Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota.

The gut microbiome is an important determinant in various diseases. Here we perform a cross-sectional study of Japanese adults and identify the Blautia genus, especially B. wexlerae, as a commensal bacterium that is inversely correlated with obesity and type 2 diabetes mellitus. Oral administration of B. wexlerae to mice induce metabolic changes and anti-inflammatory effects that decrease both high-fat diet-induced obesity and diabetes. The beneficial effects of B. wexlerae are correlated with unique amino-acid metabolism to produce S-adenosylmethionine, acetylcholine, and L-ornithine and carbohydrate metabolism resulting in the accumulation of amylopectin and production of succinate, lactate, and acetate, with simultaneous modification of the gut bacterial composition. These findings reveal unique regulatory pathways of host and microbial metabolism that may provide novel strategies in preventive and therapeutic approaches for metabolic disorders.

Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques.

Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

T-gamma delta large granular lymphocyte leukemia preceded by pure red cell aplasia and complicated with hemophagocytic syndrome caused by Epstein-Barr virus infection.

A 51-year-old man developed anemia, and was diagnosed with pure red cell aplasia through the absence of erythroid progenitors. Initially, he was treated with cyclosporine and prednisolone for 6 months but they were ineffective. Large granular lymphocyte (LGL) leukemia with the T-cell gamma delta phenotype evolved after 6 months showing CD2+, CD3+, CD8- and CD56- with the T-cell receptor beta gene rearrangement, clonalities of gamma and delta genes and complex chromosome abnormality simultaneously with hemophagocytic syndrome (HPS). Epstein-Barr virus (EBV) genomic DNA was detected in the bone marrow cells. Administration of bolus methylprednisolone was ineffective, and the patient died one month later. In the present patient, it seemed that lymphoproliferative disease of large granular lymphocytes (LDGL) manifested initially as PRCA, gammadelta LGL leukemia evolved, and finally fatal HPS become complicated, presumably caused by the EBV reactivation in the immunodeficiency state with the administration of immunosuppressants.

Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese.

Urotensin II is among the most potent vasoactive hormones known and the urotensin II (UTS2) gene is localized to 1p36-p32, one of the regions reported to show possible linkage with type 2 diabetes in Japanese. When we surveyed genetic polymorphisms in the UTS2 and urotensin II receptor (GPR14) gene, we identified two SNPs with amino acid substitutions (designated T21M and S89N and an SNP in the promotor region (-605G>A) of the UTS2 gene, and two SNPs in the non-coding region of the GPR14 gene. We then studied these three SNPs in the UTS2 gene and two SNPs in the GPR14 gene in 152 Japanese subjects with type 2 diabetes mellitus and two control Japanese populations. The allele frequency of 89N was significantly higher in type 2 diabetic patients than in both elderly normal subjects (P = 0.0018) and subjects with normal glucose tolerance (P = 0.0011), whereas the allele frequency of T21M and -605G>A in the UTS2 gene and those of two SNPs in the GPR14 gene were essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with significantly higher insulin levels on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. These results strongly suggest that subjects with S89N in the UTS2 gene are more insulin-resistant and thus more susceptible to type 2 diabetes mellitus development.