Disordered intestinal microbes are associated with the activity of Systemic Lupus Erythematosus

Abstract Intestinal dysbiosis is implicated in Systemic Lupus Erythematosus (SLE). However, the evidence of gut microbiome changes in SLE is limited, and the association of changed gut microbiome with the activity of SLE, as well as its functional relevance with SLE still remains unknown. Here, we sequenced 16S rRNA amplicon on fecal samples from 40 SLE patients (19 active patients, 21 remissive patients), 20 disease controls (Rheumatoid Arthritis (RA) patients), and 22 healthy controls (HCs), and investigated the association of functional categories with taxonomic composition by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). We demonstrated SLE patients, particularly the active patients, had significant dysbiosis in gut microbiota with reduced bacterial diversity and biased community constitutions. Amongst the disordered microbiota, the genera Streptococcus, Campylobacter, Veillonella, the species anginosus and dispar, were positively correlated with lupus activity, while the genus Bifidobacterium was negatively associated with the disease activity. PICRUSt analysis showed metabolic pathways were different between SLE and HCs, and also between active and remissive SLE patients. Moreover, we revealed that a random forest model could distinguish SLE from RA and HCs (area under the curve (AUC) = 0.792), and another random forest model could well predict the activity of SLE patients (AUC = 0.811). In summary, SLE patients, especially the active patients, show an apparent dysbiosis in gut microbiota and its related metabolic pathways. Amongst the disordered microflora, four genera and two species are associated with lupus activity. Furthermore, the random forest models are able to diagnose SLE and predict disease activity.

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Cathelicidin (LL-37) and its correlation with pro-oxidant, antioxidant balance and disease activity in systemic lupus erythematosus: a cross-sectional human study

Lupus ◽

10.1177/0961203317691368 ◽

2017 ◽

Vol 26 (9) ◽

pp. 975-982 ◽

Cited By ~ 4

Author(s):

M Sahebari ◽

G Roshandel ◽

N Saadati ◽

M Saghafi ◽

N Abdolahi ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Human Study ◽

Serum Levels ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Positive Correlation ◽

Active Patients

Background Cathelicidin (LL-37), an endogenous antimicrobial peptide, has recently been involved in the pathogenesis of autoimmune diseases. To assess whether LL-37 reflects disease activity, we measured serum levels of it in systemic lupus erythematosus (SLE) patients with active and inactive disease compared to healthy controls. LL-37 was also compared between new and old cases. Moreover, the correlation of LL-37 and pro-oxidant, antioxidant balance (PAB) was measured. Methods The study population consisted of 50 SLE patients and 28 healthy controls. Of those, 39 patients had active and 11 patients had inactive disease. Serum levels of LL-37 were measured by ELISA and PAB values by a special method. Results There was no difference in levels of LL-37 between patients and healthy controls (50.9 ± 20.8 vs. 67.7 ± 43.3 ng/ml, P = 0.31). LL-37 did not correlate with SLEDAI and its items in total patients. LL-37 had a positive correlation with SLEDAI in active patients ( P = 0.01, r = 0.4). In active patients (78% of patients), multivariate regression analysis showed significant negative correlation between LL-37 and C3 ( P = 0.01, standardized beta –0.50). No difference was found in levels of PAB between patients and controls (90.4 ± 34.1 vs. 86.9 ± 25.6 HK, P = 0.4).There was no difference in the levels of PAB between patients with active and inactive disease (93.2 ± 34.1 vs. 80.2 ± 33.7 HK, P = 0.27). No correlation was found between levels of PAB and SLEDAI items and total score. However, a positive correlation between the levels of LL-37 and PAB in SLE patients was found ( r = 0.3, P < 0.01). Conclusion Based on this study, serum LL-37 and PAB did not increase in lupus compared with healthy individuals. LL-37 serum values rose in parallel with SLEDAI in active disease. Positive correlation between serum PAB and LL-37 could be a great achievement of this study that may suggest the role of antioxidants in controlling NETosis.

