Lactobacillus reuteri joins the liver autoimmune arena.

Type 1 CD8 T cells (Tc1s) have been implicated in liver injury in autoimmune hepatitis (AIH) through mechanisms that have so far been unclear. In this issue of Cell Host & Microbe, Pandey et al. show that the aryl hydrocarbon receptor ligand-producing pathobiont Lactobacillus reuteri induces Tc1-mediated AIH-like pathology in mice with Tet-methylcytosine-dioxygenase-2 deficiency.

Fecal Microbiota Transplantation Controls Progression of Experimental Autoimmune Hepatitis in Mice by Modulating the TFR/TFH Immune Imbalance and Intestinal Microbiota Composition.

Intestinal microbiota (IM) dysbiosis contributes to the development of autoimmune hepatitis (AIH). This study aimed to investigate the potential effect of fecal microbiota transplantation (FMT) in a murine model of experimental AIH (EAH), a condition more similar to that of AIH patients. Changes in the enteric microbiome were determined in AIH patients and EAH mice. Moreover, we established an experimental model of secondary EAH mice harboring dysbiosis (ABx) to analyze the effects of therapeutic FMT administration on follicular regulatory T (TFR) and helper T (TFH) cell imbalances and IM composition in vivo. Alterations of the IM composition and bacterial translocation occurred in AIH patients compared to nonalcoholic fatty liver disease patients and healthy controls (HCs). Therapeutic FMT significantly attenuated liver injury and bacterial translocation and improved the imbalance between splenic TFR cells and TFH cells in ABx EAH mice. Furthermore, therapeutic FMT also partially reversed the increasing trend in serum liver enzymes (ALT and AST) of CXCR5-/-EAH mice on the 28th day. Finally, therapeutic FMT could effectively restore antibiotic-induced IM dysbiosis in EAH mice. Taken together, our findings demonstrated that FMT was capable of controlling hepatitis progression in EAH mice, and the associated mechanism might be involved in the regulation of the TFR/TFH immune imbalance and the restoration of IM composition.

Leaky Gut Driven by Dysbiosis Augments Activation and Accumulation of Liver Macrophages via RIP3 Signaling Pathway in Autoimmune Hepatitis.

The gut-liver axis has been increasingly recognized as a major autoimmunity modulator. However, the implications of intestinal barrier in the pathogenesis of autoimmune hepatitis (AIH) remain elusive. Here, we investigated the functional role of gut barrier and intestinal microbiota for hepatic innate immune response in AIH patients and murine models. In this study, we found that AIH patients displayed increased intestinal permeability and pronounced RIP3 activation of liver macrophages. In mice models, intestinal barrier dysfunction increased intestinal bacterial translocation, thus amplifying the hepatic RIP3-mediated innate immune response. Furthermore, GSK872 dampened RIP3 activation and ameliorated the activation and accumulation of liver macrophages in vitro and in vivo experiments. Strikingly, broad-spectrum antibiotic ablation significantly alleviated RIP3 activation and liver injury, highlighting the causal role of intestinal microbiota for disease progression. Our results provided a potentially novel mechanism of immune tolerance breakage in the liver via the gut-liver axis. In addition, we also explored the therapeutic and research potentials of regulating the intestinal microbiota for the therapy of AIH.

Anaerococcus urinimassiliensis sp. nov., a new bacterium isolated from human urine.

To date there are thirteen species validly assigned to the genus Anaerococcus. Most of the species in this genus are anaerobic and of human origin. Anaerococcus urinimassiliensis sp. nov., strain Marseille-P2143T is member of family Peptoniphilaceae, which was isolated from the urine of a 17-year-old boy affected by autoimmune hepatitis and membranoproliferative glomerulonephritis using the culturomic approach. In the current study, a taxono-genomics method was employed to describe this new species. The strain Marseille-P2143T was gram positive cocci with translucent colonies on blood agar. Its genome was 2,189,509 bp long with a 33.5 mol% G + C content and exhibited 98.48% 16S rRNA similarity with Anaerococcus provencensis strain 9,402,080. When Anaerococcus urinomassiliensis strain Marseill-P2143T is compared with closely related species, the values ranged from 71.23% with A. hydrogenalis strain DSM 7454T (NZ_ABXA01000052.1) to 90.64% with A. provencensis strain 9402080T (NZ_HG003688.1). This strain has implemented the repertoire of known bacteria of the human urinary tract.

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.

Alterations of gut microbiome in autoimmune hepatitis.

OBJECTIVE: The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. DESIGN: We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. RESULTS: The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar, the most strongly disease-associated taxa (p=8.85E-8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. CONCLUSION: Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.

Gut and oral microbiota in autoimmune liver disease.

The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The gut-liver axis involves inflammatory cells, cytokines, and other molecules that cause liver deterioration. Dysbiosis is important in understanding several liver diseases, especially in relation to the development of autoimmune liver disease. The aim of this review is to provide a current overview of alterations in the gut and oral microbiota associated with autoimmune liver diseases.

