Microbiological Research 281 (2024) 127613

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Microbiological Research
journal homepage: www.elsevier.com/locate/micres

The influence and therapeutic effect of microbiota in systemic

lupus erythematosus
Chuzi Mo a, 1, Jiaming Bi a, 1, Siwei Li a, Yunhe Lin a, Peiyan Yuan a, Zhongjun Liu a, *, Bo Jia b, *,
Shuaimei Xu a, *
a
Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
b
Department of Oral and Maxillofacial Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China

A R T I C L E I N F O A B S T R A C T

Keywords: Systemic erythematosus lupus (SLE) is an autoimmune disease involving multiple organs that poses a serious risk
Lupus erythematosus to the health and life of patients. A growing number of studies have shown that commensals from different parts
Microbiota of the body and exogenous pathogens are involved in SLE progression, causing barrier disruption and immune
Therapeutics
dysregulation through multiple mechanisms. However, they sometimes alleviate the symptoms of SLE. Many
factors, such as genetic susceptibility, metabolism, impaired barriers, food, and sex hormones, are involved in
SLE, and the microbiota drives the development of SLE either by depending on or interacting with these factors.
Among these, the crosstalk between genetic susceptibility, metabolism, and microbiota is a hot topic of research
and is expected to lay the groundwork for the amelioration of the mechanism, diagnosis, and treatment of SLE.
Furthermore, the microbiota has great potential for the treatment of SLE. Ideally, personalised therapeutic ap­
proaches should be developed in combination with more specific diagnostic methods. Herein, we provide a
comprehensive overview of the role and mechanism of microbiota in lupus of the intestine, oral cavity, skin, and
kidney, as well as the therapeutic potential of the microbiota.

1. Introduction localisation can lead to a loss of tolerance and development of autoim­

Systemic lupus erythematosus (SLE), a chronic autoimmune disease
with a striking female predominance (sex ratio: 9:1) (Krasselt MBaer­
wald, 2019), is characterised by an abnormal immune response that
results in inflammatory reactions in multiple organs or systems such as
the kidney, the skin and the intestine (Rasaratnam IRyan, 1997). The
onset and progression of SLE are influenced by genetic, environmental,
and stochastic factors (Nandakumar KSNündel, 2022). Genome-wide
association studies (GWASs) have substantially enhanced our under­
standing of the genetic basis of SLE. Using this method, more than 40
susceptibility loci have been identified and confirmed to be associated
with SLE. Most of these related genes participate in crucial processes,
including the processing of immune complexes, Toll-like (TLR) receptor
signalling, and the production of type I interferon (IFN I) (Cui et al.,
2013). In recent years, increasing evidence has shown that the micro­
biota plays an important role in the pathogenesis of autoimmune dis­
eases. Dysregulation of microbiota abundance, function, or anatomical
mune diseases (Belkaid YHarrison, 2017; Choi et al., 2020; Ruff et al.,
2020). The disturbed commensals and infections play a role in autoim­
mune diseases through several mechanisms, including hidden/cryptic
antigens, epitope spread, anti-idiotypes, molecular mimicry, adjuvant or
bystander effects, and antigenic complementarity (Christen, 2014;
Root-Bernstein and Fairweather, 2014; Ruff et al., 2020). Additionally, a
growing number of metabolomic studies are looking for potential bio­
markers for the diagnosis and disease activity surveillance of SLE (Li
et al., 2020a; Zhang et al., 2021).
SLE has distinct and independent clinical manifestations in different
organs; patients experience low-activity SLE in certain organs but not in
the entire body (Oku KAtsumi, 2018; Aringer and Johnson, 2020).
However, the treatment options for SLE primarily target immune regu­
lation and immunosuppression to maintain long-term remission or
reduce disease activity (Pan et al., 2021). This approach lacks specificity
and adequate attention to the affected organs in cases of heterogeneous
SLE (Narváez, 2020). Given this situation and the role of microbiota on

* Corresponding authors.
E-mail addresses: liuzhongjundr@smu.edu.cn (Z. Liu), dentist-jia@163.com (B. Jia), xushuaimei@smu.edu.cn (S. Xu).
1
These authors contributed equally to the article.

