Studies in lupus mouse models and controls
Authors & Reference | Mouse model | Age | Sequencing | Alpha and beta-diversity | F/B ratio | Functional pathways | Other findings |
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Wang et al. [14] | MRL+/+ MRL/lpr C57BL/6 (control) | 6–16 weeks | 16S rDNA: V4 regionIllumina Miseq | Alpha-diversity: lower in MRL/lpr 6 week-old mice but not in 18-week-old.Without difference in MRL+/+ mice.Beta-diversity: differential bacterial community composition in MRL+/+ and MRL/lpr mice at 6 weeks and 18 weeks. | Lower in 6 week-old MRL/lpr mice vs. age-matched MRL+/+ mice. | NA | In 18-week vs. 6-week MRL+/+ mice: increase in Bacteroidetes and Verrucomicrobia phyla; Akkermansiaceae and Rikenellaceae families; Akkermansia, Alistipes, Blautia, and Ruminiclostridium genus, and Akkermansia muciniphila species.Reduction in Firmicutes and Tenericutes phyla, Anaeroplasmataceae and Peptostreptococcaceae families, Anaeroplasma and Romboutsia genus, and Clostridium clostridiiforme and Faecalibacterium prausnitzii species.No statistically significant alterations were found between 18-week and 6-week MRL/lpr mice.6-week-old MRL/lpr mice vs. MRL+/+ mice: decreased Peptostreptococcaceae and Lactobacillaceae, increase in Rikenellaceae; decreased Muribaculaceae and Anaeroplasmataceae. |
Chen et al. [41] | MRL/lpr MRL/MpJ (control) | 17 weeks | Illumina HiSeq | Alpha-diversity: without significant alterations, but decreased number of species.Beta-diversity: significantly different from controls. Higher inter-group distribution in lupus mice than controls. | NA | Positively related to increase in MRL/lpr and SLE patients: biosynthesis of L-arginine and L-ornithine, tryptophan, menaquinol, palmitoleate, and oleate, phosphatidylglycerol. | Increased R. torques and genera Blautia in SLE patients and lupus mice.Decreased genera Desulfovibrio in MRL/lpr. |
Mu et al. [15] | MRL/lprMRL/lpr with no antibiotics (control) | 9–16 weeks | 16S rRNA: V4 regionIllumina MiSeq | Alpha-diversity: no alteration with a mix of antibiotics given after disease onset but reduced when only vancomycin was given. | NA | Treatment of MRL/lpr mice with vancomycin up-regulated peptidoglycan biosynthesis and transcriptional factors pathways, and down-regulated glyoxylate, decarboxylate, and histidine metabolism, and phenylalanine, tyrosine, tryptophan, and lipopolysaccharide biosynthesis. | MRL/lpr: Marked depletion of Lactobacilli, and increase of Clostridial species.Antibiotics treatment initiated after disease onset improved lupus-like symptoms; post-disease onset reduced bacterial load and did not decrease bacterial diversity.Antibiotic reshaped the composition of the gut microbiota, increasing the relative abundance of Lactobacillus spp., and decreasing Lachnospiraceae.A mix of antibiotics and vancomycin led to Lactobacillus spp. enrichment. |
Zhang et al. [16] | MRL/MpJMRL/lprB6/lprC56BL/6 (control) | 6–14 weeks | 16S rRNA: V4 regionIllumina MiSeq | Alpha-diversity: higher in lupus-prone mice.Beta-diversity: phylogenetic difference. | NA | Down-regulated in lupus mouse models: DNA replication, DNA repair, protein synthesis, galactose and glycolysis metabolism.Up-regulated in lupus mouse models: bacterial chemotaxis, flagellar assembly, sporulation, glyoxylate and decarboxylate metabolism, ABC transporters, amino-acid metabolism. | MRL/lpr: reduction in Lactobacillaceae (family), increase in Lachnospiraceae (family).The abundance of Lachnospiraceae positively correlated with lymphadenopathy and renal pathology.Treatment with retinoic acid attenuated lupus-like symptoms while increasing the Lactobacillaceae. |
Chen et al. [17] | NZB/W F1 induced by HCMVpp65422–439NZB/W F1 treated with PBS (control) | 12–24 weeks | 16S rRNA | Alpha-diversity: higher than controls.Beta-diversity: differences in microbial community composition. | Increased in lupus mice vs. controls | Differentially expressed in lupus vs. controls: cell motility, lysosomes, flagellar assembly, cytoskeleton proteins, bacterial motility proteins, bacterial chemotaxis. | Increase in lupus mouse models: families Saccharimonadaceae, Marinifiaceae, and Desulfovibrionaceae.Candidatus Saccharimonas showed significant positive correlations with the creatinine level, anti-dsDNA IgG titer, and glomerulonephritis severity. All four lupus-like effects were positively correlated with Odoribacter, Desulfovibrio, and Roseburia. |
Johnson et al. [18] | (SWRxNZB)F1 (SNF1)C57BL/6 (control) | 4–24 weeks | 16S rRNA: V3–V4 regionIllumina Miseq | Alpha-diversity: lower in 24-week SNF1 females than males.Alpha-diversity: significantly different in 16-week mice.Beta-diversity clustering of gut microbiota of 16-week males and females but not at 4 weeks. | NA | Up-regulated in female 16-week mice lupus model: glycol degradation, glycosphingolipid biosynthesis pathways, nitrogen, amino sugar, nucleotide sugar, galactose, starch, and sucrose metabolism pathways.Down-regulated in female 16-week mice lupus model: secondary metabolite synthesis and degradation, fatty acid, glycerophospholipid, and lysine metabolism. | The gut microbiota composition of lupus-prone SNF1 mice is different at adult ages but not at juvenile ages.Females at 16 weeks: higher abundance of Bacteroidetes and Parabacteroides genus members, and lower Dysgonomonas genus members of Bacteroidetes phylum.Significant age-dependent differences in the abundance of multiple microbial communities in 16-week mice. |