Celiac Disease and Liver Disorders: From Putative Pathogenesis to Clinical Implications.

Immunologically mediated liver diseases belong to the common extraintestinal manifestations of celiac disease. We have reviewed the current literature that addresses the association between celiac disease and liver disorders. We searched relevant articles on MEDLINE/PubMed up to 15 June 2018. The objective of the article is to provide a comprehensive and up-to-date review on the latest hypotheses explaining the pathogenetic relationship between celiac disease and liver injury. Besides the involvement of gut⁻liver axis, tissue transglutaminase antibodies, and impairment of intestinal barrier, we integrate the latest achievements made in elucidation of the role of gut microbiota in celiac disease and liver disorders, that has not yet been sufficiently discussed in the literature in this context. The further objective is to provide a complete clinical overview on the types of liver diseases frequently found in celiac disease. In conclusion, the review highlights the clinical implication, recommend a rational approach for managing elevated transaminases in celiac patients, and underscore the importance of screening for celiac disease in patients with associated liver disease.

Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management.

Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.

Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis.

The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic, progressive, and immunologically mediated inflammatory liver disorder. The etiology of AIH still remains unknown. The aim of this study was to investigate the changes in intestinal permeability, bacterial translocation, and intestinal microbiome in patients with AIH and to evaluate the correlations of those changes with the stages of the disease. METHODS: 24 patients with autoimmune hepatitis and 8 healthy volunteers were recruited for this study. We assessed (1) the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 and occludin expression in duodenal biopsy specimens; (2) changes in the enteric microbiome by 16S rDNA quantitative PCR; and (3) the presence of bacterial translocation by the level of lipopolysaccharide (LPS) using ELISA. RESULTS: Increased intestinal permeability, derangement of the microbiome and bacterial translocation occurred in AIH, which correlated with the severity of the disease. CONCLUSIONS: Autoimmune hepatitis is associated with leaky gut and intestinal microbiome dysbiosis. The impaired intestinal barrier may play an important role in the pathogenesis of AIH.

Acute liver failure, autoimmune hepatitis, and leptospirosis: a case report.

The etiology of acute liver failure varies widely in children, but the most common causes are viral hepatitis, drugs, and toxins. We report herein a case of autoimmune hepatitis and acute liver failure caused by leptospirosis, which is involved rarely in etiology.

Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity.

Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common genetic pathways affect general immunological tolerance mechanisms in autoimmunity, the effects of such genes could vary under distinct immune challenges within different tissues. In this study, we demonstrate this by observing that autoimmune type 1 diabetes-protective haplotypes at the insulin-dependent diabetes susceptibility region 10 (Idd10) introgressed from chromosome 3 of C57BL/6 (B6) and A/J mice onto the NOD background increase the severity of autoimmune primary biliary cirrhosis induced by infection with Novosphingobium aromaticivorans, a ubiquitous alphaproteobacterium, when compared with mice having the NOD and NOD.CAST Idd10 type 1 diabetes-susceptible haplotypes. Substantially increased liver pathology in mice having the B6 and A/J Idd10 haplotypes correlates with reduced expression of CD101 on dendritic cells, macrophages, and granulocytes following infection, delayed clearance of N. aromaticivorans, and the promotion of overzealous IFN-γ- and IL-17-dominated T cell responses essential for the adoptive transfer of liver lesions. CD101-knockout mice generated on the B6 background also exhibit substantially more severe N. aromaticivorans-induced liver disease correlating with increased IFN-γ and IL-17 responses compared with wild-type mice. These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aromaticivorans.

Hepatitis autoinmune en niños: diagnostico / Autoimmune hepatitis in children: diagnosis

El diagnóstico de la hepatitis autoinmune (HAI), se basa en una serie de criterios definidos por elGrupo Internacional de HAI (IAIHG) que permite clasificarla como HAI probable o definitiva. Un criterio clave para el diagnóstico de la HAI es la detección de ANA, SMA, y anti- LKM-1 por inmunofluorescencia indirecta. Otros anticuerpos menos frecuentes probados, pero de importancia diagnóstica en HAI pediátrica incluyen los anticuerpos tipo: citosol 1 hígado (LC-1), anti- citoplasma de los neutrófilos (ANCA) y el antígeno soluble hepático (SLA). La Ig G está usualmente elevada en ambos tipos de HAI, cerca del 15% de niños con HAI I y el 25% de niños con HAI tipo II tienen valores normales. La biopsia hepática es necesaria para establecer el diagnóstico de HAI.

The diagnosis of autoimmune hepatitis (HAI), is based on a set of criteria defined by the International HAI Group (IAIHG) that allows classified as a probable or definite HAI. A key criterion for the diagnosis of HAI is the detection of ANA, SMA, and anti-LKM-1 by indirectimmunofluorescence. Other less common antibodies tested, but important diagnostic tool in pediatric HAI include antibodies such as: liver cytosol 1 (LC-1), anti-neutrophil cytoplasmic (ANCA) and soluble liver antigen (SLA). The Ig G is usually high in both types of HAI, about 15% of children with HAI I and 25% of children with HAI type II are normal. Liver biopsy is necessary to establish the diagnosis of HAI.

