Background/Purpose: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). Current investigations implicate microbiome changes in disease pathogenesis, particularly pathobiont expansions of Ruminococcus gnavus (RG) ranging from minor dysbiosis to extreme blooms. Transient spikes in RG communities in human and mouse models have been associated with disease activity.

Methods: A methodical search of MEDLINE, Science Direct, and EMBASE was conducted to evaluate the understanding of Ruminococcus involvement in LN up to May 28, 2023. Two reviewers independently assessed the literature for the inclusion and exclusion criteria methodically by title, abstract, and full text resulting in a cumulative 83 articles. Once screened for duplicates and open-access content on relevant primary literature, 13 remaining articles were identified.

Results: The 13 included articles commonly recognized RG population blooms in active SLE including LN, outnumbering other members of the genus. These blooms correlated with the presence of anti-native DNA autoantibodies. LN patients were found to have elevated fecal RG based on 16S rRNA amplicon analysis with serum IgG anti-RG Ab in concordance with anti-dsDNA. Furthermore, anti-RG Ab targeted to bacterial cell-wall lipoglycans correlated with SLE disease activity index indicating a disease model in which specific strains of gut commensal contribute to the immunopathogenesis of LN. Distorted tryptophan metabolism toward the kynurenine pathway is reported in SLE; differential microbial catabolism has been implicated since tryptophan and the metabolite tryptamine increase pro-inflammatory T cell metabolism and mTOR activation thus promoting damage to renal tubular epithelial cells. RG expresses tryptophan decarboxylase necessary to synthesize tryptamine from tryptophan, contributing to elevated tryptamine levels in LN pathogenesis. The experimental administration of Lactobacillus casei Zhang shows evidence of delayed kidney disease in mice. Short-chain fatty acids and nicotinamide in these studies reduced renal inflammation, suggesting the commensal metabolic impact can mitigate or progress renal decline in mice models. Despite SLE disease heterogeneity, pathobiont blooms may impair gut barriers and fuel systemic inflammation. In another study, SLE mouse models given acidic pH water developed nephritis slower compared to those given neutral pH water. A higher level of circulating auto-Ab against plasma cells and nuclear antigen were found in the latter with notable variations in 16S rRNA gene-targeted sequencing of the gut microbiome and immune responses shifted to TH17 and Th9-associated factors. This suggests that dietary changes can influence SLE flares through the regulation of the microbiome.

Conclusion: The microbiomes of SLE patients show a decrease in species diversity; disease activity, including LN development, is associated with RG pathobiont blooms. Given the demonstrated association between the microbiome and immunomodulation, RG populations may be a novel therapeutic target in the treatment of patients with LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ruminococcus-implicated-in-the-clinical-development-of-lupus-nephritis-a-systematic-review-of-the-literature/