Alterations of the gut microbiota in the lupus nephritis: a systematic review

Figures & data

Figure 1. Study selection flowchart. SLE, systemic lupus erythematosus. LN, lupus nephritis.

Table 1. Characteristics of clinical studies included in this systemic review.

Study	Region	LN (n)	SLE (n)	HCs (n)	Age	F: M	Sequencing	Higher abundance of gut microbiota	Lower abundance of gut microbiota	Conclusion
Azzouz et al. 2023 [26]	America	9	16	22	LN: 34.8 ± 4.7 SLE:38.9 ± 7.9 HCs: N/A	N/A	16S rRNA	Ruminooccus gnavus	N/A	Temporal instability within longitudinal gut microbiota communities, from which Ruminooccus gnavus blooms arose concordant with clinical disease flares.
Wang et.al 2022 [39]	China	7	19	19	LN: N/A SLE:36.11 ± 12.19 HCs:39.32 ± 10.96	LN: N/A SLE: 16:3 HCs: 7:12	16S rRNA	Genus: Streptococcus	Genus: Turicibacter	Streptococcus was extremely enriched among patients with LN.
Yu et al. 2022 [37]	China	17	0	27	LN: 41, 19-55 HCs: 51, 19-73	LN: 11:4 HCs: 14:13	16S rRNA	Phylum: Proteobacteria Family: Negativicutes, Betaproteobacteria	Phylum: Firmicutes, Bacteroidetes	Firmicutes and Bacteroidetes had a lower proportion, while Proteobacteria had a higher proportion in feces of LN patients than HCs.
Li et al. 2022 [32]	China	6	19	16	LN: N/A SLE: 28.89 ± 8.88 HCs: 32.25 ± 9.43	LN: N/A SLE: 18:1 HCs: 16:0	16S rRNA	Phylum: Proteobacteria, Fusobacteria Genus: Fusobacterium, Erysipelatoclostridium, Romboutsia, Intestinibacter, Eisenbergiella, Escherichia, Parabacteroides, Pseudobutyrivibrio	Phylum: Firmicutes, F/B ratio Genus: Ruminiclostridium, Prevotella, Lactobacillus, Oscillospira, Ruminiclostridium	The composition of gut microbiota has changed in patients with SLE.
Gerges et al. 2021 [29]	Egypt	4	20	20	LN: N/A SLE: 25.6 ± 6.3 HCs:29.9 ± 6.6	LN: N/A SLE: 18:2 HCs: 16:4	Q-PCR	N/A	F/B ratio	F/B ratio and Lactobacillus abundance were lower in recently diagnosed SLE Egyptian patients compared to HCs, which is correlated with disease activity.
Tomofuj et al. 2021 [35]	Japan	20	47	203	LN: N/A SLE: 42.9 ± 15.9 HCs:35.4 ± 12.0	LN: N/A SLE: 43:4 HCs: 104:101	Shotgun sequencing	Species: Streptococcus intermedius, Streptococcus anginosus	N/A	The abundance of Streptococcus anginosus and Streptococcus intermedius was increased in the SLE metagenome.
Chen et al. 2020 [28]	China	22	117	115	N/A	N/A	Shotgun sequencing	Genus: Ruminococcus torques Species: Ruminococcus gnavus, Clostridium nexile, Olsenella uli, Actinomyces johnsonii, Staphylococcus aureus, Enterococcus avium	N/A	Ruminococcus gnavus was the most discriminative species enriched in LN, followed by Clostridium nexile, Olsenella uli, Actinomyces johnsonii, Staphylococcus aureus, and Enterococcus avium.