https://doi.org/10.1016/j.micres.2024.127613
Received 14 September 2023; Received in revised form 18 December 2023; Accepted 9 January 2024
Available online 14 January 2024
0944-5013/© 2024 Elsevier GmbH. All rights reserved.
C. Mo et al.
SLE, it is important to focus on the effects of disturbed commensals and
infections in different lupus-affected sites, and therapeutic approaches
that can regulate or target microbial disturbance and infections are ur­
gently required.
This review discusses the disturbance of commensal microbiota and
their roles on various organs and sites to shed light on the bidirectional
relationship between SLE and microbiota (He et al., 2020; Huang et al.,
2020), and the effects of infections in SLE are also summarised (James
Jog and James, 2020). Certain serological markers and changes in mi­
crobial abundance are potential markers for the diagnosis (Jog et al.,
2019; Huang et al., 2020). In addition, therapeutic modalities based on
microbiota are discussed (Manfredo Vieira et al., 2018; Esmaeili et al.,
2021). Although most of these methods are still in the experimental
stage and serve as supplementary treatment, their specificity and effi­
cacy show promise for the development of individualised SLE
treatments.
2. Microbiota in lupus affected sites
2.1. Gastrointestinal tract
The intestinal epithelial cells limit the penetration of exogenous
antigens and leakage of endogenous substances by forming tight junc­
tions (TJs), and gut microbiota plays an important role in maintaining
the gut permeability and the immunity of an organism (Fasano, 2012;
Miyamoto et al., 2015; Erttmann et al., 2022). In contrast, mucosal
barrier dysfunction that increases intestinal permeability (known as
leaky gut syndrome), and microbial disturbance can be observed in
various diseases, including autoimmune diseases (Hu et al., 2016; Kin­
ashi YHase, 2021). For example, lupus-derived Ruminococcus gnavus
strains can induce high levels of intestinal permeability, which is asso­
ciated with R. gnavus translocation to the mesenteric lymph nodes and
increased serum levels of zonulin, a regulator of TJ formation in the gut
barrier (Silverman et al., 2022). Additionally, alterations in the intesti­
nal microbiota change the metabolic environment and activate specific
pattern recognition receptors in epithelial cells, thereby inducing a
pro-inflammatory state. Cytokines, such as tumour necrosis factor
secreted in response, result in the destruction of the intestinal barrier (Le
et al., 2020). Epithelial barrier leakage caused by other stimuli (e.g.
chronic stress, dietary imbalance, or antibiotic administration) leads to
tissue microinflammation by triggering microbial disturbance and bac­
terial translocation to the interepithelial and subepithelial areas.
Although open epithelial TJs drain immune cells and pro-inflammatory
molecules from subepithelial inflammation, they allow the entry of
foreign substances, such as allergens and microbial product, deeper into
the tissues (Sugita et al., 2018; Akdis, 2021).
Therefore, the intestinal barrier function and gut microbial
homoeostasis are critical for the health of an organism. Current studies
also suggest that intestinal homoeostasis and leakage are potential
contributors to SLE-associated gastrointestinal involvement (Brewer and
Kamen, 2018) and play a non-negligible role in LN (see Microbiota and
LN). Simultaneously, microbial disturbance and translocation interact
with the immune system and constitute the mechanism underlying
abnormal IFN I production and autoimmune responses in SLE (Manfredo
Vieira et al., 2018).
2.1.1. The role of microbiota in SLE-related gastrointestinal involvement
Gastrointestinal involvement is a common complaint in 40–60% of
patients with SLE (Frittoli et al., 2021), with three main manifestations:
intestinal pseudo-obstruction (IPO), lupus mesenteric vasculitis (LMV),
and protein-losing gastroenteropathy (PLGE). SLE-related gastrointes­
tinal lesions, such as mesenteric vasculitis and thrombosis, are associ­
ated with lupus anticoagulants and cause severe colonic ischaemia,
leading to intestinal infarction, perforation, and SLE-related pancrea­
titis, which are life-threatening when left untreated. Clinically, these
conditions require urgent surgery (Takeno MIshigatsubo, 2006; Chng
2
Microbiological Research 281 (2024) 127613
et al., 2010; Tian and Zhang, 2010).
The role of microbiota in the development of this disease remains
inadequate and unclear. The proposed microbial trigger factors of LMV
include infections changing the intestinal microbiota, cytomegalovirus
infections, and animal viruses (Tian and Zhang, 2010). However, the
specific mechanisms and their interactions with the gut microbiota have
not been reported. Pneumatosis cystoides intestinalis is an uncommon
type of SLE-related gastrointestinal involvement with only 14 reported
cases, and bacteria that produce gas in the mucosa may be involved in its
pathogenesis (Tian and Zhang, 2010). In addition, SLE-related PLGE has
been reported to be potentially associated with intestinal infections
(Chng et al., 2010).
The lack of adequate experimental studies on the gastrointestinal
manifestations of SLE could be due to the diversity of its manifestations,
unclear mechanisms, and complicated diagnostic processes resulting
from a broader differential diagnosis (Brewer and Kamen, 2018). In
addition, effective and reliable animal and cellular models of
SLE-related gastrointestinal involvement have not been established,
leading to the inability to conduct specific studies. Current treatments
for gastrointestinal manifestations include corticosteroids and immu­
nosuppressants (Li et al., 2017); however, these can lead to a loss of the
overall diversity of the gastrointestinal microbiota, thus aggravating
autoimmune diseases (Flannigan et al., 2018; Wei et al., 2020). Simul­
taneously, abnormal microbiota and a leaky gut are common in auto­
immune diseases (Christovich and Luo, 2022). Studies on the
interrelationship between the microbiota and autoimmune diseases, as
well as microbiota-related therapies, are ongoing. If the microbiological
basis of SLE can be explored by establishing reproducible models of
gastrointestinal manifestations and experimental protocols, effective
and specific treatments for SLE-related gastrointestinal involvement can
be developed.
2.1.2. The crosstalk between SLE and intestinal microbiota
Both intestinal leakage and SLE-specific intestinal microbiota exac­
erbate SLE (Thim-Uam et al., 2020). Current studies on SLE microbial
disturbance and translocation have mostly focused on abnormal IFN I
production and autoimmune reactions (Fig. 1).
The crosstalk between genetic susceptibility, alterations in the
microbiota, and metabolism has also been the emphasis of current
studies. A metabolomic profiling study of serum and faecal samples of
patients with SLE showed a deficiency of gut microbiome mediated
transformation of bile acids and its potential effects on host lipid
metabolism (He et al., 2020). Lipid metabolism is important for the
regulation of inflammation in acute and chronic diseases, and various
lipids have immunomodulatory and proinflammatory/anti-
inflammatory properties (Andersen, 2022). Moreover, patients with
SLE have elevated low-density lipoprotein cholesterol and
medium-chain/free fatty acids as well as reduced high-density lipopro­
tein and long-chain fatty acids (Robinson et al., 2022). Interestingly,
dysfunctional high-density lipoprotein, which becomes
pro-inflammatory during inflammation, was described in 48.2% of fe­
male patients with SLE, and greatly increased the risk of developing
subclinical atherosclerosis (McMahon et al., 2009). Based on these
studies so far, it is urgent to fill the gap that whether intestinal micro­
biota plays a direct or significant role to lipid metabolism in SLE.
Additionally, microbiota under the SLE condition significantly im­
pacts amino acid metabolism. A recent combined plasma metabolomic
and transcriptomic analysis revealed that plasma histidine levels are
potential biomarkers for patients with SLE, and that this decrease is
associated with damage accrual (Iwasaki et al., 2023). Germ-free mice
that underwent faecal microbiota transplantation from patients with
SLE showed markedly altered histidine metabolism and developed
several lupus-like phenotypic characteristics (Ma et al., 2021).
Furthermore, patients with SLE exhibit defects in macrophage-
mediated phagocytosis of apoptotic cells (efferocytosis), whereas the
male murine lupus model exhibits enhanced splenic macrophage
C. Mo et al. Microbiological Research 281 (2024) 127613