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Disease course patterns in systemic lupus erythematosus

Lupus ◽

10.1177/0961203318817132 ◽

2018 ◽

Vol 28 (1) ◽

pp. 114-122 ◽

Cited By ~ 7

Author(s):

K. Tselios ◽

D.D. Gladman ◽

Z. Touma ◽

J. Su ◽

N. Anderson ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Disease Course ◽

Systemic Lupus Erythematosus Disease ◽

Systemic Lupus ◽

Relapsing Remitting ◽

Active Patients

Background Disease activity in systemic lupus erythematosus follows three different courses: long quiescent, relapsing remitting and persistently active. However, the patterns of disease course since diagnosis are not known. This study aimed to assess the prevalence and characteristics of such patterns over 10 years. Patients and methods The inception cohort of the Toronto Lupus Clinic (≥10 year follow up, between visit interval ≤18 months) was investigated. Prolonged remission was defined as a clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 achieved within 5 years of enrolment and maintained for ≥10 years. The relapsing-remitting pattern was defined based on ≥2 remission periods (clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 for two consecutive visits). Patients with no remission were categorized as persistently active. Groups were compared for baseline characteristics, cumulative damage, flare rate, mortality and certain co-morbidities. Results Of 267 patients, 27 (10.1%) achieved prolonged remission, 180 (67.4%) relapsing-remitting and 25 (9.4%) persistently active. In total, 35 (13.1%) had only one remission period (hybrid). At enrollment, there were no differences regarding clinical and immunological variables. At 10 years, persistently active patients had accumulated significantly more damage than the prolonged remission and relapsing-remitting patients. Being of Black race and higher adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 over the first 2 years were associated with a more severe disease course. Relapsing-remitting and persistently active patients had an increased flare rate and accrued more osteoporosis, osteonecrosis and cardiovascular events. Conclusions Approximately 70% of systemic lupus erythematosus patients followed a relapsing-remitting course, whereas 10% displayed prolonged remission and another 10% a persistently active course. Early response to treatment was associated with a less severe course and better prognosis.

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OP0307 GUT MICROBIOTA AND ITS RELEVANCE TO PERIPHERAL LYMPHOCYTE SUBPOPULATION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3021 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 188-189

Author(s):

T. Cheng ◽

X. Wang ◽

S. X. Zhang ◽

J. Yang ◽

C. Zhao ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Gut Microbiota ◽

Disease Activity ◽

Lupus Erythematosus ◽

Lymphocyte Subsets ◽

Treg Cells ◽

Peripheral Lymphocyte ◽

Lymphocyte Subpopulations ◽

Systemic Lupus ◽

T Lymphocyte Subsets

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease with disturbance of lymphocyte subpopulations1. Growing experimental and clinical evidence suggests that chronic inflammatory response induced by gut microbiome critically contribute to the development of SLE2 3.Objectives:To investigate the characteristics of gut microbiome and the associations between flora and peripheral lymphocyte subpopulations in SLE patients.Methods:A total of 19 SLE patients who fulfilled the 2019 American college of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria and 16 age- and sex- matched healthy controls (HC) were enrolled in this study. The peripheral T lymphocyte subsets of these participants were assessed by flow cytometry and the gut microbiota were investigated via 16s rRNA. Indicators of disease activity such as erythrocyte sedimentation rate (ESR), complement C3 and C4 were recorded at the same time. Mann-Whitney U test was applied to compare T lymphocyte subsets between SLE patients and HC. Spearman analysis was used for calculating correlation between T subsets and highly expressed differential flora as well as their correlation with disease activity indicators. All P-values reported herein were two-tailed and P-value<0.05 was taken as statistically significant.Results:SLE patients had higher proportions of Th17 cells (P=0.020) and γδT cells (P=0.018) but lower levels of Treg cells (P=0.001), Tfh cells (P=0.018) and Naïve CD4+T cells (P=0.004) (Figure 1a-e). The diversity and relative abundance of intestinal flora in patients with SLE were significantly different from those in HCs. Detailly, the α-diversity was decreased in SLE (P<0.05) (Figure 2a-c). Compared with HC, 11 species of flora were discovered to be distinctly different(P<0.05) (Figure 2d-e). Moreover, there was a significant positive correlation between Treg levels and Ruminococcus2 (P=0.042), Th17 and Megamonas (P=0.009), γδT and Streptococcus (P=0.004) as well as Megamonas (P=0.003), Tfh and Bacteroides (P=0.040). Whereas Th1 levels and Bifidobacterium were negatively correlated in these participants (P=0.005). As for clinical disease measures, there were negative correlations not only between ESR and Treg cells (P=0.031) but also C4 and the amount of Unclassified Ruminococcaceae (P=0.032).Conclusion:Abnormality of T cell subsets, especially the level of Naïve CD4+T, γδT, Tfh, Treg, and Th17 cells contributes to the occurrence and progression of SLE, which may be related to the disturbance of gut microbiota. Therefore it is necessary to attach importance to the alteration of gut microbiota to prevent the outbreak of inflammation and maybe they can be identified as biomarkers predicting disease activity.References:[1]Katsuyama T, Tsokos GC, Moulton VR. Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus. Front Immunol 2018;9:1088. doi: 10.3389/fimmu.2018.01088 [published Online First: 2018/06/06][2]López P, de Paz B, Rodríguez-Carrio J, et al. Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients. Sci Rep 2016;6:24072. doi: 10.1038/srep24072 [published Online First: 2016/04/06][3]Esmaeili SA, Mahmoudi M, Momtazi AA, et al. Tolerogenic probiotics: potential immunoregulators in Systemic Lupus Erythematosus. J Cell Physiol 2017;232(8):1994-2007. doi: 10.1002/jcp.25748 [published Online First: 2016/12/21]Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared.

