Microbiome Poster Presentation

P0676 - Ocrelizumab impacts IgA coating of immunomodulatory gut bacteria in multiple sclerosis patients (ID 1887)

Speakers
  • G. Janda
Authors
  • G. Janda
  • I. Cohen
  • W. Ruff
  • E. Longbrake
Presentation Number
P0676
Presentation Topic
Microbiome

Abstract

Background

The mechanisms by which B-cell depletion ameliorates multiple sclerosis (MS) have not been fully delineated. Gut bacteria and their metabolites are important regulators of the systemic immune response, and early work demonstrated dysbiosis in MS. Dysregulation of immunomodulatory bacteria may contribute to the pathologic immune response in MS. We hypothesized that ocrelizumab, a B-cell depleting monoclonal antibody used to treat MS, would normalize the phenotype of gut bacteria, promoting an anti-inflammatory immune milieu.

Objectives

To characterize the taxonomic and functional shifts in the gut microbiota of MS patients induced by B-cell depletion.

Methods

We enrolled untreated, new onset MS patients and obtained longitudinal samples of paired blood and stool. We also recruited healthy controls. To date, 11 healthy controls, 16 baseline MS, 8 1-month, 9 6-month and 3 12-month post-ocrelizumab samples have been sequenced. Recruitment and follow up are ongoing; updated numbers will be presented. Gut microbiota were characterized using high-throughput long amplicon sequencing of the 16S-ITS-23S rRNA operon, allowing increased bacterial taxonomic resolution. We also performed IgA-Seq, a technique differentiating immune-reactive (IgA-coated) bacteria from those not eliciting an immune response (IgA-uncoated). IgA coating index (ICI) was calculated by dividing the IgA-coated bacteria by the uncoated fraction. Intestinal inflammation was measured using lipocalin-2 ELISA.

Results

Alpha and beta-diversity in the fecal microbiome of untreated MS patients appeared similar to that of healthy controls. B-cell depletion was not associated with changes in overall alpha or beta diversity. Analysis of composition of microbiomes (ANCOM) comparing all MS to healthy samples indicated enrichment of Monoglobus species. There was concurrent elevation of the ICI for Monoglobus. B-cell depletion was associated with trends for individual-level reductions in ICI for organisms that were highly coated at baseline. Fecal lipocalin-2 was significantly increased in MS patients and decreased after B-cell depletion.

Conclusions

Untreated MS patients exhibit increased intestinal inflammation. Moreover, a subset of immunomodulatory gut bacteria recognized as pathogenic by the immune system of untreated MS patients (e.g. with high levels of IgA coating) is less targeted by the immune system after B-cell depletion. This could impact differentiation of circulating immune cells and contribute to the efficacy of B-cell depletion in MS.

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