Fig. 1. The effect of gut microbiota on SLE. In SLE, disturbance occurs in the intestinal microbiota, leading to abnormal IFN I production or autoimmune responses in
the local immune or tissue cells. Some microbiota and their products can induce the above-mentioned responses by translocating to other organs or tissues via
intestinal leakage. IFN I dysregulation can cause autoantibody production, aggravating SLE progression. Created using BioRender.com. Abbreviations: AhR, aryl
hydrocarbon receptor; B. theta, Bacteroides thetaiotaomicron; ERV gp70, endogenous retrovirus glycoprotein 70; ERV gp70-ICs, ERV gp70 immune complexes; GC B,
germinal centre B cells; GLB, gut-lymph barrier; GVB, gut-vascular barrier; JAM-A, junctional adhesion molecule-A; MLN, mesenteric lymph node; pDCs, plasma­
cytoid dendritic cells; RS, resistant starch; SCFAs, short-chain fatty acids; SFB, segmented filamentous bacteria; SLOs, secondary lymphoid organs; TFH, Follicular
helper T cell; Th17, T helper 17; TLR7, Toll-like receptor 7; TRP, tryptophan GALT, gut-associated lymphoid tissue; β2GPI, β2-glycoprotein I. (Tesser et al., 2021)
(Manfredo Vieira et al., 2018) (Zegarra-Ruiz et al., 2019) (Choi et al., 2020) (Brown et al., 2022) (Shirakashi et al., 2022) (Greiling et al., 2018a) (Steinberg
et al., 1969).

efferocytosis in an androgen-dependent manner. Macrophage effer­
ocytosis was deficient in female mice, but was restored when fed with
male microbiota (caecal contents). One of the intestinal microbial me­
tabolites, phytanic acid, was reported to restore macrophage effer­
ocytosis activity of the splenic macrophages of female mice by activating
the PPARγ/LXR signalling pathway, which may have an impact on the
development of SLE (Harder et al., 2023) and also illustrated that an­
drogens affect both immunity and microbial composition, shedding light
on the disproportionate prevalence of SLE in males and females.
The gut microbiota in the context of SLE disease not only holds the
potential to foster the progression of SLE itself but also may contribute to
the advancement of cardiovascular disease among individuals with SLE.
It was reported that transplantation of intestinal microbiota from hy­
pertensive SLE mice to recipient normotensive mice led to elevated
blood pressure, with Bacteroides and Parasutterella being the major
harmful bacteria. However, vancomycin or broad-spectrum antibiotic
treatment can inhibit hypertension, ameliorate endothelial dysfunction
and vascular oxidative stress and reduce aortic Th17 infiltration (de la
Visitación et al., 2021). Another study showed that endothelial
dysfunction in SLE was associated with increased superoxide production
initiated by NADPH oxidase and eNOS phosphorylation at the inhibitory
Thr495 (Toral et al., 2019). The activity of these factors returned to
normal levels after oral gavage of Lactobacillus fermentum in lupus-prone
mice, thus reducing endothelium-dependent vasodilator responses to
acetylcholine of aortas (de la Visitación et al., 2020).
The virus is also a component of gut microbiota (Shanahan et al.,
2021), but the effect of gut viruses on SLE remains insufficiently studied.
Based on results of current studies, the diversity and taxonomic
composition of gut virome has altered in patients with SLE (Chen et al.,
2022), and crAss-like phages, one of the main components of a healthy
gut virome, have been significantly reduced (Tomofuji et al., 2022). In
addition, an in vitro study showed that virus-like particles extracted
from faecal samples of patients with SLE increased IFN-α production in
immune cells, suggesting a potential effect of SLE-related virus-like
particles on SLE pathogenesis (Chen et al., 2023); nevertheless, this
conclusion needs to be further verified by more complete research.
However, there is insufficient evidence to support the idea that mi­
crobial disturbance initiates SLE. A research (Choi et al., 2020) sug­
gested that gut microbiota abnormality did not trigger but amplified
autoimmune phenotypes and that a leaky gut does not necessarily imply
lupus development. In their study, lupus autoimmune response was
triggered in healthy control mice after transplanting faeces from aged
lupus-prone mice (which had exhibited lupus-associated phenotypes),
whereas faeces from young lupus-prone mice (which did not develop
lupus-associated phenotypes) did not elicit a similar effect. Furthermore,
bacterial translocation was not observed prior to the production of au­
toantibodies in lupus-prone mice, and a small number of translocated
Staphylococcus did not significantly correlate with autoimmune mani­
festations. In contrast, it has been shown that the faecal microbiome of
SLE mice induced the production of anti-dsDNA antibodies, stimulated
inflammatory responses, and altered the expression of SLE susceptibility
genes in germ-free mice (Ma et al., 2019). A recent study offered a more
detailed demonstration of the roles of host genetics and the gut micro­
biota in autoimmunity. This shows that defective TCR signalling disrupts
the gut microbiota by inhibiting the positive selection of certain
microbe-reactive T cells. Altered gut microbiota promotes the