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Altered Profile of Fecal Microbiota in Newly Diagnosed Systemic Lupus Erythematosus Egyptian Patients

International Journal of Microbiology ◽

10.1155/2021/9934533 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Marian A. Gerges ◽

Noura E. Esmaeel ◽

Wafaa K. Makram ◽

Doaa M. Sharaf ◽

Manar G. Gebriel

Keyword(s):

Systemic Lupus Erythematosus ◽

Gut Microbiota ◽

Disease Activity ◽

Lupus Erythematosus ◽

Healthy Subjects ◽

Fecal Microbiota ◽

Healthy Controls ◽

Newly Diagnosed ◽

Systemic Lupus ◽

Egyptian Patients

Background. Dysbiosis of gut microbiota could promote autoimmune disorders including systemic lupus erythematosus (SLE). Clarifying this point would be of great importance in understanding the pathogenesis and hence the development of new strategies for SLE treatment. Aim. This study aimed to determine the fecal microbiota profile in newly diagnosed SLE patients compared to healthy subjects and to investigate the correlation of this profile with disease activity. Methods. Newly diagnosed SLE patients who fulfilled at least four of the American College of Rheumatology (ACR) criteria were enrolled during the study period. Patients with lupus were matched to healthy subjects. SLE activity was evaluated using the Systemic Lupus Disease Activity Index (SLEDAI-2K). Fresh fecal samples were collected from each subject. Genomic DNA was extracted from fecal samples. Quantitative real-time PCR was applied for quantitation of Firmicutes phylum, Bacteroidetes phylum, and Lactobacillus genus in comparison to the total fecal microbiota. Results of patients’ samples were compared to those of healthy subjects and were correlated to patients’ SLEDAI-2K score. Results. Twenty SLE patients’ samples were compared with 20 control samples. There was a significant alteration in SLE patients’ gut microbiota. A significantly lower ( p ≤ 0.001 ) Firmicutes/Bacteroidetes (F/B) ratio in SLE patients (mean ratio: 0.66%) compared to healthy subjects (mean ratio: 1.79%) was found. Lactobacillus showed a significant decrease in SLE patients ( p = 0.006 ) in comparison to healthy controls. An inverse significant correlation between SLEDAI-2K scores for disease activity and F/B ratio (r = −0.451; p = 0.04 ) was found. However, an inverse nonsignificant correlation between SLEDAI-2K scores for disease activity and Lactobacillus (r = −0.155; p = 0.51 ) was detected. Conclusion. Compared to healthy controls, recently diagnosed SLE Egyptian patients have an altered fecal microbiota profile with significant lowering of both F/B ratio and Lactobacillus abundance, which is weakly correlated with disease activity.

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Gut Microbiome and Metabolites in Systemic Lupus Erythematosus: Link, Mechanisms and Intervention

Frontiers in Immunology ◽

10.3389/fimmu.2021.686501 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lingshu Zhang ◽

