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511 Disease flares in lupus are concordant with Ruminococcus Blautia Gnavus blooms arising within unstable gut microbiota communities
  1. Doua F Azzouz1,
  2. Ze Chen1,
  3. Peter Izmirly1,
  4. David Fenyo2,
  5. Jill Buyon1,
  6. Alexander V Alekseyenko3 and
  7. Gregg J Silverman1
  1. 1Department of Medicine, NYU Grossman School of Medicine, New York
  2. 2Institute for Systems Genetics, NYU Grossman School of Medicine, New York
  3. 3Biomedical Informatics Center, MUSC Charleston, 29203


Background Whereas genetic susceptibility for the development of the archetypic autoimmune disease, Systemic Lupus Erythematosus, has been well explored the precipitants for clinical disease flares remain a mystery. We have therefore investigated for dynamic time-dependent relationships between gut-microbial communities and Lupus disease activity.

Methods Patients fullfilled ACR criteria and were not treated with recent antibiotics or cytotoxic agents. Disease activity defined by modified SLEDAI, with fecal 16S rRNA libraries generated, and data were analyzed as previously described. Taxonomic surveys were performed on sequential 16S rRNA gene amplicon-libraries from 16 individual female Lupus patients and 22 healthy volunteers from fecal samples obtained at serial timepoints, over many months to several years.

Results Lupus patients commonly displayed significant imbalances in alpha and beta microbiota-diversity, and patients were uniquely different from the healthy individuals as well as different from other Lupus patients -- a pattern of disease-associated heterogeneity in dysbiotic communities termed the Anna Karenina Principle. From community-wide ecological multivariate analysis of sequential libraries obtained overtime, patients displayed significantly greater longitudinal microbiota community instability that was most exaggerated in Lupus Nephritis patients. Furthermore, taxonomic analyses documented an absence of bacterial intestinal blooms in 9 healthy adults with up to 12 serial fecal 16S libraries. In contrast, many of the microbiota communities of 16 Lupus patients demonstrated transient spikes of pathogenic bacterial species, with by far the most prevalent were blooms of Ruminococcus blautia gnavus (RG), which were documented in 4/9 Lupus Nephritis and 1/7 non-renal patients, concordant with disease flares. Importantly, recent in vivo pathogenesis studies in mice, have shown that intestinal colonization by RG strains isolated from Lupus patients in flare, but not RG strains from healthy adults, induce zonulin-dependent increases in intestinal permeability, RG translocation to mesenteric lymph nodes as well as serum IgG anti-RG antibody and anti-native DNA autoantibody responses.

Abstract 511 Figure 1

Lupus patients have more unstable gut microbiota than healthy individuals, and a subset of Lupus patients have blooms of Ruminococcus blautia gnavus concordant with disease flares. (A) To compare the overall dynamics of shifts in fecal communities sampled overtime in different subjects, subject variances were computed based on Jensen-Shannon Divergence using the Tw2 statistic. Variances in these three groups were significantly different (Kruskal Wallis ANOVA, p = 0.03). Patients with Lupus nephritis, based on ACR criteria, whereas the patients in the non-renal group were without a history of documented lupus nephritis. Temporal-dependent variance documents instability in the gut microbiota communities of Lupus patients compared to healthy. (B) In 11 SLE patients, a stable low abundance of RG representation was detected. (C) In 5/16 (31%) of SLE patients evaluated overtime, abundance of RG fluctuated greatly overtime. In these cases, RG abundance at much higher levels were present in fecal samples obtained proximal to visits in which disease flares were documented. In all but one excluded of these patients had documented LN. RG relative abundance was evaluated for 16 SLE in 44 samples obtained at different time points, and for CTL subjects in 49 samples obtained at different time points, which ranged from 2-12 samples per donor. Dotted line depicts 1% threshold of 16S rRNA amplicon representing RG abundance. Note that in panel C, for patient S78 the greater range of RG abundance necessitated a different scale. SLEDAI ≥ 8 was considered high disease activity.

Conclusions As many Lupus patients are known to suffer relapsing illness despite appropriate treatment, we speculate that gut blooms of pathogenic bacteria that impair gut barrier function and stoke systemic inflammation directly contribute to immunopathogenesis. We propose that future therapeutic interventions designed to promote a durable remission consider the potential necessity to target both the immunologic abnormalities of the disease, as well as re-establish stability within the gut microbiota community.

Acknowledgments This work was supported in part by National Institutes of Health Grants; R01-AR42455, P50 AR070591, the Lupus Research Alliance, and the Judith and Stewart Colton Autoimmunity Center (GJS). 16S rRNA amplicon sequence determinations and analysis were supported by the P. Robert Majumder Charitable Trust.

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