ObjectiveThe causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS).MethodsWe conducted MWAS of the RA gut microbiome in the Japanese population (n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).ResultsPhylogenetic case–control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case–control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case–control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.ConclusionOur shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

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An acute type rejection episode occurred in one of two patients treated with Interferon alpha (IFN alpha) for type C hepatitis (CHC). Histopathological examination of the graft kidney revealed focal cellular infiltration and chronic transplant glomerulopathy which showed acute or chronic type rejection. In spite of bolus administration of methyl-prednisolone, the elevation of serum creatinine level continued. After administration of anti-human lymphocyte globulin (AHLG), renal function improved, but urinary protein was still positive. Another patient had no episode of rejection during or after IFN alpha therapy.

The effect of ascorbic acid on the hydroxylase and dehydrogenase activities was studied in vivo to clarify its role in the biological oxidation.Tyrosine hydroxylase and tryptophan-5-hydroxylase which require 2-amino-4-hydroxy-6, 7 -dimethyltetrahydropteridine (DMPH4), NADP and molecular oxygen were investi gated with the non-scorbutic and scorbutic guinea pigs. Several dehydrogenases such as glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase and malic enzyme, which require no molecular oxygen but NADP, were also studied by comparing the activities in the non-scorbutic guinea pig with those in the scor butic guinea pig. The results indicated that the activities of tyrosine hydroxylase and tryptophan-5-hydroxylase of the adrenal gland, liver and brain of the non scorbutic guinea pig were higher than the values found in the scorbutic guinea pig, although no significant change in the activity of dehydrogenase was ob served in the tissues of the non-scorbutic and scorbutic guinea pigs.