Pingying Qing ◽

Hang Yang ◽

Yongkang Wu ◽

Yi Liu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Gut Microbiota ◽

Lupus Erythematosus ◽

Gut Microbiome ◽

Intestinal Bacteria ◽

Systemic Lupus ◽

Diagnostic Strategies ◽

Host Interaction ◽

Adaptive Immune Cells ◽

Genetic And Environmental Factors

Systemic lupus erythematosus (SLE), often considered the prototype of autoimmune diseases, is characterized by over-activation of the autoimmune system with abnormal functions of innate and adaptive immune cells and the production of a large number of autoantibodies against nuclear components. Given the highly complex and heterogeneous nature of SLE, the pathogenesis of this disease remains incompletely understood and is presumed to involve both genetic and environmental factors. Currently, disturbance of the gut microbiota has emerged as a novel player involved in the pathogenesis of SLE. With in-depth research, the understanding of the intestinal bacteria-host interaction in SLE is much more comprehensive. Recent years have also seen an increase in metabolomics studies in SLE with the attempt to identify potential biomarkers for diagnosis or disease activity monitoring. An intricate relationship between gut microbiome changes and metabolic alterations could help explain the mechanisms by which gut bacteria play roles in the pathogenesis of SLE. Here, we review the role of microbiota dysbiosis in the aetiology of SLE and how intestinal microbiota interact with the host metabolism axis. A proposed treatment strategy for SLE based on gut microbiome (GM) regulation is also discussed in this review. Increasing our understanding of gut microbiota and their function in lupus will provide us with novel opportunities to develop effective and precise diagnostic strategies and to explore potential microbiota-based treatments for patients with lupus.

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POS0787 BERBERINE MODULATE LUPUS SYNDROME VIA THE REGULATION OF GUT MICROBIOTA IN MRL/LPR MICE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3838 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 646.2-646

Author(s):

Y. Bao ◽

J. Ji ◽

Z. Xue ◽

Z. Gu

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Gut Microbiota ◽

Disease Activity ◽

Lupus Erythematosus ◽

Intestinal Flora ◽

Systemic Lupus ◽

Gut Barrier ◽

Qrt Pcr ◽

Intestinal Dysbacteriosis

Background:Intestinal flora disorder and immune abnormalities have been reported in systemic lupus erythematosus (SLE) patients1,2. Berberine (BBR) showed significant effects in regulating the intestinal flora, repairing gut barriers and regulating immune cells3,4. While few reports mentioned the abnormal gut microbiota and metabolites in Chinese SLE patients.Objectives:Our investigation tried to illustrate the relationship between gut microbiota, intestinal metabolites and disease activity in Chinese SLE patients. And the effect of BBR to intestinal dysbacteriosis, multiple organ damages and over-activated immune system in MRL/Lpr mice.Methods:16S high-throughput (16S rRNA) sequence, qRT-PCR and gas chromatography technology were used to determine the gut microbiota and metabolites in 104 SLE patients from Affiliated Hospital of Nantong University, China. BBR was orally treated to the MRL/Lpr mice in low, medium and high doses. After 6 weeks treatment, mice were sacrificed. Serum, faeces and organs were collected for further studies.Results:Chinese SLE patients showed higher abundance of Bacteroidetes and lower abundance of Firmcutes. The results of qRT-PCR showed high Firmcutes/Bacteroidetes (F/B) ratio of SLE patients. The F/B ratio was negative correlated with SLE disease activity index (SLEDA) score. Almost all the tested short-chain fatty acids (SCFAs) found statistically significant results in SLE and LN (lupus nephritis) patients, especially the propanoic acid and butyric. BBR altered the relative abundance of Bacteroides and Verrucomicrobia and the butyric acid content in colon of MRL/Lpr mice. The increase of tight junction protein also indicated the gut barrier was repaired by BBR. Treg and Tfr cells in spleen and mesenteric lymph node (MLN) were increased. These results revealed a positive therapeutic effect of berberine on SLE from gut microbiota to immune status.Conclusion:Our study highlights current status of intestinal dysbacteriosis in Chinese patients with SLE and differences in intestinal metabolites among patients with different disease states. The regulation of intestinal flora and the repairment of gut barrier by intestinal metabolites in BBR treated mice seemed to be the factor that directed the immune responses and disease outcomes. The ultimate goal of our study was to determine the beneficial effects of regulating the gut microbiota on the treatment of SLE. The application of berberine is a relatively safe and convenient way. In the coming investigations, we plan to focus on the study of berberine and its metabolites on intestinal function and systemic immunity.References:[1]Guo, M. et al. Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus. Gut microbes11, 1758-1773, doi:10.1080/19490976.2020.1768644 (2020).[2]Mu, Q. et al. Control of lupus nephritis by changes of gut microbiota. Microbiome5, 73, doi:10.1186/s40168-017-0300-8 (2017).[3]Habtemariam, S. Berberine pharmacology and the gut microbiota: A hidden therapeutic link. Pharmacological research155, 104722, doi:10.1016/j.phrs.2020.104722 (2020).[4]Cui, H. et al. Berberine Regulates Treg/Th17 Balance to Treat Ulcerative Colitis Through Modulating the Gut Microbiota in the Colon. Frontiers in pharmacology9, 571, doi:10.3389/fphar.2018.00571 (2018).Figure 1.Disclosure of Interests:None declared

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CD44v3 and CD44v6 isoforms on T cells are able to discriminate different disease activity degrees and phenotypes in systemic lupus erythematosus patients

