Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese

Abstract

ObjectiveAlteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.MethodsWe performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals (Ncase=47, Ncontrol=203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.ResultsVia species level phylogenetic analysis, we identified and validated increases of Streptococcus intermedius and Streptococcus anginosus in the patients with SLE. Microbial gene analysis revealed increases of Streptococcus-derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with Streptococcus intermedius, an SLE-associated taxon.ConclusionOur MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.

Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease

“…prausnitzii , which were positively associated with Podoviridae , also tended to decrease in the gut metagenome of the patients with SLE ( figure 3D ). In the bacterial microbiome-wide association study of the patients with SLE conducted with subsets of dataset, 34 (sequencing batch 1, 2 and 5), nonsignificant decreases of Faecalibacterium spp and Faecalibacterium cf. prausnitzii were observed (effect size = −0.04, P = 0.79; effect size = −0.11, P = 0.50, respectively).…”

“…The sequencing data from the patients with RA in sequencing batch 3 were newly obtained for this study, while other sequencing data were derived from previous studies, 32 33 or a recently conducted SLE metagenome study. 34 The sequence reads were converted to FASTQ format using bcl2fastq (V.2.19).…”

“…Most of these subjects were derived either from previous studies, 32 33 or a recently conducted SLE metagenome study. 34 The patients with RA were enrolled at the Osaka University Hospital, National Hospital Organization Osaka Minami Medical Center, and Daini Osaka Police Hospital. The patients with SLE were enrolled at the Osaka University Hospital and National Hospital Organization Osaka Minami Medical Center.…”

Alterations of Plasma Microbiome: A Potentially New Perspective to the Dysbiosis in Systemic Lupus Erythematosus?

“…As a critical environmental factor, dysbiosis is linked to SLE immunopathogenesis. 3,4,8,9,10,11 Patients with SLE displayed decreased richness and diversity of gut microbiota compared to controls. 8,9,10,11 Further, a significantly lower ratio of Firmicutes to Bacteroidetes in patients with SLE was reported in several studies.…”

“…3,4,8,9,10,11 Patients with SLE displayed decreased richness and diversity of gut microbiota compared to controls. 8,9,10,11 Further, a significantly lower ratio of Firmicutes to Bacteroidetes in patients with SLE was reported in several studies. 3 The implication of gut dysbiosis in SLE pathogenesis was further corroborated by the findings that cecal microbiota transfer from SLE-prone mice induced autoimmune phenotypes in germ-free congenic C57BL/6 mice.…”