Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis
Martin Diebold, Marco Meola, Srinithi Purushothaman, Lena K. Siewert, Elisabeth Pössnecker, Tim Roloff, Raija L.P. Lindberg, Jens Kühle, Ludwig Kappos, Tobias Derfuss, Adrian Egli, Anne‐Katrin Pröbstel
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.