Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis

Gut Microbes. 2022 Jan-Dec;14(1):2147055. doi: 10.1080/19490976.2022.2147055.

Abstract

Mounting evidence points towards a pivotal role of gut microbiota in multiple sclerosis (MS) pathophysiology. Yet, whether disease-modifying treatments alter microbiota composition and whether microbiota shape treatment response and side-effects remain unclear. In this prospective observational pilot study, we assessed the effect of dimethyl fumarate (DMF) on gut microbiota and on host/microbial metabolomics in a cohort of 20 MS patients. Combining state-of-the-art microbial sequencing, metabolome mass spectrometry, and computational analysis, we identified longitudinal changes in gut microbiota composition under DMF-treatment and an increase in citric acid cycle metabolites. Notably, DMF-induced lymphopenia, a clinically relevant safety concern, was correlated with distinct baseline microbiome signatures in MS patients. We identified gastrointestinal microbiota as a key therapeutic target for metabolic properties of DMF. By characterizing gut microbial composition as a candidate risk factor for DMF-induced lymphopenia, we provide novel insights into the role of microbiota in mediating clinical side-effects.

Keywords: Multiple sclerosis; dimethyl fumarate; lymphopenia; metabolomics; microbiome; therapeutic biomarker.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dimethyl Fumarate / adverse effects
  • Gastrointestinal Microbiome*
  • Humans
  • Lymphopenia* / chemically induced
  • Multiple Sclerosis* / drug therapy
  • Prospective Studies
  • Risk Factors

Substances

  • Dimethyl Fumarate

Grants and funding

This study was conducted as an investigator-initiated trial with funding from Biogen Switzerland, which had no influence on the manuscript. The study was further funded by the Swiss National Science Foundation [PCEFP3_194609], the National MS Society [FG-1708-28871], the Propatient Foundation, the Goldschmidt Jacobson Foundation, and the Gottfried and Julia Bangerter Rhyner Foundation (to A.-K.P.). Ad-personam funding for M.D. was received from the Swiss National Science Foundation [project-number 199310], the German Research Foundation [IMM-PACT-Program, 413517907] and the Julia Bangerter Rhyner Foundation.