, 154 DILI cases were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was the second most frequent putative agent causing DILI (23 of all 154 DILI cases, 14,9%). The biochemical pattern on admission of metamizole-induced DILI cases was hepatocellular with median levels of alanine transaminase (779 U/L, 64-3532 U/L) by far exceeding median alkaline phosphatase levels (131 U/L, 42-578 U/L). In 17 of the 23 cases (74%) liver biopsy was performed. Moderate to severe inflammatory histological activity and severe centrilobular necrosis (>30%) was present in 76.5 and 35.3%, respectively. Metamizole was involved in 2 DILI cases progressing to acute liver failure, then receiving liver transplantation and still alive at time of assessment. Our data were supported by re-exposure in 4 patients. Furthermore, a database search for metamizole-induced liver injury in the European Medicines Agency's database identified about 300 reports on suspected metamizole-induced DILI in Europe. CONCLUSION: Elevation of liver enzymes or acute liver failure are not mentioned in the German drug label of metamizole as potential side effects. Our study reveals that in Germany and Europe, metamizole is a frequent and underrated agent causing DILI.

DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation.

BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.

[Evaluation of Treatment of Mothers at the Family Day Hospital in Münster, Germany]. / Evaluation einer tagesklinischen Mutter-Kind-Behandlung für belastete Mütter psychisch kranker Kinder.

Evaluation of Treatment of Mothers at the Family Day Hospital in Münster, Germany. Mothers of preschool children have limited access to mental health treatment services. The Family Day Hospital for Preschool Children at the University Hospital Münster, Germany, offers therefore a specialized treatment for mothers with their preschool children. The therapy outcome of mothers is evaluated in effectiveness study by a pre-post-design. For mothers, therapy was composed of individual session and couple sessions with the partner, video-based parent-child-interaction therapy, and parent group sessions. We evaluated the psychiatric symptom burden of N = 103 mothers at admission and discharge with the Symptom Checklist-90-Revised (SCL-90-R) above the clinical cut-off ≥ 0.57. After treatment the mothers showed significant improvement on the global severity index (GSI) with an average Cohen's d = 1.64 (p0.001). We identified the following positively associated moderator variables of maternal improvement by a multiple regression analysis: the initial symptom burden, the educational level of the mother, not restricted housing conditions, and the age of the child. We conclude that especially distressed parents benefit from the treatment in the Family Day Hospital for Preschool Children.

Listening to music during intranasal (es)ketamine therapy in patients with treatment-resistant depression correlates with better tolerability and reduced anxiety.

Background: Although the effectiveness of (es)ketamine for therapy-resistant depression (TRD) has been established, potential treatment-limiting factors include side effects like dissociation, anxiety, or elevated blood pressure. Music can reduce stress and negative emotions as anxiety. This study aimed to investigate the impact of listening to music during intranasal (es)ketamine administration on both tolerability and efficacy. Methods: Records of 494 sessions (of 37 patients) with intranasal (es)ketamine administration, each containing data of blood pressure measurements, DSS-IV (dissociation symptoms scale-IV), anxiety and euphoria analogue scale, MADRS (Montgomery-Åsberg Depression Rating Scale) and BDI (Beck's Depression Inventory) were evaluated. Results: The between-group analysis, comparing participants who listened to music with those who did not, revealed significant differences in the administered dose (p-value: 0.003, mean: 131.5 mg with music vs. 116.7 mg without music), scores on the DSS Item 1 (p-value: 0.005, mean: 3 points vs. 2.4 points), levels of anxiety (p-value: <0.001, mean: 0.4 points vs. 1.4 points), and measurements of maximal systolic blood pressure after administration (p-value: 0.017, mean: 137.9 mmHg vs. 140.3 mmHg). Listening to music had no impact on the MARDS-change score between the sessions. Limitations: Key limitations include a non-randomized naturalistic design and the non-standardized selection of music, which was based on individual patient preferences. Conclusion: Listening to music during intranasal (es)ketamine therapy appears to be linked to reduced anxiety and lower blood pressure, stable or increased dissociation levels, and improved tolerance for higher doses. These findings could potentially contribute to the optimization of (es)ketamine therapy, both in terms of treatment efficacy and managing side effects.

Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

RATIONALE: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. OBJECTIVES: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. METHODS: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. RESULTS: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (ß = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (ß = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. CONCLUSIONS: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.