3
C. Mo et al.
differentiation of Th17 cells and the development of systemic autoim­
mune diseases (Shirakashi et al., 2022). In individuals susceptible to
autoimmune diseases, the genetic factor-mediated changes in immunity
and metabolism, and the consequential responses of the microbiota
remain an area to be further explored.
2.2. Oral cavity
Oral lesions are common lupus symptom (AlSaleh et al., 2008;
Khatibi et al., 2012; Kudsi et al., 2021). As described for the gastroin­
testinal manifestations (Brewer and Kamen, 2018), they are interpreted
as mucosal counterparts of cutaneous LE because they represent mucosal
lesions (Nico et al., 2008).
Epstein-Barr virus (EBV) DNA was present in 71.4% of the patients
with SLE-associated oral lesions, and most patients with Epstein-Barr
virus (EBV) DNA-positive SLE present with oral lesions (Buonavoglia
et al., 2021). However, the relationship between systemic or local EBV
infection and oral lupus lesions requires further research. It is currently
reported that different regions of the EBV EBNA-1 protein cause auto­
immunity through molecular mimicry, epitope expansion, and other
mechanisms, which in turn lead to the clinical characteristics of SLE
(James Jog and James, 2020). A cohort study found a strong association
between the serological markers of EBV and SLE, with elevated numbers
of EBV-infected cells, increased viral loads, and higher early antigen IgG
levels in patients with SLE. Moreover, serological reactivation of EBV
increases the likelihood of transitioning to SLE (Jog et al., 2019). Sub­
sequently, EBV-specific CD8+ cytotoxic T cell damage and irregular
cytokine production in plasmacytoid dendritic cells (DCs) and
CD69+CD4+ T cells occur in patients with SLE (James and Robertson,
2012).
In addition to EBV, disturbance in the oral microbiota of patients
with SLE is not negligible. The plaque index was twice as high in patients
with SLE than in healthy controls despite brushing with fluoride at the
same rate. Moreover, the abundance and diversity of the oral microbiota
in patients with SLE have decreased, creating a favourable environment
for pathogenic strains to flourish. A microbial disturbance between acid-
producing uropathogenic bacteria and alkaline-producing commensal
bacteria present in the oral cavity increases the risk of caries in patients
with SLE (Yang et al., 2018). With respect to periodontitis, patients with
SLE exhibit a higher prevalence of periodontitis at a younger age and
have more severe forms of periodontitis with higher bacterial loads and
decreased microbial diversity (Corrêa et al., 2017). In addition, there is a
strong positive correlation between disease activity and oral health
status in patients with SLE. The prevalence of dental caries, periodon­
titis, and oral mucosal lesions was higher in patients with SLE than in
those without SLE (Aurlene et al., 2020). A survey of 91 female patients
with SLE showed that low-grade systemic inflammation influencing SLE
disease activity and severity was correlated with oral microbiota ab­
normality in periodontal diseases (Pessoa et al., 2019). A two-sample
Mendelian randomisation (MR) analysis suggested that periodontitis
was likely causally associated with an increased risk of SLE, although
one of its analyses (MR–Egger regression) failed to find a significant
causal association (p = 0.394) (Bae SCLee, 2020). Bouchra et al. found a
possible bidirectional association between periodontitis and SLE
through recent clinical and translational research that should be
considered when managing patients with SLE (Sojod et al., 2021).
In summary, the mechanism by which SLE impairs the homoeostasis
of the oral microbiota and how this disturbance causes oral LE lesions
remains unclear. Similarly, although there are a growing number of
surveys on the relationship between periodontitis and the risk of
developing SLE, there is a lack of direct evidence that periodontitis plays
a role in the development of oral LE lesions. Therefore, more in-depth
research should be conducted to understand this relationship and
develop strategies for managing oral LE in patients with SLE. Pathogens
that can cause infections and symptomatic management to alleviate oral
LE in SLE patients require special attention.
4
Microbiological Research 281 (2024) 127613
2.3. Skin
Cutaneous lupus erythematosus (CLE) affects the skin and is divided
into two subgroups based on the lesion type: subacute cutaneous LE
(SCLE) and discoid lupus erythematosus (DLE). Acute CLE (ACLE) is a
common manifestation of SLE (Li et al., 2020c). Discoid lesions and
butterfly rashes are typical SLE skin lesions (Zhao et al., 2020) that occur
in 5–25% of patients with CLE. These lesions can progress to SLE.
However, clear predictive guidelines are still lacking (Zhou et al., 2020).
Skin commensals play an important role in the maturation and
homoeostasis of skin immunity (Chen et al., 2018) and a disturbance in
the skin microbiota causes inflammatory skin diseases such as atopic
dermatitis (Condrò et al., 2022). The results of 16 S rRNA sequencing of
SLE skin lesions revealed a lower alpha diversity of the microbiota and
different bacterial communities compared to adjacent healthy skin cells.
At the species level, Staphylococcus aureus and S. epidermidis remained
two strong discriminative signatures for SLE lesions. Therefore, S. aureus
and S. epidermidis may serve as markers for the diagnosis of SLE.
Notably, the ratio of Firmicutes/Bacteroidetes of the skin microbiota of
SLE patients is higher, contrary to previous observations from the in­
testinal microbiota of SLE patients. This is possibly due to the different
bacterial profiles of the skin and intestines (Huang et al., 2020).
Furthermore, based on the gut-skin axis, the gut affects skin health
owing to its immune and metabolic properties, and a highly diverse gut
microbiota can affect skin microbiota; however, the exact mechanisms
involved in this relationship are not fully understood, and factors such as
altered gut permeability and immune and endocrine factors may also be
involved (Sinha et al., 2021). However, probiotic therapy reduces dis­
ease activity and decreases corticosteroid dose (Navarro-López et al.,
2018). IL-37b considerably increases the diversity of the skin microbiota
by modulating autophagy in atopic dermatitis and reducing intestinal
bacterial diversity and metabolite secretion, substantially alleviating
eosinophil-mediated allergic inflammation (Hou et al., 2020).
Although there are reports describing changes in the microbiota of
LE skin lesions, few have demonstrated the direct impact of the micro­
biota on disease progression. Therefore, further studies on the rela­
tionship between the microbiota and the development of LE skin lesions
are needed to deepen our knowledge of how the microbiota interacts
with the immune system. Therefore, microbial markers for the accurate
diagnosis of LE skin lesions and new therapeutic strategies are urgently
required.
3. Microbiota and LN
LN is a form of glomerulonephritis and is one of the most severe
manifestations of SLE. Twenty-five to fifty percent of unselected patients
with SLE develop kidney disease symptoms at the time of disease onset
and up to 60% of adult patients with SLE experience these signs or
symptoms over the course of the disease (Anders et al., 2020). The
mechanisms underlying LN include genetic polymorphisms, environ­
mental triggers, complement and neutrophil extracellular traps, intrinsic
and adaptive immunity, and intrarenal inflammation (Lintner et al.,
2016; Yin et al., 2021; Yu et al., 2022). Studies have been conducted on
the use of drugs aimed at specific targets in combination with immu­
nosuppressants for the treatment of SLE, such as the combination of
prednisolone and tacrolimus (a calcineurin inhibitor). The rate of renal
response was superior to that of a combination of prednisolone and
mycophenolate mofetil; however, the long-term results showed a higher
proportion of proteinuric and nephritic renal flares (although with no
significance) (Mok et al., 2016). Patients who received belimumab plus
standard therapy had a higher primary efficacy renal response than
those who received standard therapy alone; however, the percentages
were both < 50% (Furie et al., 2020). Therefore, there is an urgent need
to develop novel therapeutic methods for exploring the pathogenesis of
LN.
Inflammation and damage to the kidneys are significantly influenced
C. Mo et al. Microbiological Research 281 (2024) 127613

