Effects of fecal microbiota transplant on DNA methylation in patients with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of autoantibodies. Decreased intestinal flora diversity and disruption of homeostasis have been proven to be associated with pathogenesis of SLE. In previous study, a clinical trial was conducted to verify the safety and effectiveness of fecal microbiota transplantation (FMT) in the treatment of SLE. To explore the mechanism of FMT in the treatment of SLE, we included 14 SLE patients participating in clinical trials, including 8 in responders group (Rs) and 6 in non-responders group (NRs), and collected peripheral blood DNA and serum. We found that the serum of S-adenosylmethionine (SAM), methylation group donor, was upregulated after FMT, accompanied by an increase in genome-wide DNA methylation level in Rs. We further showed that the methylation levels in promoter regions of Interferon-γ (IFN-γ), induced Helicase C Domain Containing Protein 1 (IFIH1), endoplasmic reticulum membrane protein complex 8 (EMC8), and Tripartite motif-containing protein 58 (TRIM58) increased after FMT treatment. On the contrary, there was no significant change in the methylation of IFIH1 promoter region in the NRs after FMT, and the methylation level of IFIH1 in the Rs was significantly higher than that in the NRs at week 0. We included 850 K methylation chip sequencing, combining previous data of metagenomic sequencing, and metabolomic sequencing for multi-omics analysis to discuss the relationship between flora-metabolite-methylation in FMT. Finally, we found that hexanoic acid treatment can up-regulate the global methylation of peripheral blood mononuclear cells in SLE patients. Overall, our results delineate changes in methylation level after FMT treatment of SLE and reveal possible mechanisms of FMT treatment in terms of the recovery of abnormal hypomethylation.