Helicobacter species DNA in liver and gastric tissues in children and adolescents with chronic liver disease.

OBJECTIVE: Enterohepatic Helicobacter species (EHS) have previously been found in adults with hepatobiliary diseases. Here, we report the prevalence of Helicobacter pylori and EHS in liver and gastric tissue in children and adolescents with chronic liver disease (CLD). MATERIAL AND METHODS: Seventy-seven consecutive children and adolescents with CLD with or without ulcerative colitis or Crohn's disease (UC/CD) were investigated. Tissue samples were analysed using a Helicobacter genus-specific 16S rDNA polymerase chain reaction (PCR) assay and DNA-sequence analysis. Sera from 61 subjects were also analysed using enzyme immunoassay and immunoblotting. RESULTS: The Helicobacter PCR was positive in 3/23 (13%) livers from patients with primary sclerosing cholangitis and UC, and in 1/2 livers from patients with autoimmune hepatitis (AIH) and UC. Sequenced PCR products matched the 16S rDNA of H. hepaticus, H. muridarum, H. canis, and H. pylori, respectively. H. ganmani and H. bilis were detected in gastric tissues from two AIH patients. H. hepaticus and H. pullorum were found in livers from two patients with acute liver failure and intrahepatic cholestasis. Antibody reactivity to Helicobacter cell-surface proteins was negative. CONCLUSIONS: H. pylori and EHS can be detected in the livers of some patients with UC and concomitant liver disease, as well as in other children with liver diseases. Multicentre studies from different locations are needed to find out whether these bacteria play a pathogenetic role or whether their presence is an epiphenomenon.

Atypical p-ANCA in PSC and AIH: a hint toward a "leaky gut"?

Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are enigmatic chronic inflammatory diseases of the liver, which are frequently associated with chronic inflammatory bowel diseases. Both types of liver disease share various distinct autoantibodies such as atypical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and thus are considered autoimmune disorders with atypical features. The discovery that atypical p-ANCA recognize both tubulin beta isoform 5 in human neutrophils and the bacterial cell division protein FtsZ has renewed the discussion on the potential role of microorganisms in the pathogenesis of both diseases. In this paper, we review the evidence for microbial infection in PSC and AIH and discuss new concepts how cross-recognition between microbial antigens in the gut and host components by the immune system along with stimulation of pattern recognition receptors might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.

Liver autoimmunity triggered by microbial activation of natural killer T cells.

Humans with primary biliary cirrhosis (PBC), a disease characterized by the destruction of small bile ducts, exhibit signature autoantibodies against mitochondrial Pyruvate Dehydrogenase Complex E2 (PDC-E2) that crossreact onto the homologous enzyme of Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium. Here, we show that infection of mice with N. aromaticivorans induced signature antibodies against microbial PDC-E2 and its mitochondrial counterpart but also triggered chronic T cell-mediated autoimmunity against small bile ducts. Disease induction required NKT cells, which specifically respond to N. aromaticivorans cell wall alpha-glycuronosylceramides presented by CD1d molecules. Combined with the natural liver tropism of NKT cells, the accumulation of N. aromaticivorans in the liver likely explains the liver specificity of destructive responses. Once established, liver disease could be adoptively transferred by T cells independently of NKT cells and microbes, illustrating the importance of early microbial activation of NKT cells in the initiation of autonomous, organ-specific autoimmunity.

Lack of an association between Helicobacter infection and autoimmune hepatitis in children.

An association between Helicobacter infection and autoimmune hepatitis (AIH) in children was investigated. The prevalence of antibodies to H. pylori did not differ between the AIH and the control group, (22% versus 14%), and antibodies to non-gastric Helicobacter were not detected in either group. H. pylori DNA was found in two AIH liver tissues, but Helicobacter was not cultured from any sample.

Etiological role of brucellosis in autoimmune hepatitis.

To show that brucellosis may trigger autoimmune hepatitis (AIH), in addition to nonspecific liver involvement and toxic hepatitis, due to a class effect of tetracycline family used for treatment. We present a female patient admitted to our hospital due to partially improved fatigue and elevated liver enzymes following doxycycline and streptomycin usage for brucellosis. Brucellosis is endemic in our country, Turkey. It may involve any organ in the body. Liver is frequently involved. Doxycycline used for treatment occasionally may lead to hepatotoxicity. AIH is a necroinflammatory disease of the liver. Certain drugs (e.g. minocycline), toxins, and viruses (hepatitis B, hepatitis C, EBV, etc.) can trigger AIH. Only one case of AIH probably caused by doxycycline and brucellosis was reported. We discuss the relationship between brucellosis, AIH, and hepatotoxicity of doxycycline. Brucellosis may trigger AIH.