Azzouz et al. 2019 [25]	America	21	61	17	LN: N/A SLE: 42.85 ± 14.46 HCs: ≥18	LN: N/A SLE: 61: 0 HCs: 17: 0	16S rRNA	Class: Erysipelotrichi Order: Erysipelotrichales Family: Veillonellaceae, Erysipelotrichacea Genus: Ruminococcus Species: Ruminococcus gnavus, Bacteroides fragilis	Order: Ruminococcacea Genus: Blautia Species:Bacteroides uniformis	The abundance of Ruminococcus gnavus was associated with lupus disease activity and LN.
Bellocchi et al.2019 [27]	Milan	7	27	27	LN: N/A SLE:47.70 ± 16.55 HCs: 52.47 ± 9.96	LN: N/A SLE: 24:3 HCs: 20:7	16S rRNA	Genus: Bifidobacterium, Ruminiclostridium, Streptococcus, Collinsella	Genus: Lachnoclostridium, Lachnospira, Sutterella	SLE, undifferentiated connective tissue, Sjögren’s syndrome, and primary anti-phosholipid syndrome patients share common intestinal microbiome and metabolomic profiles.
van der Meulen et al. 2019 [36]	Netherlands	5	30	965	LN: N/A SLE: 47.0 ± 14.0 HCs: 45.0 ± 13.0	LN: N/A SLE: 28: 2 HCs: 557: 408	16S rRNA	Phylum: Bacteroidetes, Proteobacteria Genus: Bacteroides, Alistipes	F/B ratio Family: Synergistaceae Species: Bacteroides vulgatus, Bacteroides uniformis, Bacteroides ovatus, Bacteroides thetaiotaomicron	The main characteristics of the gut microbiota composition in SLE patients are lower bacterial richness, lower F/B ratio and higher relative abundance of Bacteroides species.
Zegarra-Ruiz et al. 2019 [38]	America	4	12	22	LN: N/A SLE:≥18 HCs: N/A	LN: N/A SLE: 12: 0 HCs: N/A	16S rRNA	Genus: Lactobacillus	N/A	Lactobacillus spp. was increased in a longitudinal cohort of SLE patients compared with HCs.
Greiling et al. 2018 [30]	America	4	18	11	N/A	LN: N/A SLE: 17:1 HCs: N/A	16S rRNA	N/A	F/B ratio	The F/B ratio was lower in SLE patients compared to HCs.
Luo et al. 2018 [33]	England	6	14	17	LN: N/A SLE: 43.2 ± 18.1 HCs: N/A	LN: N/A SLE: 10:4 HCs: N/A	16S rRNA, metagenome prediction	Phylum: Proteobacteria Genus: Blautia	Genus: Odoribacter, unnamed genus under the family Rikenellaceae	The abundance of Proteobacteria and Blautia was higher but the abundance of Odoribacter was lower in SLE patients.
Rodríguez-Carrio et al. 2017 [34]	Spain	3	21	25	N/A	LN: N/A SLE: 21:0 HCs: 23:2	16S rRNA	N/A	F/B ratio	The F/B ratio was lower in SLE patients.
Hevia et al. 2014 [31]	Spain	3	20	20	LN: N/A SLE:49.2 ± 10.7 HCs: 46.9 ± 8.6	LN: N/A SLE: 20:0 HCs: 20:0	16S rRNA	N/A	F/B ratio, some Firmicutes families	Challenging the immune system with the bacteria depleted in SLE, or substances promoting their growth, could influence SLE physiology.

