Early and Short-Term Interventions in the Gut Microbiota Affects Lupus Severity, Progression, and Treatment in MRL/lpr Mice

Abstract

There have been attempts to reveal the possible associations between systemic lupus erythematosus (SLE) and gut microbiota. Using MRL/lpr mice, this study was performed to reveal whether early and short-term interventions in gut microbiota affect lupus. MRL/lpr mice were treated with antibiotics or fecal microbiota transplantation (FMT) before onset. Then, prednisone was used to treat the lupus mice with initially different gut microbiota compositions. The compositions of gut microbiota were assessed by the V3-V4 region of 16S rRNA gene sequence. Early and short-term antibiotics exposure aggravated lupus severity by depleting beneficial gut microbiota for lupus, such as Lactobacillus and Bifidobacterium, and enriching harmful gut microbiota for lupus, such as Klebsiella and Proteus. FMT alleviated lupus severity by renovating the antibioticinduced dysbiosis of gut microbiota in the following 1 week after antibiotics exposure. Besides, short-term antibiotics exposure before onset imposed no significant effects on lupus progression, but the following one week of FMT suppressed lupus progression. Moreover, the short-term antibiotics or FMT before onset inhibited the therapeutic efficiency of prednisone on lupus from 9 to 13 weeks old of MRL/lpr mice. These data demonstrate that the gut microbiota before onset is important for lupus severity, progression and treatment.

Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies

“…Similarly, Zhang et al. showed that antibiotic treatment exacerbated the disease in MRL/lpr mice, possibly due to a short course and insufficient dose of antibiotics before lupus onset ( 31 ). Alternatively, another study found that vancomycin treatment ameliorated lupus symptoms in common MRL/lpr mice, but aggravated lupus in pregnant and postpartum (PP) mice.…”

“…However, another study showed that treatment with antibiotics has no significant effect on both the gut microbiota and SLE progression in NZB/WF1 lupus mice, the mechanism of which is unclear (91). Similarly, Zhang et al showed that antibiotic treatment exacerbated the disease in MRL/lpr mice, possibly due to a short course and insufficient dose of antibiotics before lupus onset (31). Alternatively, another study found that vancomycin treatment ameliorated lupus symptoms in common MRL/lpr mice, but aggravated lupus in pregnant and postpartum (PP) mice.…”

Gut microbiota mediated the therapeutic efficacies and the side effects of prednisone in the treatment of MRL/lpr mice

“…The gut microbiota affects not only the activity of lupus but also the treatment effects of lupus with glucocorticoids [ 12 , 22 ]. At the same time, one of the mechanisms of GCs is regulating the gut microbiota to play the therapeutic effect [ 23 , 24 ].…”

“…Gut microbiota inhabits the intestine, forming a complex ecological community that influences normal physiology and susceptibility to disease through its collective metabolic activities and host interactions [ 11 ]. In the treatment of SLE by GCs, gut microbiota not only affects its efficiency but also serves as a therapeutic target [ 12 , 13 ]. However, little is known about whether gut microbiota plays role in the side effects of GCs in SLE.…”

Gut microbiota shape B cell in health and disease settings

“…Furthermore, IL‐35 is capable of promoting the production of IL‐10 by B cells 75 . Recently, a study found that the frequency of IL‐35 + Bregs is reduced during SLE development, 76 whereas other studies revealed a low diversity of gut microbiota in the SLE mouse model 77,78 . Thus, the reduction in IL‐35‐producing B cells in SLE is likely closely related to gut microbiota dysbiosis.…”