The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The... more The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The gutliver 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.
Interleukin (IL)-33 was recently described as a new member of the IL-1 family; members of this fa... more Interleukin (IL)-33 was recently described as a new member of the IL-1 family; members of this family have proinflammatory activity. IL-33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL-33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male-to-female ratio was 6:59. Serum IL-33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL-33 expression in liver sections from patients with AIH. In particular, serum IL-33 and sST2 levels were significantly higher in acute-onset AIH than in chronic-onset...
Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive ... more Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH). We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array. Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (s...
The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune ... more The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1β, IFN-γ, TNF-α, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1β, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD.
Objective We aimed to define the clinical features of liver dysfunction in patients with systemic... more Objective We aimed to define the clinical features of liver dysfunction in patients with systemic lupus erythematosus (SLE). Methods The frequency and causes of liver dysfunction were examined in 206 patients with SLE. Results Liver dysfunction was evident in 123 (59.7%) of the 206 patients. Liver dysfunction in patients with SLE can be drug-induced (30.9%) or caused by SLE itself (28.5%), fatty liver (17.9%), autoimmune hepatitis (AIH) (4.9%), primary biliary cirrhosis (2.4%), cholangitis (1.6%), alcohol (1.6%) or viral hepatitis (0.8%), and it tends to be mild except when caused by AIH. Values for aminotransferase were significantly increased when AIH was the cause, whereas alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GTP) were significantly increased when AIH or drugs were the cause. The liver was already dysfunctional at the time of SLE onset in 56 (45.5%) of 123 patients with liver dysfunction. Neurological involvement was more common among patients with than without liver dysfunction, whereas SLE activity and prognosis did not significantly differ between the two groups. Conclusion Liver dysfunction in the presence of SLE can be caused by many factors, but when extant at the time of SLE onset, either SLE itself or drugs can be the cause. Autoimmune hepatitis should be considered when liver dysfunction is relatively severe.
A case of anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC) associated w... more A case of anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC) associated with painless thyroiditis is reported in a 47-year-old womanwho diagnosed as PBC based on her elevated serum y-glutamyl transpeptidase and immunoglobulin Mlevels, as well as histological findings of destroyed bile ducts surrounded by mononuclear infiltrates in the biopsied liver. She was negative for AMAand had a depressed level of thyroid-stimulating hormone accompanied by increased free thyrosine, thyroxine and triiodothyronine levels and low titers of anti-microsomal and anti-thyroid peroxidase antibodies. Her thyroid disorder corresponded with painless thyroiditis. An association between PBCand hyperthyroidism is rare. Furthermore, an association between AMA-negativePBCand hyperthyroidism due to painless thyroiditis has not previously been reported.
For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide ... more For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] ¼ 1.56, p ¼ 2.84 3 10 À14 for rs4979462, and combined OR ¼ 1.39, p ¼ 2.38 3 10 À8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p ¼ 3.66 3 10 À8 , 3.66 3 10 À9 , and 3.04 3 10 À9 , respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC
A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primar... more A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10(-9)). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease...
The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The... more The gut microbiota plays a key role in the development of chronic inflammatory liver disease. The gutliver 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.
Interleukin (IL)-33 was recently described as a new member of the IL-1 family; members of this fa... more Interleukin (IL)-33 was recently described as a new member of the IL-1 family; members of this family have proinflammatory activity. IL-33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL-33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male-to-female ratio was 6:59. Serum IL-33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL-33 expression in liver sections from patients with AIH. In particular, serum IL-33 and sST2 levels were significantly higher in acute-onset AIH than in chronic-onset...
Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive ... more Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH). We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array. Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (s...
The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune ... more The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1β, IFN-γ, TNF-α, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1β, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD.
Objective We aimed to define the clinical features of liver dysfunction in patients with systemic... more Objective We aimed to define the clinical features of liver dysfunction in patients with systemic lupus erythematosus (SLE). Methods The frequency and causes of liver dysfunction were examined in 206 patients with SLE. Results Liver dysfunction was evident in 123 (59.7%) of the 206 patients. Liver dysfunction in patients with SLE can be drug-induced (30.9%) or caused by SLE itself (28.5%), fatty liver (17.9%), autoimmune hepatitis (AIH) (4.9%), primary biliary cirrhosis (2.4%), cholangitis (1.6%), alcohol (1.6%) or viral hepatitis (0.8%), and it tends to be mild except when caused by AIH. Values for aminotransferase were significantly increased when AIH was the cause, whereas alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GTP) were significantly increased when AIH or drugs were the cause. The liver was already dysfunctional at the time of SLE onset in 56 (45.5%) of 123 patients with liver dysfunction. Neurological involvement was more common among patients with than without liver dysfunction, whereas SLE activity and prognosis did not significantly differ between the two groups. Conclusion Liver dysfunction in the presence of SLE can be caused by many factors, but when extant at the time of SLE onset, either SLE itself or drugs can be the cause. Autoimmune hepatitis should be considered when liver dysfunction is relatively severe.
A case of anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC) associated w... more A case of anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC) associated with painless thyroiditis is reported in a 47-year-old womanwho diagnosed as PBC based on her elevated serum y-glutamyl transpeptidase and immunoglobulin Mlevels, as well as histological findings of destroyed bile ducts surrounded by mononuclear infiltrates in the biopsied liver. She was negative for AMAand had a depressed level of thyroid-stimulating hormone accompanied by increased free thyrosine, thyroxine and triiodothyronine levels and low titers of anti-microsomal and anti-thyroid peroxidase antibodies. Her thyroid disorder corresponded with painless thyroiditis. An association between PBCand hyperthyroidism is rare. Furthermore, an association between AMA-negativePBCand hyperthyroidism due to painless thyroiditis has not previously been reported.
For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide ... more For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] ¼ 1.56, p ¼ 2.84 3 10 À14 for rs4979462, and combined OR ¼ 1.39, p ¼ 2.38 3 10 À8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p ¼ 3.66 3 10 À8 , 3.66 3 10 À9 , and 3.04 3 10 À9 , respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC
A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primar... more A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10(-9)). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease...
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Papers by Hiromasa Ohira