Lupus ◽

10.1177/0961203319838063 ◽

2019 ◽

Vol 28 (5) ◽

pp. 621-628 ◽

Cited By ~ 2

Author(s):

L Novelli ◽

C Barbati ◽

F Ceccarelli ◽

C Perricone ◽

F R Spinelli ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Characteristic Curve ◽

Disease Activity Index ◽

Systemic Lupus ◽

Active Patients

Background Adhesion molecule CD44 contributes to T cell migration into target organs. A higher expression of CD44v3 and v6 isoforms has been identified on T cells from systemic lupus erythematosus (SLE) patients. The aim of this study was to investigate the expression of CD44v3/v6 on T cells of SLE patients in order to evaluate their correlation with clinical features. Methods Sixteen healthy subjects (HSs) and 33 SLE female patients were enrolled. Fifteen patients were in remission (Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) = 0) and 18 patients had an active disease (SLEDAI-2K ≥ 4). Experiments were conducted by flow cytometry. Results Expression of CD44v3 on CD4+ and CD8+ T cells was higher in active patients compared to HSs ( p = 0.0097 and p = 0.0096). CD44v3 on CD8+ T cells was also higher in active patients compared to patients in remission ( p = 0.038). CD44v6 was higher on CD4+ and CD8+ T cells from active patients compared to HSs ( p = 0.003 and p = 0.0036) and to patients in remission ( p = 0.01 and p = 0.02). In active patients the ratio CD44v3/v6 was unbalanced towards isoform v6 on both T cell populations. In a receiver operating characteristic curve analysis, CD44v6 on CD4+ T cells was the most sensitive and specific one (specificity of 81.8%, sensitivity of 75%). Expression of CD44v6 on CD4+ and CD8+ T cells correlated with the SLEDAI-2K ( p = 0.03, r = 0.38 and p = 0.02, r = 0.39). CD44v6 and CD44v3 on CD8+ T cells associated with nephritis and arthritis ( p = 0.047 and p = 0.023). Conclusions CD44v3/v6 can be used as biomarkers of disease activity and phenotypes; isoform v6 on CD4+ T cells can be useful as a diagnostic biomarker.

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Gut Microbiota Profiles of Systemic Lupus Erythematosus Patients with Anxiety or Depression

10.21203/rs.3.rs-885639/v1 ◽

2021 ◽

Author(s):

alvina widhani ◽

Meutia Gebrina ◽

Rudi Putranto ◽

Murdani Abdullah ◽

Ikhwan Rinaldi ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Gut Microbiota ◽

Disease Activity ◽

Lupus Erythematosus ◽

Gastrointestinal Symptoms ◽

Diversity Indices ◽

Anxiety And Depression ◽

Rrna Gene ◽

Systemic Lupus ◽

Lupus Disease Activity

Abstract Background Patients with systemic lupus erythematosus (SLE) often experience anxiety and depression. Recent studies have shown involvement of intestinal dysbiosis in SLE and also psychosomatic disorders. However, there are no reports on the gut microbiota profile of patient with both conditions: SLE and anxiety or depression. We aimed to study gut microbiota profiles among SLE patients with gastrointestinal symptoms and anxiety or depression by sequencing V3–V4 region of the 16S rRNA gene from the stool samples. Results Of the 41 SLE patients who participated in the study, 53.66% had anxiety and 14.63% had depression. We found a higher proportion of Bacteroidetes and lower diversity indices in patients with anxiety than in those without anxiety. We also found a higher proportion of Bacteroidetes and lower Firmicutes/Bacteroidetes ratios and diversity indices in patients with depression than in those without depression. Moreover, compared to other groups, patients with symptoms of both anxiety and depression had the highest proportion of Bacteroidetes and lowest proportion of Firmicutes, Firmicutes/Bacteroidetes ratios, and diversity indices. Further analysis showed that there was a significant correlation between the proportion of Bacteroides and the anxiety score (r = 0.349; p = 0.03) as well as with lupus activity (r = 0.36; p = 0.02). There was also significant correlation between diversity indices and lupus activity (r= -0.34; p = 0.03 for Chao1 index, r= -0.38; p = 0.01 for Shannon index, and r= -0.33; p = 0.03 for richness index). Conclusions SLE patients with both anxiety and depression showed more unfavorable gut dysbiosis parameter compared to SLE patients with only anxiety or depression and SLE patients without anxiety or depression. There was positive correlation between proportion of Bacteroides and lupus disease activity and negative correlation between diversity indices and lupus disease activity.

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