by microbiota. Intestinal microbiota disturbance and barrier disruption
result in microbiota producing toxins responsible for renal damage
(Mosterd et al., 2021), aberrant immune cell activation, antibody
overproduction, immune complexes, inflammatory agents, and inflam­
matory cell infiltration, all of which can directly or indirectly harm the
renal parenchyma (Chi et al., 2021; Haniuda et al., 2021). Some viruses
can cause renal damage through cytopathic actions or indirectly through
immune-mediated glomerulopathy, tubulointerstitial disease, and other
conditions (Prasad et al., 2019). Similar processes also occurred in the
LNs (Fig. 2 and below). Current approaches to LN management rely on
high-dose corticosteroids combined with broad-spectrum immunosup­
pressive therapy. This approach has limitations in LN treatment because
of its many side effects, including life-threatening infections (Parikh and
Rovin, 2016; Fontana et al., 2018). Disturbance of the commensal
microbiota is strongly associated with the development and progression
of SLE and LN (Valiente et al., 2022).
3.1. Infection and LN
3.1.1. Viral infection
As early as 1968, Fresco (Grausz et al., 1970) observed clustered
filamentous structures and dense deposits in the glomerular basement
membrane of a patient with LN, and named them mucoviruses based on
their morphology. Since then, other researchers have published com­
parable findings in patients with SLE. It has been hypothesised that SLE
could result from an immune reaction to cells carrying a foreign antigen
and that this virus is the antigen that causes the initial insult that triggers
autoimmune mechanisms (Györkey et al., 1969).
The presence of myxovirus resistance protein 1 (Mx1) also indirectly
suggests potential antiviral immunity in the kidneys of LN patients. Mx1
is an important link in the pathogenesis of SLE and is induced by IFN I,
which is abnormally produced through several mechanisms such as the
activation of TLR7 and TLR9, defects in clearing apoptotic debris, and
oxidised mitochondrial nucleoids (Haller OKochs, 2011; Caielli et al.,
2016; Khoryati et al., 2016; Monteith et al., 2016; Shen et al., 2022).
Peripheral blood Mx1 is a potential marker for the diagnosis of SLE and
LN. It is highly expressed in the kidneys of patients with LN and its
expression decreases following immunosuppressive treatment (Shimizu
et al., 2018). In addition, Mx1 inhibits various viral families, including
negative-stranded RNA viruses (Verhelst et al., 2013). Shojiro et al.
demonstrated that Mx1 was expressed primarily in the mesangial region
in the kidney and also found that the knockdown of IFN-α in human
thylakoid cells (MCs) decreased Mx1 expression induced by
polyinosinic-polycytidylic acid (poly IC; an authentic viral
double-stranded RNA). This suggests that the innate antiviral immunity
is involved in the MCs of patients and induces the expression of Mx1 in
MCs (Watanabe et al., 2013). However, there is a paucity of definitive
evidence linking Mx1 to viral infection in patients with LN, and further
research is needed to determine the link between and the consequences
of the potential upstream virus and LN infection.
Secondary viral infections after LN treatment noticeably influence
the disease progression. A retrospective study showed that cytomega­
lovirus (CMV) was the most common pathogen among infected hospi­
talised LN patients (Liu et al., 2018), and serum anti-CMV antibodies
were more prevalent in patients with SLE and a history of LN than in
those without nephritis (Brunekreef et al., 2021). CMV infection may
lead to failure of antibiotic therapy and make immunosuppressive
therapy detrimental. Despite receiving high-dose steroid therapy, the
patient with LN and CMV infections experienced persistent proteinuria
and active sedimentation, indicative of active renal lupus. Additionally,
notable ethnic differences have been reported between CMV-infected
and uninfected patients. Furthermore, baseline urine protein creati­
nine ratio levels were higher in the CMV-infected cohort than in unin­
fected individuals (Liu et al., 2018; Sebastiani et al., 2019).
3.1.2. Other infections
Cryptococcosis is a common pathogen that causes fungal meningitis.
Cryptococcal meningitis (CM) is rare in patients with LN. Patients with