Sustainability initiatives in inpatient psychiatry: tackling food waste.

Background: Food plays a dual role in promoting human health and environmental sustainability. Yet, current food systems jeopardize both. Food waste poses a major global challenge due to its significant economic, social, and environmental impacts. Healthcare facilities generate the largest amounts of food waste compared to other forms of catering provision. Food waste correlates with environmental unsustainability and diminished patient satisfaction, compounding the prevalent challenge of hospital malnutrition and contributing to suboptimal patient outcomes. Materials and methods: In a three-year interventional study (2020-2022) at a psychiatric tertiary care center, we assessed and mitigated food waste using evidence-based measures. We conducted systematic food wastage audits over three years (2020-2022) in May and June, each lasting four weeks. Costs were analyzed comprehensively, covering food, staff, infrastructure, and disposal. Environmental impact was assessed using Umweltbelastungspunkte (UBP) and CO2e/kg emissions, alongside water usage (H2O - l/kg). Results: Economic losses due to food wastage were substantial, primarily from untouched plates and partially consumed dinners, prompting meal planning adjustments. Despite a >3% increase in meals served, both food waste mass and costs decreased by nearly 6%. Environmental impact indicators showed a reduction >20%. Vegetables, salad, and fruits constituted a significant portion of waste. Overproduction minimally contributed to waste, validating portion control efficacy. Conclusion: Our study highlights significant economic and environmental losses due to hospital food waste, emphasizing the importance of resource efficiency. The strategies outlined offer promising avenues for enhanced efficiency. The decrease in food waste observed over the three-year period underscores the potential for improvement.

Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review.

Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of suicide frequently coincides with depressive episodes. Suicide is as a paramount global health concern that demands efficacious preventive strategies. Current psychiatric approaches heavily rely on pharmacological interventions but have had limited success in addressing the global burden of mental health issues. Suboptimal nutrition, with its impact on the neuroendocrine system, has been implicated in the underlying pathology of depressive disorders. Folate, a group of water-soluble compounds, plays a crucial role in various central nervous system functions. Depressed individuals often exhibit low levels of serum and red blood cell folate. Multiple studies and systematic reviews have investigated the efficacy of folic acid and its derivative, L-methylfolate, which can cross the blood-brain barrier, as stand-alone or adjunct therapies for depression. Although findings have been mixed, the available evidence generally supports the use of these compounds in depressed individuals. Recent studies have established links between the one-carbon cycle, folate-homocysteine balance, immune system function, glutamate excitation via NMDA (N-methyl-D-aspartate) receptors, and gut microbiome eubiosis in mood regulation. These findings provide insights into the complex neurobiological mechanisms underlying the effects of folate and related compounds in depression. Through a comprehensive review of the existing literature, this study aims to advance our understanding of the therapeutic potential of folic acid and related compounds in depression treatment. It also seeks to explore their role in addressing suicidal tendencies and shed light on the neurobiological mechanisms involved, leveraging the latest discoveries in depression research.

Exploring the Therapeutic Potential of Gamma-Aminobutyric Acid in Stress and Depressive Disorders through the Gut-Brain Axis.

Research conducted on individuals with depression reveals that major depressive disorders (MDDs) coincide with diminished levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain, as well as modifications in the subunit composition of the primary receptors (GABAA receptors) responsible for mediating GABAergic inhibition. Furthermore, there is substantial evidence supporting the significant role of GABA in regulating stress within the brain, which is a pivotal vulnerability factor in mood disorders. GABA is readily available and approved as a food supplement in many countries. Although there is substantial evidence indicating that orally ingested GABA may affect GABA receptors in peripheral tissues, there is comparatively less evidence supporting its direct action within the brain. Emerging evidence highlights that oral GABA intake may exert beneficial effects on the brain and psyche through the gut-brain axis. While GABA enjoys wide consumer acceptance in Eastern Asian markets, with many consumers reporting favorable effects on stress regulation, mood, and sleep, rigorous independent research is still largely lacking. Basic research, coupled with initial clinical findings, makes GABA an intriguing neuro-nutritional compound deserving of clinical studies in individuals with depression and other psychological problems.

TET2 and TET3 loss disrupts small intestine differentiation and homeostasis.

TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts.