Gut microbiota and metabolism in systemic lupus erythematosus: from dysbiosis to targeted interventions

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiorgan involvement, with pathogenesis closely linked to that of gut dysbiosis and metabolic disturbances. Studies indicate that SLE patients exhibit significantly reduced gut microbial diversity, increased abundance of pathogenic bacteria, and decreased beneficial bacteria. Dysbiosis exacerbates disease progression by disrupting the intestinal barrier, triggering autoimmune responses, and promoting proinflammatory cytokine release. Metabolomic analyses further reveal that SLE is associated with dysregulated amino acid metabolism, reduced short-chain fatty acids, and disrupted lipid homeostasis, which correlate with disease activity, renal injury, and increased atherosclerosis risk. Emerging microbiota-targeted interventions, such as fecal microbiota transplantation (FMT), probiotics/prebiotics, phage therapy, and dietary modifications, demonstrate promising therapeutic potential by restoring microbial balance, enhancing immune regulation, and improving metabolic homeostasis. This review systematically summarizes the alterations in gut microbiota and metabolism in SLE, their critical roles in disease progression, diagnosis, and pathogenesis, and explores the clinical value of microbial-targeted strategies in improving SLE outcomes.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease (AD) characterized by inflammatory responses and immune-mediated multiorgan damage, with clinical heterogeneity in disease course and prognosis. SLE commonly affects multiple systems including mucocutaneous tissues, musculoskeletal system, hematological system, and kidneys, with an estimated global prevalence of 3.4 million cases [1]. SLE demonstrates a strong female predominance, with a female-to-male ratio of 7–9:1, particularly affecting women of childbearing age (15–40 years) [2]. The pathogenesis of SLE involves complex interactions among genetic predisposition, environmental triggers, hormonal influences, and immune dysregulation [3]. Although significant progress has been made in SLE management through widespread use of antimalarials, immunosuppressants, and biologics, substantial clinical challenges remain. Notable treatment limitations include marked interpatient variability in therapeutic response, inadequate efficacy or severe adverse effects of conventional therapies in certain patients, and high relapse rates [4]. The heterogeneity of SLE poses significant obstacles for early diagnosis and precision medicine approaches, underscoring the urgent need to identify novel therapeutic targets and develop more effective intervention strategies to improve patient outcomes.

The human gut harbors diverse microbial communities, with advances in 16S rRNA and metagenomic sequencing technologies confirming the critical roles of Firmicutes, Bacteroidetes, and Actinobacteria in human health [5]. Growing evidence has established strong associations between gut microbiota and the pathogenesis of ADs, including SLE, rheumatoid arthritis, and multiple sclerosis [6, 7]. Resident gut microbiota play a dual role in maintaining host homeostasis and immune defense, serving as both essential partners in immune system evolution and potential contributors to AD development through dysbiosis. Gut dysbiosis may accelerate SLE initiation and progression through multiple mechanisms, including intestinal barrier dysfunction, molecular mimicry, antigen crossreactivity, and metabolite-mediated immune dysregulation [8]. Specific microbial species (e.g., Ruminococcus gnavus and Bifidobacterium) may participate in SLE pathogenesis via antigenic molecular mimicry or immunomodulatory metabolite production. Compositional imbalances in microbial communities can alter their metabolic profiles, thereby disrupting host immune homeostasis, compromising defense mechanisms, and potentially triggering local and systemic inflammation [9]. Notably, certain microbial metabolites (e.g., butyrate and acetate) have been shown to reduce proinflammatory cytokines [interleukin (IL)−6, IL-12, IL-17, and interferon (IFN)-γ], while enhancing anti-inflammatory cytokines (transforming growth factor-β and IL-10), consequently modulating SLE disease activity [10]. However, the precise mechanisms underlying gut microbiota and their metabolites in SLE remain incompletely understood. The current research remains preliminary, warranting further investigation to elucidate their therapeutic potential.

This review aims to summarize recent research advances regarding the roles of gut microbiota and metabolism in SLE, explore their potential mechanisms in SLE pathogenesis, and evaluate their feasibility as novel diagnostic biomarkers and therapeutic targets. Through comprehensive analysis of existing literature, we seek to provide new perspectives and theoretical foundations for precision diagnosis and treatment of SLE.

Methods

This literature screening was conducted based on the PubMed, Web of Science, and CNKI databases, with the search timeframe spanning from January 2010 to May 2025. A search strategy combining "disease terms", "mechanism/target terms", and "intervention terms" was used, with keywords connected by "AND" or "OR" operators. The core disease terms were "systemic lupus erythematosus" OR "SLE"; the mechanism/target terms included "gut microbiota" OR "intestinal microbiome" OR "metabolomics" OR "metabolism" OR "short chain fatty acids" OR "SCFAs"; the intervention terms consisted of "treatment" OR "fecal microbiota transplantation" OR "FMT" OR "Probiotics" OR "prebiotics" OR "synbiotics" OR "Diet" OR "Proton pump inhibitors" OR "PPI" OR "phages" OR "intravenous immunoglobulin". The final search query was "(disease terms) AND (mechanism/target terms OR intervention terms)", ensuring precise retrieval of studies focusing on "the association between SLE and gut microbiota/metabolism". The inclusion criteria were: (1) Study subjects involving human SLE patients (including varying disease activity levels and subtypes such as lupus nephritis) or SLE animal models; (2) Study types including original research (cross-sectional studies, cohort studies, randomized controlled trials, animal experiments), systematic reviews, and meta-analyses; (3) Study content must explicitly address changes in gut microbiota/metabolites, related mechanisms, diagnostic value, or intervention effects. The exclusion criteria were: (1) Literature not in English or Chinese; (2) Case reports, conference abstracts; (3) Lack of core data; (4) preprints. Literature screening was performed independently by two researchers. An initial screening based on titles and abstracts was conducted to exclude obviously irrelevant literature; subsequently, a full-text assessment was performed for literature passing the initial screening. Finally, the two researchers cross-checked the screening results. Any discrepancies were resolved through team discussion to reach a consensus. Ultimately, 109 articles meeting the criteria were included, providing a reliable literature foundation for the analysis in this paper.

Gut microbiota in SLE patients

Alteration of gut microbiota in SLE patients

In recent years, multiple studies utilizing 16S rRNA sequencing and metagenomic sequencing technologies have revealed significant alterations in the gut microbiota of SLE patients. SLE patients exhibit markedly reduced gut bacterial richness and diversity, along with a decreased Firmicutes/Bacteroidetes (F/B) ratio [11–14]. Specifically, the abundance of Ruminococcus, Coprococcus, and Faecalibacterium is diminished, whereas Escherichia–Shigella and Bacteroides are enriched [12]. In 16 SLE patients, the phylum Tenericutes was found to be reduced, while the family Tannerellaceae and genera Alistipes, Flintibacter, and Parabacteroides were increased [13]. A consistent finding across multiple studies is the enrichment of Streptococcus in the gut microbiota of SLE patients. Compared with healthy controls, 11 SLE patients showed significantly higher levels of Streptococcus, accompanied by reduced abundance of Dialister and Azospirillum [15]. Similarly, in 23 female SLE patients, Streptococcus was significantly enriched, along with increased Collinsella and Bifidobacterium [16]. Analysis of 19 SLE patients and 19 healthy household members demonstrated that the former had decreased α-diversity and increased microbiota heterogeneity, with a notable elevation in Streptococcus levels [17]. Whole-metagenome shotgun sequencing confirmed the significant enrichment of Streptococcus intermedius and Streptococcus anginosus in 47 SLE patients [18]. These findings collectively support the consistent enrichment of Streptococcus in SLE patients and its potential pathological significance. The abundance of Lactobacillus in SLE patients has shown inconsistency across studies: some report an increase [16, 19], whereas others observe a reduction in newly diagnosed SLE patients [20]. This discrepancy suggests that Lactobacillus abundance may vary with disease stage or severity, warranting further investigation. Metagenomic sequencing analysis of 32 SLE patients revealed decreased abundance of Eubacterium sp. CAG_38, Gemmiger formicilis, Clostridium leptum, and Asaccharobacter celatus [21]. Another metagenomic study of 117 treatment-naïve SLE patients identified enrichment of Clostridium species ATCC BAA-442, Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, which decreased following treatment [22]. In a study of 33 pediatric SLE patients, the gut microbiota exhibited a significant increase in Proteobacteria and Enterobacteriales, alongside a reduction in Ruminococcaceae [23]. These findings collectively demonstrate that SLE patients exhibit significant gut dysbiosis, characterized by reduced diversity, depletion of beneficial bacteria, and enrichment of potentially pathogenic bacteria such as Streptococcus. These microbial alterations may be closely linked to disease activity, treatment response, and pathological mechanisms in SLE, providing a promising foundation for future microbiota-based diagnostic and therapeutic strategies (Table 1). However, the current findings remain inconsistent, which may be attributed to factors, such as limited sample sizes, population heterogeneity, and confounding variables including dietary differences, medication use, geographic region, and lifestyle. Future studies should prioritize large-scale, multicenter prospective designs that systematically collect and control for these variables to enhance the reliability and generalizability of the results.

Table 1.

Alteration of gut microbiota in SLE

Studies	Sbjects	The variety of Gut microbiota	Research method
Ali AY, et al. (2025) [12]	SLE patients (n = 18)	Increased: At the phylum level: Bacteroidetes At the family level: Enterobacteriaceae, Bacteroidaceae At the genus level: Escherichia-shigella, Bacteroides Decreased: At the phylum level: Firmicutes At the family level: Ruminococcaceae, Lachnospiraceae, family XIII At the genus level: Ruminococcus, Ruminococcaceae UCG-013Faecalibacterium, Candidatus Soleaferrea, coprostanoligenes group, Agathobacter, Coprococcus	16sRNA
Zhou H, et al. (2025) [21]	SLE patients (n = 32)	Decreased: At the genus level: Eubacterium sp. CAG_38, Gemmiger formicilis, Clostridium leptum, Asaccharobacter celatus	High-throughput sequencing
Quesada S, et al. (2024) [16]	SLE patients (n = 23)	Increased: At the genus level: Collinsella, Bifidobacterium, Lactobacillus, Streptococcus, Marvinbryantia, Prevotella, Slackia	16sRNA
Ling Z, et al. (2023) [19]	SLE patients (n = 30)	Increased: At the phylum level: Firmicutes, Actinobacteria, Fusobacteria At the genus level: Lactobacillus, Gardnerella, Sneathia, Streptococcus, Anaerococcus, Finegoldia, Peptoniphilus Decreased: At the phylum level: Bacteroidetes, Proteobacteria At the genus level: Prevotella, Bacteroides, Enterobacter, Faecalibacterium, Megamonas, Phascolarctobacterium, Lachnospiraceae	16sRNA
Toumi E, et al. (2022) [13]	SLE patients (n = 14)	Increased: At the family level: Tannerellaceae family At the genus level: Alistipes, Flintibacter, Parabacteroides Decreased: Firmicutes/Bacteroidetes At the phylum level: Tenericutes	16sRNA
Wang X, et al. (2022) [17]	SLE patients (n = 19)	Increased: At the genus level: Streptococcus, Veillonella, ClostridiumXI, Rothia Decreased: At the genus level: Acidobacterium, Gemmatimonadetes, Nitrospirae, Planctomycetes, Acidobacteria_Gp6, Croceibacter, Bacillariophyta, Acetatifactor, Helicobacter, Turicibacter, Butyricicoccus, Alloprevotella	16sRNA
James WA, et al. (2022) [15]	SLE patients (n = 11)	Increased: At the phylum level: Verrucomicrobia At the genus level: Streptocococcus Decreased: At the genus level: Dialister, Azospirillum	16sRNA
Tomofuji Y, et al. (2021) [18]	SLE patients (n = 47)	Increased: At the genus level: Streptococcus intermedius, Streptococcus anginosus	Whole-genome shotgun sequencing analysis
Liu F, et al. (2021) [20]	SLE patients (n = 35)	Increased: At the genus level: Lactobacillus, L. iners, Prevotella, Blautia Decreased: At the family level: Ruminococcaceae At the genus level: B. adolescentis, B. longum	16sRNA
Chen BD, et al. (2021) [22]	SLE patients (n = 117)	Increased: At the genus level: Clostridium sp. ATCC BAA-442, Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, Clostridium leptum)	16sRNA
Wen M, et al. (2021) [23]	SLE patients (n = 33)	Increased: At the phylum level: Proteobacteria At the class level: Gammaproteo bacteria, Bacilli At the At the family level: Enterobacteriaceae At the genus level: Escherichia_Shigella, Ruminococcus, Lachnoclostridium, Kluyvera	16S rRNA
Guo M, et al. (2020) [14]	SLE patients (n = 17)	Increased: At the phylum level: Bacteroidetes At the genus level: Bacteroides, Coprococcus, Prevotella, Parabacteroides, Succinivibrio, Bilophila Decreased: Firmicutes/Bacteroidetes At the genus level: Gemmiger, Lactococcus, Bifidobacterium, Streptococcus, Desulfovibrio, Gemmiger, Dialister	16sRNA
Chen BD, et al. (2021) [22]	MRL/lpr mice (n = 9)	Increased: At the genus level: Ruminococcus torques, Blautia Decreased: At the genus level: Desulfovibrio	16sRNA
Toumi E, et al. (2022) [13]	PIL mice (n = 5)	Increased: At the phylum level: Bacteroidetes, Proteobacteria At the genus level: Blautia, Bacteroides, Parabacteroides, Lactobacillus, Ruminococcus gnavus Decreased: At the phylum level: Firmicutes, Tenericutes, Ruminococcaceae, Faecalibacterium At the genus level: Dialister, Bifidobacterium, Desulfovibrio Firmicutes/Bacteroidetes	16sRNA
Han EJ, et al. (2025) [42]	LN mice (n = 5)	Increased: At the genus level: Clostridium saudiense, Turicibacter sanguinis, Ligilactobacillus animalis, Pseudoflavonifractor phocaeensis, Intestinimonas butyriciproducens Decreased: At the genus level: Ruminiclostridium cellulolyticum, Lactobacillus johnsonii, Kineothrix alysoides	16sRNA

Role of gut microbiota in the occurrence, development, and diagnosis of SLE

Dysbiosis of the gut microbiota is strongly associated with the pathogenesis and progression of SLE. Studies have demonstrated that patients with higher SLE Disease Activity Index (SLEDAI) scores exhibit a significant reduction in the taxonomic complexity of gut microbiota. Notably, the abundance of R. gnavus from the Lachnospiraceae family increased fivefold, while protective bacterial species were concurrently diminished [24]. In newly diagnosed SLE patients, the relative abundances of Eubacterium rectale, Lachnospira pectinoschiza, and Anaerostipes hadrus were reduced and negatively correlated with SLEDAI scores, whereas Hungatella effluvii and Intestinibacter bartlettii were enriched and positively associated with SLEDAI [25]. Shotgun metagenomic sequencing revealed a marked elevation of Escherichia coli in SLE patients, which correlated positively with SLEDAI scores, particularly in those with high disease activity. Animal studies further confirmed that colonization with Escherichia coli upregulates lupus-associated serum biomarkers and exacerbates glomerular lesions in MRL/lpr mice, providing mechanistic support for the associations observed in humans, though validation in clinical settings is still required [26]. Unsupervised clustering analysis indicated that active SLE patients harbored gut microbiota enriched with Verrucomicrobia, Desulfovibrio piger, and Bacteroides thetaiotaomicron, whereas certain Firmicutes taxa (e.g., Bacilli, Clostridiales, Ruminococcaceae, and Lactobacillus) were depleted [13]. A two-sample Mendelian randomization study suggested that Bacilli and Lactobacillales were positively associated with SLE risk, whereas Bacillales, Coprobacter, and Lachnospira exhibited negative correlations. Weighted median analysis further supported Bacilli, Lactobacillales, and Eggerthella as risk factors for SLE, while Bacillales and Coprobacter served as protective factors [27]. A small-scale study involving 19 SLE patients indicated that Megamonas was positively correlated with Th17 cells, while Ruminococcus showed a positive association with Treg cells. Notably, the abundance of these bacteria did not correlate with complement C3 or C4 levels [28]. Another study of 22 iSLE patients also reported an increased abundance of Megamonas, which was negatively correlated with C3 levels [29], a finding further validated in a cohort of 50 bladder microbiome samples [30]. These findings imply a potential role of Megamonas in immune regulation and disease activity in SLE. However, it should be noted that all these studies employed cross-sectional designs and had limited sample sizes, thus indicating correlation rather than causation. The specific mechanisms underlying these observations require further validation through large-scale prospective studies and experimental investigations. Acholeplasma, Capnocytophaga, and Leptotrichia abundance decreased with rising SLEDAI scores, whereas Bacteroides, Ruminococcus, and Akkermansia levels declined with increasing serum C3 concentrations [20]. In dysbiotic microbiota, Streptococcus, Campylobacter, and Veillonella were positively associated with lupus activity, whereas Bifidobacterium correlated negatively [31]. When compared with healthy family members, lupus nephritis (LN) patients exhibited increased Streptococcus and decreased Turicibacter abundance. No significant differences were observed in the other three subgroups (rash, arthritis, and hematological involvement) [17]. Based on multiomics and bidirectional Mendelian randomization (MR) analyses, this study identified causal associations between seven gut microbial taxa and SLE. Among them, five taxa, including Lachnospiraceae UCG001 and Lactobacillus, significantly increased the risk of SLE, while two taxa, including Coprobacter and Family XIII, had protective effects. The study also revealed that SLE can reciprocally affect the abundance of Lachnospiraceae UCG004 and Prevotella7. Mediation analyses suggested that molecules including fibroblast growth factor 19 and tumor necrosis factor receptor superfamily member 9 may contribute to these causal pathways [32]. Gut microbiota alterations are not only implicated in SLE pathogenesis but may also offer novel biomarkers for early diagnosis. Machine learning (ML) algorithms leveraging significantly dysregulated microbial taxa can effectively identify SLE patients and pinpoint potential biomarkers. The expansion of the anaerobic commensal R. (Blautia) gnavus occurred exclusively during high disease activity and was detectable in nearly half of LN patients [33]. Integrated gut microbiota data enabled a random forest (RF) model to distinguish SLE, rheumatoid arthritis, and healthy controls with an area under the curve (AUC) of 0.792. Another RF model achieved an AUC of 0.811 in predicting SLE disease activity [31]. ROC analysis identified Anaerococcus, Gardnerella, and Lactobacillus as potential diagnostic biomarkers for discriminating SLE patients from healthy controls (AUC: 0.828–0.836) [19]. In summary, gut microbiota dysbiosis is closely linked to SLE disease activity, SLEDAI scores, and immunological markers, underscoring its critical role in disease progression and diagnostic potential for SLE.

Mechanisms of gut microbiota in the pathogenesis of SLE

Intestinal barrier dysfunction and gut microbiota translocation play a pivotal role in the pathogenesis of SLE. The composition of the gut microbiota, particularly the presence of Bifidobacterium, may critically regulate inflammation and coagulation processes in SLE patients, especially those with concurrent metabolic disturbances, such as hyperlipidemia [34]. In human lupus patients, especially those with active LN, the intestinal abundance of R. gnavus is significantly increased, and the bacterium translocates to mesenteric lymph nodes. This translocation elevates serum zonulin (a key regulator of intestinal tight junctions), which further impairs gut barrier integrity and increases intestinal permeability. The disruption of the intestinal barrier triggers autoimmune responses, manifesting as elevated anti-RG lipopolysaccharide IgG and anti-double-stranded DNA (anti-dsDNA) autoantibodies [35]. In juvenile lupus-prone female SNF1 mice, reduced expression of adherence junction proteins correlates with increased intestinal permeability and enhanced microbial translocation across the gut epithelial barrier [36]. In the MRL/lpr mouse model of SLE, gut microbiota dysbiosis contributes to disease pathogenesis by augmenting oxidative stress, impairing intestinal barrier function (demonstrated by decreased zonula occludens-2 expression, elevated fecal albumin, and IgA levels), and inducing local and systemic inflammation (characterized by increased phosphorylated nuclear factor-κB, IL-6, and IgG levels) [37]. Defective T-cell receptor signaling leads to aberrant Th17 cell differentiation, altering gut microbiota composition and subsequently driving systemic autoimmune disease [38]. In addition, a low-fiber diet exacerbates SLE progression by increasing white adipose tissue mass, promoting adipose inflammation, disrupting gut homeostasis, and sustaining a systemic low-grade inflammatory state [39]. In SLE patients, immune responses targeting Enterococcus gallinarum are associated with the production of lupus-specific autoantibodies, including anti-ribosomal P, anti-dsDNA, and anti-Smith antibodies. This finding supports the hypothesis that E. gallinarum may act as a pathogenic trigger in genetically susceptible individuals, implicating its potential role in SLE pathogenesis [40]. In triple congenic lupus-prone mice, expansion of Prevotella, Paraprevotella, and Lactobacillus—microbes capable of metabolizing tryptophan into immunomodulatory indole derivatives—may adversely influence immune cell function [41]. Translocated E. gallinarum induces Th17 cell differentiation and IgG3 anti-RNA autoimmune responses in both murine and human systems, elevating anti-RNA autoantibody titers and correlating with renal autoimmune pathology in gnotobiotic lupus models and disease activity in SLE patients [42]. Collectively, these studies suggest that aberrant proliferation and translocation of gut microbiota (e.g., R. gnavus and E. gallinarum) contribute to SLE development by impairing intestinal barrier function, activating autoimmune responses, and sustaining systemic inflammation (Fig. 1). Furthermore, gut microbiota dysbiosis serves as a key driver of oxidative stress in SLE. Studies in the MRL/lpr lupus-prone mouse model have demonstrated that gut dysbiosis can induce intestinal oxidative stress, compromise the gut barrier (evidenced by reduced ZO-2 and elevated fecal albumin and IgA), promote bacterial translocation, and exacerbate systemic inflammation and autoimmune responses [37]. Future research should elucidate the precise mechanisms by which gut microbiota influences SLE pathogenesis, particularly its role in barrier disruption, immune activation, and inflammatory cascades.

Fig. 1.

Mechanisms of gut microbiota in the pathogenesis of SLE. (By Figdraw)

Microbial metabolites in SLE patients

Alteration of metabolites in SLE patients

The gut microbiota exerts a profound influence on host physiology through its metabolic products, which function as signaling molecules and metabolic precursors in diverse physiological processes. Emerging evidence reveals distinct metabolic profiles in SLE patients compared to healthy individuals, characterized by alterations in amino acid metabolism, lipid metabolism, and short chain fatty acids (SCFAs) [9]. In severe lupus-prone murine models, depletion of beneficial bacterial strains, including Ruminiclostridium cellulolyticum, Lactobacillus johnsonii, and Kineothrix alysoides, is associated with significantly decreased intestinal butyrate and lactate concentrations. Such dysbiosis-induced metabolic alterations may subsequently impair FOXP3 expression, ultimately resulting in compromised Treg cell function [43]. Similarly, in SLE patients, depletion of Faecalibacterium species resulted in diminished butyrate production, attenuating its anti-inflammatory properties and thereby exacerbating both disease progression and inflammatory responses [44]. Liquid chromatography–mass spectrometry (LC–MS) analysis of serum from 28 SLE patients identified significant downregulation of L-tryptophan, patuletin, tridecanol, 3,4-dihydroxybenzeneacetic acid, and indoleacrylic acid, alongside upregulated palmitic acid levels compared to healthy controls [45]. Conversely, gas chromatography–MS of fecal samples from 33 pediatric SLE patients demonstrated enrichment of L-tryptophan, tyramine, L-phenylalanine, and L-glutamine [23]. These discordant observations regarding L-tryptophan may reflect tissue-specific differences or age-dependent metabolic regulation in SLE. Untargeted metabolomics revealed elevated serum acylcarnitine (18:1) and isocitric acid levels in 47 SLE patients, positively correlating with S. intermedius abundance [18]. LC–MS profiling of 21 SLE patients detected 43 serum and 55 fecal metabolites with significant alterations, of which > 65% were lipid-related, underscoring pervasive lipid homeostasis disruption in SLE [46]. Furthermore, analysis of 80 SLE patients without cardiovascular disease identified global shifts in lipoprotein profiles, with medium–high-density lipoprotein (HDL) cholesterol esters most discriminatory for healthy controls, and small HDL phospholipids, small very low density lipoprotein (VLDL) phospholipids, very large VLDL-free cholesterol %, and intermediate-density lipoprotein phospholipids most associated with SLE classification [47]. SLE patients exhibit pronounced disturbances in amino acid, lipid, and SCFA metabolism, potentially linked to disease mechanisms. In addition, alterations in metabolites may be influenced by various factors such as dietary intake (e.g., amino acid and lipid sources), drug metabolism, and hepatic or renal function. Therefore, caution is warranted when interpreting the association between these metabolic changes and SLE, as confounding factors must be carefully considered. The current studies are often limited by small sample sizes, which restricts the generalizability of the findings. Future large-scale, multicenter studies are needed to further validate the relationship between these metabolic disturbances and the etiology of SLE.

Role of metabolites in the occurrence, development, and diagnosis of SLE

A growing body of evidence has demonstrated significant associations between metabolomic profiles of SLE patients and key clinical features including disease activity, subclinical atherosclerosis, and renal involvement [10]. E. coli-associated metabolic pathways—particularly the super-pathway of purine nucleotide salvage and peptidoglycan maturation pathway—show positive correlations with SLEDAI scores, suggesting that E. coli exacerbates SLE progression through metabolic reprogramming [26]. Plasma analysis of 132 SLE patients revealed significantly elevated levels of tryptophan (TRP) metabolites kynurenine (KYN) and quinolinic acid (QA) compared to healthy controls. The KYN/TRP ratio was positively correlated with the disease activity index SLEDAI [48]. Further investigation confirmed that an increased QA/KYN ratio was associated with impaired working memory and visuospatial processing abilities in SLE patients. As an N-methyl-D-aspartate receptor agonist, QA may contribute to neuronal damage through glutamatergic excitotoxicity, an effect particularly pronounced in SLE subgroups with high IFN activity [49, 50]. Moreover, SLE patients with renal involvement exhibited significantly higher serum KYN levels and KYN/TRP ratios than those without renal damage, suggesting that activation of the kynurenine pathway may exacerbate glomerular mesangial cell injury via pro-oxidative mechanisms [51] (Fig. 2). Additionally, in patients with juvenile-onset SLE, comparative analysis between high versus low carotid intima–media thickness progression groups identified 48 significantly upregulated metabolites. Following stringent Bonferroni correction, the six most prominently elevated metabolites were: total esterified cholesterol, total cholesterol, phospholipids in small low density lipoprotein (LDL), cholesterol in small LDL, free cholesterol in medium LDL, and total lipids in small LDL. This distinct lipidomic profile demonstrates a proatherogenic metabolic signature characteristic of juvenile-onset SLE patients with accelerated carotid intima–media thickness progression [52]. Ultra-performance liquid chromatography-tandem mass spectrometry profiling identified 29 dysregulated metabolites primarily involved in fatty acid metabolism and phospholipid catabolism. Specifically, elevated pyroglutamic acid and L-phenylalanine levels characterized SLE patients, while taurine accumulation marked LN, indicating their potential as stage-specific biomarkers [53]. Univariate logistic regression further pinpointed four metabolites linked to subclinical plaque formation: leucine, medium VLDL-free cholesterol_%, large VLDL-free cholesterol_%, and extremely large VLDL-phospholipids_% [46]. Using these differentially expressed metabolites as features, an integrated LC–MS and machine learning (ML) approach demonstrated that a logistic regression (LR) model achieved optimal performance in classifying serum samples (AUC = 0.933), indicating its strong power to distinguish SLE from other autoimmune diseases (ADs) [45]. In female SLE patients, coronary artery calcification progression was associated with significant alterations in lipidomic and metabolomic profiles. The combination of metabolomics, lipidomics, and clinical parameters significantly enhanced coronary artery calcification prediction accuracy (AUC = 0.887) [53]. A comparative analysis of 89 SLE patients and healthy controls identified 146 differentially expressed metabolites, primarily comprising organic acids, amino acids, and bile acids. ML-assisted biomarker screening yielded an eight-metabolite panel (AUC > 0.95) showing significant correlations with clinical parameters. Subsequent validation highlighted N-methyl-L-glutamic acid and L-2-aminobutyric acid as potential SLE classifiers (AUC > 0.775), which were significantly associated with SLEDAI [54]. Collectively, these findings establish that SLE-associated metabolomic signatures are closely linked to disease activity, atherosclerotic progression, and renal impairment, with specific metabolites emerging as potential diagnostic biomarkers or therapeutic targets. However, the clinical applicability of these biomarkers requires validation of their sensitivity and specificity, and large-scale cohort studies are needed to substantiate these preliminary findings.

Fig. 2.

Mechanisms of tryptophan metabolism in the pathogenesis of SLE. (By Figdraw)

Mechanisms of metabolites in the pathogenesis of SLE

The pathogenesis of SLE involves intricate interactions between metabolic and immunoregulatory networks. Gut dysbiosis, particularly the depletion of beneficial bacteria such as Ligilactobacillus murinus and Faecalitalea rodentium, disrupts lipid and amino acid metabolism, thereby exacerbating disease progression. This microbial imbalance suppresses the production of protective metabolites (e.g., γ-linolenic acid and oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) while promoting the accumulation of pathogenic metabolites like arginine, ultimately compromising metabolic homeostasis and aggravating lupus symptoms [55]. In SLE patients, gut microbiota disturbances lead to abnormal SCFA production, which correlates with elevated serum free fatty acid (FFA) levels and endothelial activation markers. This SCFA–FFA metabolic imbalance reflects host–microbiome interplay, suggesting that gut dysbiosis contributes to SLE pathogenesis by modulating FFA profiles and SCFA concentrations [56]. Notably, deficiency of SCFAs (acetate and butyrate) not only impairs GPR43/GPR41 signaling, promotes Th17 cell differentiation, and disrupts intestinal barrier integrity, but also compromises their crucial antioxidant functions. Butyrate, acting as a histone deacetylase inhibitor, activates the core antioxidant pathway—the Nrf2 signaling axis. SCFA deficiency suppresses the expression of downstream antioxidant enzymes (such as heme oxygenase-1), thereby increasing the susceptibility of intestinal epithelial cells and immune cells to oxidative damage and exacerbating systemic oxidative stress. This mechanism ultimately aggravates hypertension and vascular dysfunction in a TLR7-driven lupus mouse model [57]. In SLE patients, the abundance of Firmicutes in the gut is significantly reduced, leading to decreased production of their metabolites, SCFAs (such as butyrate and propionic acid). This change impairs the normal function of Treg cells while triggering abnormal activation of B cells, resulting in the excessive production of autoantibodies such as anti-dsDNA. In addition, elevated levels of proinflammatory cytokines IL-6 and IL-12 and impaired intestinal barrier function increase permeability, allowing harmful substances like lipopolysaccharides to translocate into the bloodstream. This triggers systemic overactivation of the immune system, ultimately exacerbating SLE progression [58]. A two-sample Mendelian randomization and meta-analysis revealed that five lipid metabolites—1-arachidonoylglycerophosphoethanolamine, 1-oleoylglycerophosphoethanolamine, 1-myristoylglycerophosphocholine, arachidonate (20:4 n6), and glycerol—have a causal relationship with AD diseases, including SLE, providing new insights into the mechanisms of AD development mediated by serum metabolites. In SLE patients, reduced spermine levels in peripheral blood mononuclear cells are associated with enhanced IFN-I signaling activation via the Janus kinase (JAK) pathway and an intensified lupus-related gene signature. Spermine directly binds to JAK1 and inhibits its activity, alleviating autoimmune pathogenesis in SLE mouse models while reducing excessive IFN-I signaling activation in SLE patient monocytes [59]. The gut microbiota-derived metabolite inosine is a key regulator in SLE. It suppresses B cell differentiation and migration in a dose-dependent manner, reduces autoantibody production and renal B cell infiltration, thereby inhibiting core immunopathological processes in SLE. This regulatory effect depends on a critical signaling axis involving the inhibition of ERK1/2 phosphorylation and subsequent downregulation of hypoxia-inducible factor-1α expression, which constitutes the central molecular mechanism through which inosine modulates B cell function [60]. A recent study involving 41 patients with active SLE revealed a reduction in beneficial gut bacteria such as Faecalibacterium and Ruminococcus, alongside an enrichment of pathobionts like Escherichia–Shigella. These microbial alterations were associated with elevated levels of zonulin, a marker of intestinal barrier impairment. Zonulin promoted T follicular helper (Tfh) cell differentiation and suppressed T follicular regulatory (Tfr) cell function—through mechanisms yet to be fully elucidated—leading to an increased Tfh/Tfr ratio. Concurrently, gut microbiota-driven dysregulation of the IL-2/IL-21 cytokine axis further amplified this immune imbalance, ultimately exacerbating autoantibody production and organ damage. These findings highlight a significant interplay between gut dysbiosis, increased intestinal permeability, and Tfh/Tfr immune dysregulation in SLE [61]. Itaconate, a mitochondria-derived immunometabolite, is significantly downregulated in patients with active SLE, and the loss of its antioxidant protection may contribute to disease activity [62]. Its derivative, 4-octyl itaconate (4-OI), activates the Nrf2 pathway by alkylating Keap1, thereby inducing antioxidant enzymes such as HO-1 and NQO1 to scavenge reactive oxygen species and alleviate oxidative stress in SLE. Concurrently, 4-OI reduces the levels of proinflammatory cytokines including TNF-α and IL-1β in peripheral blood mononuclear cells and suppresses NF-κB activity [63]. In lupus-prone mice, 4-OI ameliorates renal immune complex deposition, decreases autoantibody production, and attenuates hyperactivation of immune cells via inhibition of JAK1 [64]. These findings suggest that targeting the regulation of gut microbiota and metabolites such as itaconate to control oxidative stress represents a promising novel therapeutic strategy for SLE.

The mTOR pathway functions as a central metabolic stress sensor, inflammatory effector, and therapeutic target in SLE, where it significantly contributes to immune dysregulation and organ damage [65]. At the metabolic level, elevated phosphatidic acid (PA) levels in T cells from both SLE patients and murine models directly activate mTORC1. This occurs through the dissociation of the inhibitory protein DEPTOR from the mTOR complex, with PA levels showing a positive correlation with downstream p-S6 phosphorylation [66]. In addition, T cell metabolic alterations, including enhanced glycolysis, mitochondrial hyperpolarization, and reduced ATP synthesis, further activate mTOR via the PI3K/Akt pathway. These effects are potentiated by increased cytosolic Ca²⁺ levels [67]. The tryptophan metabolite kynurenine also indirectly enhances mTORC1 activity through the pentose phosphate pathway. Meanwhile, oxidative stress-induced glutathione depletion sustains a feed-forward cycle of metabolic stress, leading to persistent mTOR activation [68]. From an immunological perspective, mTOR activation promotes the differentiation of CD4⁺T cells into Th17 cells while simultaneously suppressing Treg function. This results in a Th17/Treg imbalance and increased secretion of proinflammatory cytokines such as IL-17 [69]. Moreover, mTOR drives the expansion of CD4⁻CD8⁻ double-negative T cells and stimulates their production of IL-17A, thereby enhancing autoantibody generation [66]. In B cells, hyperactivation of the PI3K/Akt/mTORC1 axis facilitates plasma cell differentiation and promotes anti-dsDNA antibody production [70]. Within the context of LN, mTORC1 activation correlates positively with crescent formation and renal interstitial fibrosis. It also promotes macrophage and T cell infiltration, thereby exacerbating kidney injury. The activity level of mTORC1 serves as an indicator of disease severity and prognosis [71]. Therapeutically, the mTORC1 inhibitor rapamycin has been shown to reduce IL-17 secretion, restore Treg function, decrease autoantibody titers, and ameliorate nephritis [69]. N-acetylcysteine (NAC) suppresses mTOR activation by restoring glutathione levels and exhibits synergistic effects with rapamycin in reducing disease activity [68]. Furthermore, the dual mTORC1/mTORC2 inhibitor INK128 improves renal pathology in lupus-prone mice and suppresses NLRP3 inflammasome activation [72].

In summary, metabolic regulation and gut microbiota remodeling play pivotal roles in the pathogenesis of SLE (Fig. 3). The interplay between dysregulated metabolites (e.g., SCFAs, itaconic acid) and oxidative stress is particularly critical, which directly affects immune cell function, inflammatory pathways, and end-organ damage. However, further investigation is required to elucidate how these metabolites precisely modulate disease progression through immune, inflammatory, and oxidative stress-related pathways.

Fig. 3.

Mechanisms of metabolites in the pathogenesis of SLE. (By Figdraw)

Core regulatory network of gut microbiota–metabolite–immune axis in SLE pathogenesis

The interaction between gut microbiota, their metabolites, and the host immune system constitutes a central regulatory network in the pathogenesis of SLE. This network originates from gut dysbiosis, characterized by a reduction in beneficial bacteria and an expansion of potential pathobionts, which subsequently drives immune dysregulation and disease progression through metabolic reprogramming and barrier disruption. Dysbiosis leads to altered levels of key metabolites: reduced SCFAs (e.g., butyrate, acetate) impair support for Treg cell differentiation and inhibition of Th17 responses, while compromising intestinal barrier integrity; a shift in tryptophan metabolism toward the kynurenine pathway promotes oxidative stress and Th17 differentiation; and dysregulated lipid metabolism increases pro-inflammatory lipids, exacerbating vascular endothelial activation. Concurrently, microbial and metabolic alterations damage gut barrier function. Insufficient SCFAs result in thinning of the mucus layer and decreased expression of tight junction proteins. Translocation of opportunistic pathogens further increases intestinal permeability, allowing metabolites such as LPS to enter the circulation and activate TLR signaling, especially the TLR7/9 signaling pathway, and triggering innate immunity and type I interferon response. These changes collectively contribute to a breakdown in immune homeostasis, the Treg/Th17 balance shifts toward a pro-inflammatory state, Tfh cells promote B cell hyperactivation and autoantibody production, and mTOR pathway activation enhances glycolytic metabolism and inflammatory cytokine release in immune cells, ultimately leading to multitissue injury. This network underscores the essential role of bidirectional “microbiota–metabolite–immune” crosstalk in SLE and provides a rationale for targeted interventions (such as FMT, probiotics, metabolite supplementation, etc.), aiming to restore immune homeostasis through multiple pathways (Fig. 4).

Fig. 4.

The gut microbiota-metabolite-immune axis in SLE pathogenesis. (By Figdraw)

Microbiota and metabolism in treatment of SLE

FMT

The treatment of SLE still faces many challenges. Conventional therapies (such as glucocorticoids and immunosuppressants) have limited efficacy in some patients and may be accompanied by significant side effects [73]. FMT, as an emerging therapeutic strategy, involves transplanting fecal microbes from healthy donors into the recipient's intestines to modulate microbial and immune balance, offering a novel treatment approach for autoimmune diseases such as SLE [74]. A study involving 22 SLE patients found that FMT restored gut microbiota balance, upregulated S-adenosylmethionine levels, and increased whole-genome DNA methylation, thereby improving the methylation status of promoter regions in genes such as IFN-γ, induced helicase C domain containing protein 1, endoplasmic reticulum membrane protein complex 8, and tripartite motif-containing protein 58, correcting abnormal hypomethylation [75]. Another clinical trial confirmed that 20 SLE patients with SLEDAI scores ≥ 6 who received oral encapsulated fecal microbiota from healthy donors showed significant improvements in gut microbiota composition and metabolites. This was characterized by an increase in SCFA-producing bacteria (Eubacterium hallii group, Dorea, Marvinbryantia, and Papillibacter) and a decrease in inflammation-associated microbiota (Prevotella, Veillonella, and Burkholderiales), along with reduced serum IL-6 levels and a lower ratio of CD4 + memory/naive T cells [76]. Single-cell RNA sequencing analysis revealed that, in 13 SLE patients after FMT treatment, peripheral T lymphocytes decreased while natural killer cells increased. In addition, CD4 and CD8 T cells exhibited high expression of IL7R, CD28, GZMH and NKG7 genes. FMT reduced the expression of IFN-related genes in CD4 T, CD8 T, natural killer, and B cells. IFN-related pathways were more enriched in the FMT nonresponder group, and IFN gene expression was negatively correlated with FMT therapeutic efficacy [77]. Studies have found that compared to male BWF1 mice, female mice exhibited significantly impaired macrophage exocytosis, but this defect could be restored by feeding them the microbiota of male mice [78]. Rectal administration of fecal transplants from 2 to 4-month-old healthy mice into lupus model mice rebalanced the gut microbiota and alleviated lupus severity [79] 61. FMT shows significant potential to modulate immune responses, improve gut dysbiosis, and correct metabolic abnormalities in SLE patients. However, current research still has limitations, including small sample sizes and incomplete mechanistic understanding. Future studies should involve larger-scale and more in-depth clinical and basic research to validate the efficacy of FMT and optimize treatment protocols, providing safer and more effective therapeutic options for SLE patients.

Probiotics, prebiotics, and synbiotics

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. By restoring gut microbiota balance and enhancing immune regulation, they may help ameliorate autoimmune responses and reduce disease severity [80]. Lactobacillus rhamnosus LC-STH-13 alleviates renal inflammation and complement-mediated kidney injury by inhibiting the TLR9/NF-κB pathway while suppressing SLE progression through gut microbiota restoration, offering a novel therapeutic strategy [81]. Two randomized controlled trials demonstrated that therapy based on Bifidobacterium and Lactobacillus triple viable bacteria significantly increased complement C3 levels in SLE patients [82]. In MRL/lpr mice, supplementation with Bifidobacterium, its total metabolites, or SCFAs was found to reduce the proportions of B cells and IgG1⁺ plasma cells in the spleen and mesenteric lymph nodes, and decrease the secretion of anti-dsDNA and ANA antibodies. Furthermore, it increased the frequency of Treg cells and levels of TGF-β, while inhibiting the activation of Tfh and Th17 cells as well as the production of IL-21. These changes were accompanied by reduced inflammatory infiltration and IgG deposition in the glomeruli, along with decreased urinary protein levels. These findings provide a translational foundation for the use of probiotics as an adjunct therapy in LN [83]. Oral administration of a mixture of five Lactobacillus species (rhamnosus, gasseri, johnsonii, reuteri, and oris) effectively improved lupus-like clinical symptoms by reducing lymphadenopathy and splenomegaly [84]. Treatment with Lactobacillus spp. significantly ameliorated glomerulonephritis in female Cx3cr1-deficient MRL/lpr mice by modulating the gut microbiota, reversing disease progression [85]. Further studies revealed that supplementation with Akkermansia muciniphila and Lactobacillus plantarum promoted an anti-inflammatory environment by reducing IL-6 and IL-17 levels while increasing circulating IL-10. These interventions also partially restored gut barrier integrity, reduced renal IgG deposition, and significantly improved kidney function [86]. In a murine lupus model, oral Lactobacillus acidophilus restored cecal microbiota composition in lupus-prone mice and regulated the Th17/Treg cell balance by decreasing Th17 cells and increasing Treg cell proportions, while enhancing the efficacy of the immunosuppressant tacrolimus [87]. Additionally, the probiotics Lactobacillus fermentum CECT5716 and Bifidobacterium breve CECT7263 prevented hypertension and endothelial dysfunction in a TLR-7-activated SLE model by modulating gut microbiota, suppressing autoimmune responses, improving immune balance, and restoring vascular endothelial function [88]. Treatment with L. fermentum CECT5716 also significantly reduced disease activity in lupus mice, as demonstrated by decreased plasma proinflammatory cytokines, improved endothelial dysfunction, and reduced NADPH-oxidase-driven superoxide production; thereby, alleviating lupus-associated vascular damage. This intervention simultaneously enhanced gut barrier integrity and increased Bifidobacteria abundance in the gut microbiota [89].

In exploring adjuvant therapeutic strategies for SLE, prebiotics and their related bioactive substances have demonstrated potential therapeutic value. Curcumin has shown significant efficacy in reducing proteinuria and alleviating renal inflammation, but its optimal dose and treatment duration require further investigation, particularly in different SLE subtypes [90]. Resveratrol mediates therapeutic effects through multiple mechanisms, including suppressing immune cell hyperactivation, reducing proinflammatory cytokine levels, and decreasing autoantibody production, which makes it a promising candidate for SLE treatment [91]. In imiquimod-induced lupus mice, the prebiotic Hirsutella sinensis polysaccharides and the probiotic Parabacteroides goldsteinii significantly reduced disease markers, including spleen weight, proteinuria, anti-dsDNA autoantibodies, and STAT signaling levels, while improving renal and hepatic function parameters. Although these prebiotics and probiotics did not markedly alter gut microbiota composition or colonic histology, their potential in alleviating lupus symptoms suggests they could serve as complementary strategies within a healthy lifestyle intervention to combat autoimmune diseases [92].

Synbiotics, a combination of prebiotics and probiotics, demonstrate significantly enhanced efficacy as compared to individual components due to their synergistic effects [93]. A randomized double-blind controlled trial revealed that synbiotic supplementation increased the F/B ratio in the gut microbiota of SLE patients, promoted butyrate metabolism, reduced IL-6 levels and systemic inflammation, thereby improving SLEDAI scores [94]. Another randomized double-blind controlled trial confirmed that synbiotic intervention significantly decreased IL-17A protein and its mRNA expression levels in SLE patients while improving SLEDAI score, suggesting that synbiotics serve as an adjunctive therapy for SLE [93]. In 12 newly diagnosed LN patients, synbiotic administration induced significant alterations in gut microbiota composition: the relative abundance of pathogenic bacteria (including Prevotella, Bacteroides, and unclassified Enterobacteriaceae) decreased, whereas beneficial bacterial populations (such as Actinobacteria and Firmicutes) showed marked increases [95]. These studies suggest that probiotics, prebiotics, or synbiotics could have multifaceted therapeutic effects in SLE by modulating the gut microbiota, improving immune balance, restoring vascular endothelial function, and attenuating inflammatory response.

However, the current research remains largely limited to animal models and small-scale clinical trials, necessitating further large-scale, multicenter clinical studies to validate their efficacy and safety.

Diet

Although pharmacotherapy remains the mainstay of treatment, adjunctive measures such as dietary modifications and nutritional supplementation can provide additional benefits, improving patients' overall health and quality of life [96]. Resistant starch and inulin-type fructans have been shown to improve intestinal inflammation, endotoxemia, and immune responses in SLE mouse models by increasing the proportion of acetate-producing bacteria (e.g., Bacteroides acidifaciens) and butyrate-producing bacteria (e.g., A. muciniphila), and concurrently decrease Th17 cell proportions [97]. In addition, resistant starch reduces organ involvement and mortality rates by decreasing the abundance and translocation of Lactobacillus reuteri, thus inhibiting plasmacytoid dendritic cells and interferon signaling pathways [98]. High dietary fiber intake significantly reduces systemic low-grade inflammation by maintaining gut homeostasis, reducing white adipose tissue accumulation, and suppressing adipose inflammation, thus slowing the progression of lupus-like diseases [99]. Clinical evidence further supports the efficacy of nutritional interventions. A meta-analysis demonstrated that omega-3 fatty acid supplementation significantly reduces disease activity in adult SLE patients (with an average decrease of 0.9 points in SLEDAI scores) [100]. Diets rich in unsaturated fatty acids (e.g., omega-3 and omega-6) not only lower SLEDAI scores but also improve HDL levels [101]. Furthermore, reduced dietary tryptophan intake has a protective effect in lupus mouse models, whereas high-tryptophan diets exacerbate inflammatory phenotypes [41]. High-fat diets and obesity may play a significant role in SLE pathogenesis by influencing adipokine (e.g., leptin and adiponectin) levels and gut microbiota diversity. Vitamin D deficiency is common among SLE patients, and supplementation may have positive implications for immunoregulation and disease management [102]. A cross-sectional study of 280 SLE patients further indicated that higher adherence to a Mediterranean diet was significantly associated with lower disease activity, reduced cumulative organ damage, and decreased cardiovascular risk, suggesting that the Mediterranean diet may benefit SLE management and health improvement [103]. Although pharmacotherapy remains central to SLE management, current treatment strategies have limitations, such as inadequate response or side effects in some patients. An integrated management approach combining nutritional and dietary interventions may offer SLE patients more comprehensive treatment options, thereby improving disease prognosis and quality of life. Future research should further explore optimal personalized nutritional interventions and their potential applications across different SLE subtypes.