Fig. 2. Positive and negative effects of identified microbiota on LN. Various commensal and exogenous microbiota are involved in the progression and amelioration
of LN. They cause changes in multiple kidney factors, and lead to different outcomes in terms of renal function and pathology. Created using BioRender.com.
Abbreviations: BUN, blood urine nitrogen; Cre, creatinine; IgG 2a: immunoglobulin G 2a; IL-10/IL-6, interleukin-10/interleukin-6; MCP-1: Monocyte chemo­
attractant protein-1; RBP, renin-binding protein; RS, resistant starch; Th 17, T helper cell 17; Treg, Regulatory T cell; UPCR, urine protein-to-creatinine ratio.
(Al-Quraishy et al., 2013) (Johnson et al., 2015) (Mu et al., 2017) (Li et al., 2020b) (Zegarra-Ruiz et al., 2019) (Valiente et al., 2022) (Chen and Chen, 2020) (Liu
et al., 2018).

5
C. Mo et al.
LN and CM had considerably higher prednisone doses and SLE Disease
Activity Index scores than those without CM. The mortality rate of pa­
tients with LN and CM is 25% and is associated with low serum albumin
levels and high cumulative doses of prednisolone (Chen and Chen,
2020).
By contrast, tropical infections, particularly malaria, may protect
against SLE. Epidemiological studies have shown that people in the rural
areas of tropical Africa and Asia, where malaria is common, rarely
develop SLE (Adebajo, 1997). It has been reported that young
lupus-prone mice infected with Plasmodium have a higher survival rate
and lower oxidative stress in renal tissues (Al-Quraishy et al., 2013).
However, malarial infection is also associated with the production of
large amounts of autoantibodies, and DNA-reactive antibodies in ma­
laria are comparable to those in SLE and may play a role in the devel­
opment of immune deposits in nephritic malarial kidneys (Lloyd et al.,
1994).
Therefore, primary and secondary infections caused by immuno­
suppressive agents should be considered. Doses of immunosuppressive
agents and possible infection-related symptoms should be evaluated
scientifically. However, in vitro and animal model studies are necessary
to elucidate the precise mechanisms of the pathogens in LN, as most
studies assessing the effects of infection on LN have mainly focused on
clinical indicators.
3.2. Intestinal microbial homoeostasis and LN
Not only is the intestinal microbiota important for gut homoeostasis,
but several studies have shown that gut microbiota diversity is strongly
correlated with LN. The SLE subgroup with LN was markedly associated
with a decline in the Shannon index (Chen et al., 2021). Moreover,
patients with LN have an increased R. gnavus abundance, which is
directly proportional to the LN and overall LN activity (Azzouz et al.,
2019; Azzouz et al., 2023). R. gnavus can cross-react with native DNA,
eliciting an immune response against double-stranded DNA (Azzouz
et al., 2019; Kim et al., 2019). Teri et al. used an inducible lupus mouse
model for Bacteroides thetaiotaommicron (B. theta) mono-colonisation in
a germ-free setting and detected LN-like immune complex deposition in
88% of the glomeruli of the mice model (Greiling et al., 2018b). Gian­
carlo et al. found that the transplantation of segmented filamentous
bacteria (SFB) can lead to intestinal microbiota disturbance and LN
progression (Valiente et al., 2022). In contrast, chronic oral adminis­
tration of the probiotic L. fermentum in lupus-prone mice inhibited the
infiltration of Th17 and Th1 cells, the increased pro-inflammatory cy­
tokines levels, NADPH oxidase activity in kidney and also significantly
improved renal damage (de la Visitación et al., 2020). Interestingly, SFB
are substantially increased in the ileum of immunosuppressed mice, and
transplantation of L. plantarum restores SFB numbers (Fuentes et al.,
2008). It is valuable to further investigate the mechanism of
L. plantarum, possibly lies at the antagonistic of probiotics (Peng et al.,
2022). Similarly, B. fragilis restored the Th17/Treg balance and allevi­
ated disease activity in a murine lupus model by lowering autoantibody
levels and alleviating LN symptoms (Li et al., 2020b). However, the
beneficial effects of Lactobacillus on LN can only be detected in female
and castrated male mice and not in normal male mice, suggesting that
the gut microbiota also control LN in a sex hormone-dependent manner
(Mu et al., 2017). The gut microbiome is involved in excretion and
recycling of sex hormones. Sex steroids also influence the gut micro­
biome composition. The term “microgenderome” has been proposed to
reflect how sex hormones affect the gut microbiota (Thackray, 2019;
Yoon and Kim, 2021).
Notably, one study indicated that L. reuteri worsens lupus by
increasing glomerulonephritis, plasmacytoid dendritic cell activation,
and IFN I expression, which is inconsistent with other studies showing
the positive effects of Lactobacillus. This study used a TLR7-dependent
lupus mouse model in which the effects of L. reuteri on LN were
observed under certain conditions, suggesting that microbiota can show
6
Microbiological Research 281 (2024) 127613
adverse effects under certain genetic and environmental conditions
(Zegarra-Ruiz et al., 2019). In fact, the gut microbiota is known to be
influenced by both genetic factors and the environment, exerting a
significant impact on the development of diseases (Yoo et al., 2021).
Furthermore, once the homoeostasis is disrupted, it can potentially
cause harm to the body (Zheng et al., 2020). In addition, potential dif­
ferences in the strains used in the study may also serve as a significant
factor in experiment results.
Diet can also affect LN by altering the intestinal microbiota. The pH
of drinking water affected LN by alterations the microbial composition
(Johnson et al., 2015). The intestinal microbiota of lupus-prone mice
was characterised by a notable reduction in Lactobacillaceae, which was
negatively correlated with signs of lupus (lymphadenopathy and
glomerulonephritis) and was restored by vitamin A (Zhang et al., 2014),
consistent with the findings of Mu et al. (2017). Furthermore, predicted
metagenomes showed that retinoic acid (a vitamin A metabolite)
reversed numerous lupus-associated changes in microbial activation,
deviating from the control (Zhang et al., 2014). Additionally, resistant
starch (fermented to short-chain fatty acids) improved LN by lowering
intestinal epithelial permeability and IFN-I expression (Zegarra-Ruiz
et al., 2019), and prevented the development of hypertension in murine
lupus model apart from renal injury (Moleón et al., 2023).
4. Progress in microbiota-associated treatment of SLE
Despite advances in SLE treatment, SLE remains associated with high
morbidity and premature death. Furthermore, an overreliance on
corticosteroid therapy leads to long-term organ damage (Durcan et al.,
2019). Supplementary therapeutic approaches using microbiota com­
ponents are a viable and highly valuable choice in conjunction with
analysis of the predominant pathogenic microbiota (Fig. 3).
4.1. Probiotic therapy
Probiotic therapy has been extensively studied for the treatment of
autoimmune diseases (Jakubczyk et al., 2020). It is effective in allevi­
ating lupus-associated syndromes (de la Visitación et al., 2020), and may
also improve gut integrity (Ahmadi et al., 2020; de la Visitación et al.,
2020; Robles-Vera et al., 2020). However, probiotics may not be bene­
ficial for immunocompromised individuals, further exacerbating the
condition (Kothari et al., 2019). Additionally, studies related to Heli­
cobacter pylori eradication have shown that probiotics alone cannot
provide sufficient treatment effects and thus should be combined with
conventional therapy for better results (Feng et al., 2017; Losurdo et al.,
2018).
Most studies of probiotics have focused only on their immunomod­
ulatory effects. L. delbrueckii and L. rhamnosus alone or in combination,
can reduce the expression of chemokine receptors on the surface of DCs
in SLE patients and prevent DCs migration, thereby alleviating inflam­
mation (Esmaeili et al., 2021). The combination of tacrolimus and
L. acidophilus restored the dysregulated intestinal microbiota in an SLE
mouse model, considerably inhibited Th17 cell differentiation, and
induced Treg cell differentiation (Kim et al., 2021). In addition, Akker­
mansia muciniphila and L. plantarum were shown to not only promote an
anti-inflammatory environment by regulating cytokine levels in the
circulation and remodelling the gut microbiota but also to exert pro­
tective effects on intestinal barrier integrity by restoring the TJ structure
of colonic epithelial cells (Guo et al., 2023), indicating that the benefi­
cial effects of probiotics are multifaceted.
Therefore, probiotics can be used as a complementary therapy to
immunosuppressive therapy for SLE to reduce adverse effects and
maintain intestinal microbial homoeostasis and integrity in patients in
an evidence-based manner.
C. Mo et al.
Fig. 3. Envisioned microbiota-related therapeutic approaches to SLE lesions. The dominant pathogenic microbiota in the SLE lesions was identified using indi­
vidualised microbiome analysis and/or anti-microbial antibody testing. It can subsequently be treated with antimicrobial vaccines, probiotic therapies or FMT to
alleviate or cure lupus in the affected organs. Created using BioRender.com.
4.2. Faecal microbiota transplantation
Faecal microbiota transplantation (FMT) is a method to transfer stool
from a healthy donor to a patient, directly changing the recipient’s gut
microbiota to normalise the composition and gain a therapeutic benefit
(Vindigni and Surawicz, 2017; Wang et al., 2019). FMT has proven to be
effective and relatively safe in various diseases including autoimmune
diseases (Matsuoka, 2021; Zeng et al., 2022; Zhang et al., 2022).
A study showed that early and short-term antibiotic exposure led to a
significant increase in serum anti-dsDNA autoantibodies in lupus-prone
mice, and FMT reduced serum anti-dsDNA autoantibodies to pre-
antibiotic levels, inhibiting the progression of lupus (Zhang et al.,
2020). Notably, the intestinal microbiota of prednisone-treated lupu­
s-prone mice transplanted to the blank lupus-prone mice also had a
similar therapeutic effect as prednisone, but did not exhibit side effects
as prednisone, suggesting that FMT is a effective treatment with various
ways for improvement and can avoid the side effects of glucocorticoids
(Wang et al., 2021). Recently, Huang et al. conducted the first clinical
trial of FMT in patients with active SLE. After 12 weeks of oral encap­
sulated faecal microbiome from healthy donors, 20 patients with active
SLE experienced significant decrease in SLEDAI-2 K scores and serum
anti-dsDNA antibody level, and bacterial taxa that produced short-chain
fatty acids and a reduction in inflammation-associated bacterial taxa
were also observed (Huang et al., 2022).
FMT is usually reported to work by gut microbiota remodelling,
bowel permeability reduction and immunoregualtion (Shen et al., 2018;
Belvoncikova et al., 2022). The latest study suggested that FMT treat­
ment showed potential curative effect on SLE by reducing the major
FMT-responder lymphocyte populations (Zheng et al., 2023). Epige­
netics is also a crucial part of research in autoimmune diseases. It is
reported that global DNA methylation is decreased in lymphocytes in
patients with SLE and correlates with disease activity (Hedrich et al.,
2017). FMT was showed to upregulated global methylation in some
patients with SLE, and its possible mechanism was that FMT induced the
gut microbiota to interact with DNA methylation. Although the exact
relationship between the methylation and altered gut mircobiota needs