Abbreviations: LN, lupus nephritis. SLE, systemic lupus erythematosus. HCs, healthy controls. F, female. M, male. N/A, not available. PCR, polymerase chain reaction. Q-PCR, quantitative real-time polymerase chain reaction. F/B, Firmicutes/Bacteroidetes.

Table 2. Characteristics of animal studies included in this systemic review.

Study	Experimental group	Control group	Intervention	Sequencing	Increased abundance of gut microbiota	Decreased abundance of gut microbiota	Conclusion
Wang et al. 2023 [44]	High humidity group (MRL/lpr mouse)	MRL/lpr mouse	Environment with 80 ± 5% (High humidity)	16S rRNA	Female: Phylum: Firmicutes;Genus: Rikenella; Escherichia-Shigella; Romboutsia, Turicibacter Male: Lachnospiraceae UCG-001	Female: Phylum: Bacteroidetes Genus: Lachnospiraceae UCG-006; Tuzzerella; g_unclassified_f_Rikenellaceae Male: Ruminococcus torques group; Escherichia-Shigella; g_unclassified_f_Rikenellaceae	This study has demonstrated that high humidity exacerbated lupus by modulating gut microbiota in female MRL/lpr mice.
Chancharoenthana et al. 2023 [43]	FcγRIIb−/− mice	WT mice	Water	16S rRNA	Phylum: Proteobacteria Genus: Lactobacillus;	Phylum: Bacteroidetes Genus: Alistipes; Alloprevotella; Helicobacter	This study found that lupus-prone mice with kidney involvement will appear to gut microbiota disorder.
Valiente et al. 2022 [41]	colonized NZM2410 mice with SFB	NZM2410 mice free of SFB	Colonization	16S rRNA	Family: Prevotellaceae, Lactobacillaceae Genus: Ruminococcus torques spp.	Family: Lachnospiraceae	Gut microbiota disorder can accelerate the progress of LN.
Chen et al. 2021 [28]	MRL/lpr mice	LPR/MpJ mice	N/A	16S rRNA	Genus: Ruminococcus torques, Blautia	Genus: Desulfovibrio	Increased abundance of species R. gnavus, Clostridium nexile, Olsenella uli, Actinomyces johnsonii, Staphylococcus aureus, and Enterococcus avium can discriminate LN.
Zegarra-Ruiz et al. 2019 [38]	TLR7-dependent spontaneous and induced mice	WT mice	Cecal microbiota transfer, Gavage, Mono-colonization	16S rRNA	Family: Rikennellaceae Genus: Desulfovibrio Species: Lactobacillus reuteri	N/A	Lactobacillus reuteri engages type I interferon pathway worsening autoimmune manifestations. Lactobacillus reuteri overgrowth is suppressed by metabolites from a special starch diet, thereby improving lupus outcome.
Mu et al. 2017 [40]	MRL/lpr mice	MRL mice	Cecal microbiota transplantation, Gavage	PCR	N/A	Order: Lactobacillales	Lactobacillus treatment can alleviate LN.
Johnson et al. 2015 [42]	AW-SNF1 mice	NW-SNF1 mice	Drink	16S rRNA	N/A	Genus: Turicibacter spp. Species: Lactobacillus reuteri	The pH of drinking water can influence lupus nephritis incidence and affect the composition of gut microbiota.

Abbreviations: SFB, Segmented Filamentous Bacteria. WT, wild type. LN, lupus nephritis. PCR, polymerase chain reaction. ZO1, zonula occludens-1. N/A, not available. NW, neutral pH water. AW, acidic pH water.

Figure 2. Changes in the abundance of the gut microbiota in the LN in the clinical and animal studies. The abundance of the phylum Proteobacteria, genus Streptococcus, and species Ruminococcus gnavus were enriched in LN. The F/B ratio was decreased in the LN. F/B, Firmicutes/Bacteroidetes. LN, lupus nephritis.

Figure 3. Possible mechanism linking gut microbiota dysbiosis to LN. Alteration of specific microbial taxa may contribute to the pathogenesis and progression of LN through the following four factors. First, the alteration of specific microbial taxa can induce LN by promoting kidney M2-like macrophage infiltration and leukocyte recruitment. Second, the gut microbiota may contribute to LN by enhancing the autoimmune response. Third, Streptococcus combined with Veillonella can enhance the autoimmune response, including by increasing IL-6, IL-8, IL-10, and TNF-α levels, whereas decreased IL-12p70 may induce LN. Fourth, the alteration of specific microbial taxa can increase the abundance of Tregs, while the decrease in the deposition of IgG2a may alleviate LN. SFB, Segmented Filamentous Bacteria. L. reuteri, Lactobacillus reuteri. R. gnavus, Ruminococcus gnavus. B. theta, Bacteroides thetaiotaomicron. F/B, Firmicutes/Bacteroidetes. pDCs, plasmacytoid dendritic cells. IL-12p70, interleukin-12p70. IL-10, interleukin-10. IL-8, interleukin-8. IL-6, interleukin-6. TNF-α, tumor necrosis factor α. Tregs, regulatory T cells. LN, lupus nephritis.

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Data availability statement

All data generated or analyzed in the course of this study are included in the document and its supplementary materials. Further inquiry can be available from the corresponding author.