Others

In the recent years, alongside the recognized roles of FMT, probiotics, prebiotics, synbiotics, and dietary interventions in SLE management, therapies such as phage-based treatments have gained increasing attention. Bacteriophages modulate gut microbiota by lysing host bacteria or altering their physiological functions [104]. Specific phages like CrAss-like phages and Podoviridae may restore gut microbial balance by targeting bacterial species such as Ruminococcus and Faecalibacterium, offering potential therapeutic strategies for SLE. Notably, certain microbial signatures—particularly Prevotella spp.—show significant positive correlation with proteinuria levels and contribute to renal dysfunction progression [105]. Furthermore, Prevotella is associated with increased plasma cell proportions in mesenteric lymph nodes of lupus-prone mice. Targeted modulation of specific Prevotella spp. may effectively ameliorate lupus symptoms and suppress disease progression, providing a translational foundation for microbiota-targeted therapies in SLE patients [106]. Proton pump inhibitors, originally developed as acid-suppressing agents for gastric ulcer treatment in SLE patients, demonstrate unexpected benefits in normalizing gut microbial α-diversity. Their use correlates with increased abundance of beneficial bacteria (e.g., Lactobacillus, Roseburia, Oxalobacter, and Desulfovibrio) while reducing opportunistic pathogens (e.g., Veillonella, Escherichia, Morganella, Pseudomonas, and Stenotrophomonas) [107]. Intravenous immunoglobulin provides a novel therapeutic direction for SLE by modulating gut microbiota balance and improving the intestinal microenvironment. In addition, its antioxidant properties reduce oxidative stress markers and regulate immune responses, further supporting its potential in SLE treatment [108]. In a preclinical study using MRL/lpr mice at early-stage SLE (6–10 weeks old), researchers administered three intravenous transplantations of human umbilical cord mesenchymal stem cells (hUC-MSCs) via the tail vein. The treatment significantly enriched beneficial gut bacteria such as Lactobacillus johnsonii and Romboutsia ilealis, while promoting the generation of tryptophan metabolites and butyrate precursors in plasma. These metabolites stably bound to and activated the aryl hydrocarbon receptor, triggering downstream signaling that enhanced the expression of the tight junction protein ZO-1, thereby restoring intestinal barrier integrity. Concurrently, the treatment suppressed aberrant B-cell activation and pro-inflammatory cytokine release. Ultimately, these effects led to reduced autoantibody levels, amelioration of LN, and sustained therapeutic benefits observable up to 22 weeks of age [109]. Various gut microbiota-targeted interventions, including phage therapy, proton pump inhibitors, intravenous immunoglobulin, and hUC-MSC open new avenues for SLE management. Future studies should further elucidate their mechanisms and promote clinical translation (Fig. 5).

Fig. 5 .

The therapeutic strategies of SLE based on gut microbiota. (By Figdraw)              Please insert Figure 5 image here.

Microbiota-targeted therapy is an emerging potential strategy for SLE treatment, but it needs to overcome three core issues: safety, feasibility, and regulation. Regarding safety, FMT currently lacks standardized donor screening criteria, and safe abundance thresholds for potentially harmful bacteria such as Streptococcus remain undefined, raising concerns that inappropriate transplantation may exacerbate autoimmunity. Bacteriophage therapy carries risks related to horizontal gene transfer and off-target effects. Long-term use of PPIs is associated with gastrointestinal adverse events, while IVIg presents a risk of transfusion-transmitted infections. Even probiotics may cause gastrointestinal discomfort or disrupt ecological balance in susceptible individuals. In terms of feasibility, FMT is procedurally complex and not yet widely standardized. Bacteriophage therapies face challenges in large-scale production and regulatory alignment with conventional pharmaceutical standards. PPIs require precise dosing strategies to minimize off-target effects. IVIg is limited by supply constraints and high costs. Probiotics exhibit considerable interindividual variability in response, complicating the development of personalized regimens. Regulatory frameworks for these interventions remain underdeveloped, with an urgent need for targeted quality control standards and trial guidelines specific to each modality. Therefore, rigorous clinical trials, long-term safety monitoring, and multidisciplinary collaboration are essential to establish evidence-based protocols and facilitate the safe and effective clinical application of microbiota-targeted therapies in SLE.

Conclusion and prospects

This review systematically examines the compositional characteristics of gut microbiota and serum metabolites in SLE patients, while elucidating the diagnostic applications of microbiome and metabolome profiling and their functional roles in disease progression. The abnormal proliferation of specific microbial taxa and their metabolites (such as SCFAs and tryptophan derivatives) contribute to SLE development by compromising intestinal barrier integrity, triggering autoimmune responses, and promoting systemic inflammation. Microbiota-targeted interventions, including FMT, probiotics, prebiotics, synbiotics, and phage therapy, have shown potential to restore immune homeostasis, improve the gut microenvironment, and alleviate clinical symptoms. Furthermore, dietary modifications (e.g., resistant starch and Mediterranean diet) have been proven to modulate microbial composition and metabolic profiles, thereby improving SLE outcomes. These findings provide novel insights for precision medicine approaches in SLE management, particularly for refractory cases that respond poorly to conventional therapies.

However, several limitations remain in current research. The causal relationship between gut microbiota and SLE has not been fully established, and the precise mechanisms by which microbial metabolites regulate immune responses require further elucidation. Moreover, most clinical trials are constrained by small sample sizes and a lack of long-term follow-up data. Future studies should prioritize the systematic recording and control of potential confounders (e.g., diet, medication, geographic region, and lifestyle). Employing multivariable statistical models or machine learning to adjust for these variables will enhance the specificity and predictive power of microbiome and metabolome markers. Furthermore, multicenter, multiethnic cohort studies are needed to determine the universality and specificity of SLE-associated microbial and metabolic signatures. Subsequent research should also integrate multiomics technologies such as metagenome, metabolome, and single-cell sequencing to gain deeper insights into the microbiota-host interaction network. Large-scale prospective cohorts will be essential to validate the diagnostic and prognostic value of specific microbial or metabolic biomarkers. Ultimately, the development of personalized intervention strategies and combination therapies holds promise for advancing more precise and effective treatment paradigms for SLE.

Abbreviations

AD

Autoimmune disease

anti-dsDNA

Anti-double-stranded DNA

AUC

The receiver-operating characteristic curve

C3

Complement 3

CIMT

C arotid intima-media thickness

F/B

Firmicutes/Bacteroidetes

FFA

Free fatty acid

FMT

Fecal microbiota transplantation

HDL

High-density lipoprotein

IL

Interleukins

IFN

Interferon

JAK

Janus kinase

LC–MS

Liquid chromatography-mass spectrometry

LN

Lupus nephritis

LDL

Low density lipoprotein

ML

Machine learning

RF

Random forest

SLE

Systemic lupus erythematosus

SLEDAI

SLE disease activity index

SCFAs

Short chain fatty acids

TLR

Toll-like receptor

VLDL

Very low density lipoprotein

KYN

Kynurenine

QA

Quinolinic acid

TRP

Tryptophan

Tfh

T follicular helper cells

Tfr

T follicular regulatory cells

Treg

Regulatory T cells

Th17

T helper 17 cells

4-OI

4-Octyl itaconate

NAC

N-acetylcysteine

hUC-MSCs

Human umbilical cord mesenchymal stem cells

Author contributions

J.Y. and X.C:writing–original draft preparation; J.Y. L.W. and J.Z:writing–review & editing; L,D., S.Z. and X.L:references collection, tables and figures organization; J.Y. and J.Z:visualization, investigation. J.Y.:acquisition of funds.

Funding

This study was supported by the Special Fund Project of Yancheng Science and Technology Bureau (No.YCBE202475), the Medical Research Project of Yancheng Health Commission (No.YK2023130), and the Special Scientific Research Fund for Clinical Medicine of Nantong University (No.2024LZ006), (2024LZ008).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.