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.

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.

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.

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.

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.

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.

A prospective pilot study of a gluten-free diet for primary sclerosing cholangitis and associated colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC-IBD). AIM: To investigate whether patients with PSC-IBD benefit from a gluten-free and amylase trypsin inhibitor (ATI)-free diet (GFD). METHODS: We performed a prospective clinical pilot study administering an eight-week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis. RESULTS: Fifteen patients with PSC-IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro-inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down-regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin-2 and -4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well-being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly. CONCLUSIONS: This study did not demonstrate a clinical improvement with short-term GFD in patients with PSC-IBD. However, a gluten/ATI-free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated changes in the enteric microbiota. Further investigation of the therapeutic potential of the GFD in PSC-IBD is warranted.

The intestinal and biliary microbiome in autoimmune liver disease-current evidence and concepts.

Autoimmune liver diseases are a group of immune-mediated liver diseases with three distinct entities, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. The interplay of genetic and environmental factors leads to the breakdown of self-tolerance, resulting in hyper-responsiveness, and auto-aggressive immune activation. Emerging evidence links autoimmune liver diseases with alterations of the commensal microbiome configuration and aberrant immune system activation by microbial signals, mainly via the gut-liver axis. Thus, the microbiome is a new frontier to deepen the pathogenetic understanding, uncover biomarkers, and inspire innovative treatments. Herein, we review the current evidence on the role of the microbiome in autoimmune liver diseases from both clinical and basic research. We highlight recent achievements and also bottlenecks and limitations. Moreover, we give an outlook on future developments and potential for clinical applications.

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.

Who is afraid of Christmas? The effect of Christmas and Easter holidays on psychiatric hospitalizations and emergencies-Systematic review and single center experience from 2012 to 2021.

Background: Major holidays such as Christmas and New Year's Eve are regular occasions for get-togethers in families and other social groups. Socially, these days are often loaded with memories and expectations but also involve the potential for interpersonal tension and conflicts and disappointments. In addition, loneliness might also be most intense during these days. All these factors might lead to the expectation of increased mental distress and subsequently increased help-seeking in psychiatric contexts resulting in emergency psychiatric contacts, psychiatric hospitalizations, and even suicidal behavior. But is there evidence for increased psychiatric emergencies and hospitalizations around the days of Christmas? Methods: The existing evidence is systematically reviewed here (studies in PubMed in English investigating annual and Christmas-related variations in suicide (attempts), psychiatric emergencies and hospitalizations, last search date (13.07.2022) and complemented by an analysis of acute admissions at the University Psychiatry Clinics Basel, Switzerland, around Christmas and Easter holidays compared to the other days of the year. Easter was chosen as a comparison holiday. Results: In 25 reviewed studies, Christmas holidays were not associated with increased utilization of emergency psychiatric services. In contrast, hospitalizations were lower on Christmas and other holidays than the rest of the year. Analyzing the annual variation of 26,088 hospitalizations in our center between 2012 and 2021 revealed the same pattern. Conclusion: The assumption of increased utilization of psychiatric emergency services on Christmas and other major holidays is not confirmed by multiple studies around the globe in various socio-cultural and medical settings. The study is registered in the international prospective register for systematic reviews (PROSPERO; 351057). Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier 351057.

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.

Breakthroughs and Bottlenecks in Microbiome Research.

Over the past 15 years, the research community has witnessed unprecedented progress in microbiome research. We review this increasing knowledge and first attempts of its clinical application, and also limitations and challenges faced by the research community, in mechanistically understanding host-microbiome interactions and integrating these insights into clinical practice.

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.

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.

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.

Inflammasome activation and regulation: toward a better understanding of complex mechanisms.

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1ß and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.

Interaction between microbiota and immunity in health and disease.

The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.

A disease-specific decline of the relative abundance of Bifidobacterium in patients with autoimmune hepatitis.

BACKGROUND: The pathogenesis of autoimmune hepatitis (AIH) is poorly understood and little is known about enteric microbiota in AIH. AIM: To investigate disease-specific microbiome alterations in AIH. METHODS: The V1-V2 variable regions of the 16S rRNA gene were sequenced in faecal samples from 347 patients with AIH and controls (AIH n = 72, healthy controls (HC) n = 95, primary biliary cholangitis (PBC) n = 99 and ulcerative colitis (UC) n = 81). RESULTS: Biodiversity (Shannon entropy) was decreased in AIH patients compared to HC (P = 0.016), which was partially reversed by azathioprine (P = 0.011). Regarding between-sample diversity, AIH patients separated from HC, PBC and UC individuals (all P = 0.001). Compared to HC, decreased relative abundance of anaerobic genera such as Faecalibacterium and an increase of Veillonella and the facultative anaerobic genera Streptococcus and Lactobacillus were detected. Importantly, a disease-specific decline of relative abundance of Bifidobacterium was observed in AIH patients. Lack of Bifidobacterium was associated with failure to achieve remission of AIH (P < 0.001). Of potential therapeutic implication, Bifidobacterium abundance correlated with average protein intake (P < 0.001). Random forests classification between AIH and PBC on the microbiome signature yielded an area under receiver operating characteristic curve (AUC) of 0.787 in the training cohort, and an AUC of 0.849 in an external validation cohort. CONCLUSION: Disease-specific faecal microbial alterations were identified in patients with AIH. Intestinal dysbiosis in AIH was characterised by a decline of Bifidobacterium, which was associated with increased disease activity. These results point to the contribution of intestinal microbiota to AIH pathogenesis and to novel therapeutic targets.