Background/Purpose: Anti-Ro autoantibody production often precedes the development of systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS) by years. Anti-Ro+ mothers of children with manifestations of neonatal lupus such as congenital heart block are a unique cohort at risk for pathologic autoimmunity; many are asymptomatic or have an undifferentiated autoimmune syndrome with vague symptoms (Asym/UAS) and become aware of autoantibodies solely based on identification of disease in the fetus or infant.  Over time, a third may progress to established diseases such as SLE or SS (SS/SLE).  This study was initiated to investigate the hypothesis that stool microbiome compositional variation and taxa-specific interactions with class II HLA alleles may correlate with transition to SS/SLE.

Methods: The stool microbiome of 125 anti-Ro+ women (Asym/UAS, N=43; SS/SLE, N=82) and 23 healthy controls (HC) were 16S ribosomal RNA sequenced and assigned to taxa (SILVA). At each taxonomic level, the ranks of the centered log ratio transformed relative abundances were compared, adjusting for batch, to test for differences among groups (HC vs. Asym/UAS vs. SS/SLE); false discovery rate (FDR) adjusted p-values were computed. Class II HLA at DRB1 and DQB1 four-digit alleles were assigned by imputation (HIBAG) or sequencing and tested for an interaction between FDR-significant genera and HLA allele (cumulative logit models).

Results: There were reductions in genera and species diversity (Shannon Index) for the SS/SLE patients (g. 2.62±0.53; spp. 2.36±0.43) compared to Asym/UAS (g. 2.74±0.44; spp. 2.53±0.43) and HC (g. 2.77±0.36; spp 2.50±0.52) (p< 0.05). There were also differences in the microbial relative abundances among the three groups. Of note, the majority (76.9%) of taxa with significant differences among the three groups were in the class Clostridia, which includes the genera Romboutsia and Coprococcus 3. Specifically, by ranking the conditions by disease severity (HC < Asym/UAS < SS/SLE), there was a reduction in the relative abundance of Romboutsia and Coprococcus 3 (P=2.38E-06 and P=1.58E-3, respectively). Given the overall sample size, HLA allelic frequencies and genus-HLA allele interactions (i.e., differential effect of genus depending on which HLA allele was present) were not significant (FDR P >0.05).  However, notable findings include the allele frequencies of the DQB1*0602 allele in Asym/UAS, SS/SLE and HC were 22%, 17% and 10%, respectively (P=0.03). DQB1*0602 taxa by HLA-genus interaction analysis revealed that 70% of the top 20 taxa were contained within Clostridia, including Romboutsia and the 5 taxa below. Suggestive interactions between taxa within Clostridia and DQB1*0602 were Lachnospiraceae UCG-010 (OR=0.52, P=0.006), Oscillibacter (OR=0.57, P=0.01), Intestinimonas (OR=0.60, P=0.02) and Lachnospiraceae_NK4A136 (OR=0.65, P=0.03), and Anaerotruncus (OR=0.61, P=0.05).

Conclusion: Given Clostridia’s critical role in gut homeostasis, including immune functions, reductions in this taxa combined with autoimmune related HLA alleles may serve as harbingers of a shift toward a pathologic gut microbiome that may, in part, explain progression from benign to pathologic autoimmunity and overt SLE and/or SS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/contraction-of-the-stool-taxa-clostridia-is-associated-with-the-development-of-clinical-disease-among-anti-ro-mothers-of-children-with-neonatal-lupus/