Gut microbiota compositional alteration may have an association with immune dysfunction in patients with Behcet’s disease (BD). We conducted a fecal metagenomic analysis of BD patients. We analyzed fecal microbiota obtained from 12 patients with BD and 12 normal individuals by sequencing of 16S ribosomal RNA gene. We compared the relative abundance of bacterial taxa. Direct comparison of the relative abundance of bacterial taxa demonstrated that the genera Bifidobacterium and Eggerthella increased significantly and the genera Megamonas and Prevotella decreased significantly in BD patients compared with normal individuals. A linear discriminant analysis of bacterial taxa showed that the phylum Actinobacteria, including Bifidobacterium, and the family Lactobacillaceae exhibited larger positive effect sizes than other bacteria in patients with BD. The phylum Firmicutes and the class Clostridia had large effect sizes in normal individuals. There was no significant difference in annotated species numbers (as numbers of operational taxonomic unit; OTU) and bacterial diversity of each sample (alpha diversity) between BD patients and normal individuals. We next assigned each sample to a position using three axes by principal coordinates analysis of the OTU table. The two groups had a significant distance as beta diversity in the 3-axis space. Fecal sIgA concentrations increased significantly in BD patients but did not correlate with any bacterial taxonomic abundance. These data suggest that the compositional changes of gut microbes may be one type of dysbiosis (unfavorable microbiota alteration) in patients with BD. The dysbiosis may have an association with the pathophysiology of BD.

SummaryExcessive T helper type 1 (Th1) cell activity has been reported in Behçet's disease (BD). Recently, association of Th17 cells with certain autoimmune diseases was reported, and we thus investigated circulating Th17 cells in BD.

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Relapsing polychondritis (RP) is an inflammatory disease of unknown causes, characterized by recurrent inflammation in cartilaginous tissues of the whole body. Recently, researchers have reported that, in mouse experiments, altered gut microbe-dependent T cell differentiation occurred in gut associated lymphoid tissues. Here, we investigated whether gut microbe alteration existed, and if so, the alteration affected peripheral T cell differentiation in patients with RP. In an analysis of gut microbiota, we found increased annotated species numbers in RP patients compared with normal individuals. In the RP gut microbiota, we observed several predominant species, namely Veillonella parvula, Bacteroides eggerthii, Bacteroides fragilis, Ruminococcus bromii, and Eubacterium dolichum, all species of which were reported to associate with propionate production in human intestine. Propionate is a short-chain fatty acid and is suggested to associate with interleukin (IL)10-producing regulatory T (Treg) cell differentiation in gut associated lymphoid tissues. IL10 gene expressions were moderately higher in freshly isolated peripheral blood mononuclear cells (PBMC) of RP patients than those of normal individuals. Six hours after the initiation of the cell culture, regardless of the presence and absence of mitogen stimulation, IL10 gene expressions were significantly lower in RP patients than those in normal individuals. It is well known that PBMC of patients with autoimmune and inflammatory diseases show hyporesponsiveness to mitogen stimulation. We suggest that, in RP patients, continuous stimulation of intestinal T cells by excessive propionate leads to the spontaneous IL10 production and a subsequent refractory period of T cells in patients with RP. The hyporesponsiveness of Treg cells upon activation may associate with inflammatory cytokine production of PBMC and subsequently relate to chondritis in RP patients.

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Transplantation of neural cells is a promising therapeutic strategy for spinal cord injury (SCI). Here we generated neurons including those with spinal motoneuron phenotype from human induced pluripotent stem (hiPS) cells by leading to formation of embryoid bodies (EB) and subsequent adherent culture for 4 days during which retinoic acid (RA), noggin (NOG) and sonic hedgehog (SHH) were introduced twice. Spinal motoneuron specific HB9 mRNA expression remarkably increased in the presence of RA, NOG and SHH. With this culture condition, the neurons expressed neurofilament middle chain (NFM), βIII tubulin and HB9 proteins in vitro. We then transplanted the hiPS derived human neurons into SCI mice with complete transection of Th11. Motor function of neuron transplanted SCI mice was significantly improved compared with those of vehicle injected SCI mice. Grafted cells survived and expressed βIII tubulin and HB9 diffusely 36 days after the transplantation. Galactocerebroside positive cells increased and glial fibrillary acidic protein (GFAP) expression reduced in the transection site of neuron transplanted SCI mice. The grafted motoneurons elongated human neural cell adhesion molecule (hNCAM) positive axons over the L1 spinal level. NCAM positive axons at L1 carried a neuron tracer cholera toxin β subunit (CTβ), which had been injected into Th10 of spinal cord, cranial region of the SCI/motoneuron grafted site (Th11). Collectively we succeeded in generating neurons which include those with HB9 positive spinal motoneuron phenotype from hiPS cells. The neurons brought about restoration of the motor function and histological improvement in an SCI. Rec.1/23/2015, Acc.4/15/2015, pp154-163