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

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with multiple clinical manifestations. Immune imbalance including abnormal differentiation, activation of T cells and overexpression of autoantibodies produced by B cells are the main features of SLE [1]. Glucocorticoid and immunosuppressive therapy have limited therapeutic efficiency with side effects. Thus, effective and safe biologic therapeutics are being explored and multiple omics studies have attempted to uncover the mechanism of novel therapy for SLE.

As the interactions between gut flora and the immune system emerge, the importance of microbiome in cancer, neurological diseases, and autoimmune diseases has been discovered. Gut microbiota dysbiosis in SLE, including the reduction of bacterial diversity and the change of Firmicutes/Bacteroidetes ratio, has been proved in some studies [2,3]. In addition, the feeding of SLE feces to germ-free mice can also cause an autoimmune phenotype [4]. At present, fecal microbiota transplantation (FMT) is being investigated for several immune-mediated disorders, such as inflammatory bowel disease (IBD) [5], psoriatic arthritis (PsA) [6], and type 1 diabetes (T1D) [7], for pre-clinical and clinical studies and have been proven to be a powerful attempt of microbiota-targeting strategy. Restoring a healthy repertoire of intestinal microbiota may also be a treatment for SLE. So we conducted a single-arm pilot clinical trial of FMT as treatment in 12 active SLE patients to evaluate the safety and efficacy of FMT treatment in SLE. No serious adverse events occurred during the trial, and the SLE Responder Index-4 (SRI-4) response rate at the observed endpoint was 42.12%, with significant reductions in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores and the level of serum anti-dsDNA antibody [8]. This indicated that FMT was a novel, safe, and effective therapy for patients with SLE. However, the mechanism of the interaction between FMT therapy and the homeostasis response of the immune system remains unclear.

Several studies have focused on interactions between environmental and epigenetic modification in the pathogenesis of SLE, especially DNA methylation has been shown to be a key role. Demethylation and high expression of CD40L in female CD4+T cells revealed the gender bias in SLE [9]. And similar methylation change and overexpression of CD70 in CD4+T cells lead to activation of B cells and up-regulation of IgG secretion [10]. High expression of interferon plays a central role in the occurrence of SLE. Interferon genes including Interferon (IFN)-induced protein 44-like (IFI44L), Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), Myxovirus resistance protein 1(MX1), signal transducer and activator of transcription 1 (STAT1), Deficiency of ubiquitin-specific peptidase 18 (USP18), bone marrow stromal cell antigen 2 (BST2), and tripartite motif containing 22 (TRIM22) are also hypomethylated in SLE patients [11]. Excessive UVB and high salt diets have been shown to be involved in hypomethylation of SLE [12,13]. The gut flora and its metabolites are recognized as crucial environmental factors which can interact with epigenetic modifications. However, whether FMT therapy alleviates clinical symptoms by reversing abnormal methylation changes in SLE remains unclear.

Gut microbiota are able to induce DNA methylation via short-chain fatty acids predisposing obesity-prone individuals to diabetes [14]. FMT has also been found to have an effect on methylation in patients with metabolic syndrome [15]. At the same time, certain metabolites of gut flora, for example S-adenosylmethionine (SAM), act as methylated donors [16]. Based on these evidences, we decided to investigate whether abnormal methylation in SLE was changed after FMT treatment. Our results demonstrate the underlying mechanism of FMT in treating SLE, which provides more evidence for the effectiveness of FMT in SLE.

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