Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal

Abstract

Background/PurposeTo search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.MethodsIn a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.ResultsCompared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.ConclusionThese findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.

Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice

“…Dietary factors can also have a profound impact on the gut and systemic immune responses [4][5][6][7][8]. Recent studies that used human samples and rodent models have shown that gut microbiota composition influences the rate of disease progression and the overall disease outcome [9][10][11][12][13]. In addition to direct effects on the systemic and gut immune cell functions, dietary factors can change the composition of gut microbiota and affect autoimmune outcomes [10,14,15].…”

Metabolic determinants of lupus pathogenesis

“…142 Fecal metabolomics may be important considering increasing reports of altered SLE fecal microbiomes both in patients and murine models of lupus. [143][144][145][146][147][148][149] Pathway analyses of serum metabolite profiles also suggested an altered gut microbial metabolism in SLE patients compared to HCs, 135,150 including an increase in total free fatty acids (FFAs) and short-chain fatty acids (SCFAs) synthesized by bacteria. 146 Additionally, disrupted metabolic pathways were found in the urine of SLE patients compared to HCs including amino acid, TCA cycle, and purine/pyrimidine metabolism.…”

Host-Microbial Interactions in Systemic Lupus Erythematosus and Periodontitis

“…Wilcoxon rank-sum test on two datasets related to SLE phenotypes. The first dataset was based on relative abundance and the second dataset was based on logistic regression model binary abundances 15 (presence/absence) to evaluate prevalence. Based on the relative abundance profiles, and the hierarchical clustering using Spearman's rank correlation coefficients, we identified two distinct groups of bacterial species in SLE individuals with and without periodontitis when compared to their respective controls ( Figure 2B, Figure 3A).…”

“…Although complex diseases have shown to be influenced by genetic and environmental forces, the gut microbiome, and recently the oral microbiome, showed direct impact on SLE subjects 14 , the complexity of chronic diseases such as SLE is beyond isolated body compartments, and it requires the integration of host-microbial interactions. The heterogeneity of disease presentation and organ involvement contribute to clinical challenges for diagnosis and effective management 15 . While several studies reported associations among human oral microbiota compositions in SLE [16][17][18][19] , co-occurrences of specific periodontal pathogens and inflammatory cytokines important for low grade inflammation and chronic disease remains to be explored 4 .…”