Choi et al. [19] | TCC57BL/6 (control) | 6 weeks to 6 months | 16S rDNA: V4–V5 regionsIllumina Miseq | Alpha-diversity: no alterations. | NA | Up-regulated in TC mice: Tryptophan metabolism, microbial metabolism derived from shikimate pathway, purine and pyrimidine metabolism, protein digestion and absorption, biosynthesis of antibiotics, biosynthesis of amino acids, nucleoside pathways. | TC mice: marked alterations in Prevotellaceae, Paraprevotella, and Lactobacillus.Different bacterial taxa composition between young and adult TC and controls. |
Luo et al. [42] | NZB/W F1 treated with dexamethasone NZB/W F1 (control) | 10–33 weeks | 16S rRNA: V4 regionIllumina Miseq | Alpha-diversity: increased bacterial diversity with disease progression in NZB/W F1 mice.Beta-diversity: difference between pre-disease and diseased time points. | NA | NA | Genera Clostridium, Dehalobacterium, Lactobacillus, Oscillospira, Dorea, Bilophila, and AF12, and an unnamed genus within the family Ruminococcaceae, increased from the pre-disease stage to the diseased stage.Decrease of Akkermansia muciniphila and a species within the genus Anaerostipes from the pre-disease stage to the diseased stage.The relative abundance of Lactobacillaceae increased significantly from the pre-disease stage to the post-disease stage, and treatment with dexamethasone was able to significantly decrease its abundance. |
Ma et al. [20] | TCC57BL/6 (control) | 34–36 weeks | 16S rRNA genes: V4 regionIonS5™XL | Alpha-diversity: decreased richness and diversity in TC mice.Beta-diversity: differences between mouse-models.Fecal transplantation to GF mice: the recipient mice maintained the same tendency of diversity as donors. | NA | NA | TC mice showed a dysbiotic gut microbiota when compared to controls.Increased Firmicutes and Actinobacteria phylum in TC mice.Fecal transplantation induced a gut mucosal immune response, higher with TC than with feces of control mice.The expression of Irf7 and Csk genes was significantly higher in germ-free mice that received TC fecal transplant than in germ-free mice that received fecal transplant from controls.Fecal transplant with feces of TC mice triggered alterations in gene expression in the colon. |
Mu et al. [21] | MRL/lprMRL/MpJ (control) | 3–14 weeks | 16S rRNAIllumina Miseq | NA | NA | NA | Sugestive positive correlation between a higher abundance of Lactobacillales and improved lupus-like symptoms.Before disease onset, Lactobacillus treatment significantly increased the survival of female lpr mice. L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects.Lactobacillus spp. in the gut can attenuate kidney inflammation in lupus-prone mice in a sex hormone-dependent manner when given before disease onset. |
Valiente et al. [22] | NZM2410C57BL/6 | 10–30 weeks | 16S rRNA: V4 regionIllumina Miseq | Alpha-diversity: higher in SFB+ mice than in SFB– mice (not statistically significant). | Trend towards a reduced F/B ratio at 30-week-old SFB+ mice without statistical significance. | NA | SFB+ mice showed increased gut permeability and a decrease in gut barrier integrity.SFB+: increased Prevotellaceae, Lactobacillaceae, and Clostridiaceae, and decreased Ruminococcaceae and Lachnospiraceae.30-week-old mice had significant enrichment of R. torques spp. when compared to 15-week-old SFB+ and SFB– mice. |
Cabana-Puig et al. [23] | MRL/lpr(2 different colonies) | 3–15 weeks | 16S rRNA: V4 regionIllumina Miseq | Alpha-diversity: different between colonies of MRL/lpr mice. | NA | NA | Housing/environmental differences justify alterations in the gut microbiota of two different colonies of MRL/lpr mice.Some phenotypic differences may be explained by the alterations in the gut microbiota. |
Hong et al. [24] | BXD2C57BL/6 (control) | 6 months or 12 months | 16S rRNA: V4 regionIllumina Miseq | NA | NA | NA | Lupus phenotype is not influenced by the gut microbiota composition.The gut microbiota composition favors the maintenance of immune dysregulation and disease progression in older mice. |
Shirakashi et al. [25] | B6SKGB6SKG germ-free (control) | 3–12 months | 16S rRNA: V1–V2 regionsIllumina Miseq | Alpha-diversity: moderate decrease. | NA | NA | In B6SKG mice, dysbiosis may occur due to altered Tfh and germinal center development in Peyer’s patches, and IgA production.An altered T cell receptor signaling, which contributes to the alteration of the gut microbiota, favors autoimmunity. |
B6SKG: SKG mice with a B6 background; Csk: tyrosine-protein kinase; dsDNA: double-stranded DNA; F/B ratio: Firmicutes/Bacteroidetes ratio; HC: healthy controls; IgG: immunoglobulin G; Irf7: interferon Regulatory Factor 7; MRL: Murphy Roths large; NA: not applicable; NZB/W: New Zealand black x New Zealand white; PBS: phosphate-buffered saline solution; R.: Ruminococcus; rDNA: ribosomal DNA; rRNA: ribosomal RNA; SFB–: not inoculated with segmented filamentous bacteria; SFB+: inoculated with segmented filamentous bacteria; TC: triple congenic (B6.Sle1.Sle2.Sle3); Tfh: T follicular helper cells