7
Microbiological Research 281 (2024) 127613
further investigation, this study has shown new evidence for FMT
application in individuals with SLE (Zhang et al., 2023).
In conclusion, FMT is a novel supplementary treatment modality for
patients with SLE, and it is worth investing in more clinical studies to
clarify the efficacy and safety. Furthermore, the mechanism of FMT in
SLE should also be further studied.
4.3. Vaccination
Unlike antibiotics, which are associated with the risks of bacterial
disturbance and resistance, anti-microbial vaccines are more specific,
and vaccine technology has a strong foundation and is dependable.
Enterococcus gallinarum exacerbates SLE progression during bacterial
disturbance. Some studies developed a vaccine from heat-killed
E. gallinarum and intramuscularly administered it to a murine lupus
model to prevent the translocation of E. gallinarum, reduce serum
autoantibody levels, and prolong survival (Manfredo Vieira et al., 2018).
In addition to microbial antigens, some studies have focused on the
effectiveness of vaccine adjuvants on microbiota. Flagellin is an excel­
lent vaccine adjuvant, and flagellin from non-pathogenic bacteria is safe
(Cui et al., 2018). A previous study has shown that repeated injections of
purified flagellin triggered a robust anti-flagellin faecal IgA response in
mice. Flagellin-specific IgA encapsulates intestinal bacteria, prevents
microbiota encroachment, remodels microbiota composition, and re­
duces flagellin expression, thereby protecting against colitis induced by
IL-10 deficiency. However, systemic rather than mucosal responses to
flagellin may be detrimental. Therefore, the development of flagellin
injections into the intestinal mucosal immune system, perhaps using
nanoparticles targeting the mucosa, may provide safer and more effec­
tive preferential induction of mucosal antibodies for the treatment of
various chronic inflammatory diseases (Tran et al., 2019). However, the
availability of mucosal vaccines is limited because of the lack of delivery
systems that maintain antigen integrity and the strong adjuvanticity of
vaccines (Miquel-Clopés et al., 2019). Recently, researchers developed a
parenteral vaccine with emulsified curdlan and CpG oligodeox­
ynucleotides as adjuvants that could induce antigen-specific mucosal
C. Mo et al.
and systemic immune responses with high titres of IgA after stimulation
with a small amount of antigen on the target mucosal surface, even if the
antigen-specific IgA on the mucosa is lost (Fujimoto KUematsu, 2020).
This optimised delivery system could be applied for the development of
various mucosal vaccines in the future.
Although vaccine development against microbiota specifically
altered in patients with SLE and the induction of a strong immune
clearance response through mucosal immunity are important, these still
remains challenging. Moreover, there is a causal relationship between
vaccine and adverse events such as anaphylaxis, arthralgia or arthritis,
disseminated varicella infection and so on (Dudley et al., 2020). Current
data also suggests an increased risk of some auto-immune illnesses
following vaccination, which is mostly based on the concept of molec­
ular mimicry (Conklin et al., 2021). As a result, new vaccines need to go
through more stringent testing before clinical translation.
5. Conclusion
Both exogenous microbiota and disturbance of commensal micro­
biota can not only promote SLE development but also can act as targets
for individualised therapy. Furthermore, some microbiota plays a posi­
tive role in SLE, but can be hazardous to other individuals or under
specific genetic, environmental, and metabolic circumstances, as well as
in the presence of certain sex hormones. Therefore, individualised care
for SLE is urgently required. In addition to clinical indicator detection
and microbiomics, experimental studies should comprehensively assess
the immunoreactions and signalling pathways.
Various microbiota-related therapeutic methods have been proposed
to enhance the treatment of SLE and other autoimmune diseases using
nonspecific treatments with unfavourable side effects. However, lengthy
clinical studies are required to improve these processes, conduct thor­
ough safety checks, and review ethical issues. In addition, anti-microbial
antibody testing and personalised microbiome testing are crucial for
precise microbiota targeting and rely mainly on 16 S rRNA testing
(Azzouz et al., 2019) and shotgun sequencing (Chen et al., 2021). It
would be beneficial and influential to develop more practical and
affordable microbiome testing methods.
Funding
This work was supported by Scientific Research Cultivation Project
of Stomatological Hospital, School of Stomatology, Southern Medical
University (grant number PY2021018) and Hebei Natural Science
Foundation (grant number H2023104011).
CRediT authorship contribution statement
Lin Yunhe: Writing – review & editing. Yuan Peiyan: Writing –
review & editing. Bi Jiaming: Writing – review & editing, Writing –
original draft, Visualization, Supervision. Li Siwei: Writing – review &
editing. Mo Chuzi: Writing – review & editing, Writing – original draft,
Visualization, Supervision, Conceptualization. Xu Shuaimei: Writing –
review & editing, Supervision, Funding acquisition. Jia Bo: Supervision,
Funding acquisition. Liu Zhongjun: Supervision, Funding acquisition.
Declaration of Competing Interest
None.
Data availability
No data was used for the research described in the article.
Acknowledgements
We thank all the reviewers for reviewing this manuscript and Editage
8
Microbiological Research 281 (2024) 127613
(www.editage.cn) for providing English language editing. Biorender.
com (Toronto, Ontario) tool was used to create the figures.
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