Disease-modifying therapies alter gut microbial composition in MS

Abstract

ObjectiveTo determine the effects of the disease-modifying therapies, glatiramer acetate (GA) and dimethyl fumarate (DMF), on the gut microbiota in patients with MS.MethodsParticipants with relapsing MS who were either treatment-naive or treated with GA or DMF were recruited. Peripheral blood mononuclear cells were immunophenotyped. Bacterial DNA was extracted from stool, and amplicons targeting the V4 region of the bacterial/archaeal 16S rRNA gene were sequenced (Illumina MiSeq). Raw reads were clustered into Operational Taxonomic Units using the GreenGenes database. Differential abundance analysis was performed using linear discriminant analysis effect size. Phylogenetic investigation of communities by reconstruction of unobserved states was used to investigate changes to functional pathways resulting from differential taxon abundance.ResultsOne hundred sixty-eight participants were included (treatment-naive n = 75, DMF n = 33, and GA n = 60). Disease-modifying therapies were associated with changes in the fecal microbiota composition. Both therapies were associated with decreased relative abundance of the Lachnospiraceae and Veillonellaceae families. In addition, DMF was associated with decreased relative abundance of the phyla Firmicutes and Fusobacteria and the order Clostridiales and an increase in the phylum Bacteroidetes. Despite the different changes in bacterial taxa, there was an overlap between functional pathways affected by both therapies.InterpretationAdministration of GA or DMF is associated with differences in gut microbial composition in patients with MS. Because those changes affect critical metabolic pathways, we hypothesize that our findings may highlight mechanisms of pathophysiology and potential therapeutic intervention requiring further investigation.

Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

“…In EAE, GA administration ameliorated the disease phenotype coupled with an increase in gut Prevotella, and the administration of GA combined with GI colonization with live Prevotella led to the further attenuation of disease [83]. GA treatment in patients with MS was shown to exert an effect in the relative abundance of gut microbiota, especially the Lachnospiraceae and Veillonellaceae families [76]. Similarly, another case-control study in patients with RRMS treated with GA reported alterations in the relative composition of the gut microbiome with respect to several Clostridium [84].…”

“…Clinical data stemming from metagenomics analysis of gut microbiota alterations in patients receiving DMF and glatiramer acetate (GA) further verified that DMTs exert a profound effect on the relative composition of gut microbiota. The above could shed light into potential additional mechanisms of action [76].…”

“…Similarly, DMF administration in Lewis rats was shown to mediate (i) a reduction in the TLR-4 expression by the GALT, (ii) a reduction in IFNγ, and (iii) a concomitant increase in lamina propria's Foxp-3+ expression and the abundance of CD4+CD25+ Tregs in Peyer's patches [86]. A case-control study implementing metagenomics techniques reported an association between DMF treatment and decreased relative abundance of Firmicutes and Clostridia, as well as an increase of Bacteroidetes, relative to untreated patients [76].…”

Rolle des Darmes bei der Multiplen Sklerose

“…Alle diese Studien zeigen konsistent eine veränderte Zusammensetzung des Mikrobioms von MS-Patienten gegenüber Kontrollen, bleiben aber rein deskriptiv. Auch die immunmodulatorische Therapie der MS ist in der Lage, das Mikrobiom zu verändern [16]. Auffällig ist vor allem die große Varianz der Ergebnisse, sodass fast jede Studie zu einem anderen Ergebnis hinsichtlich der mit MS-assoziierten Mikrobiomveränderungen kam.…”

N2 year in review

“…[43][44][45][46] However, previous human studies were limited by small sample sizes, enrollment of patients with longer disease duration, and confounding effects of immunomodulatory therapy, thus precluding conclusions regarding the causal influence of the gut microbiome on the MS immune system, or in other words, leaving the "chicken or egg dilemma" unresolved. 47 Katz Sand et al 48 investigated in a crosssectional study the effects of 2 widely used disease-modifying drugs, glatiramer acetate (GA) and dimethyl fumarate (DMF), on gut microbial composition. Stool samples from 168 participants with MS from 2 MS centers (75 treatment naive, 33 on DMF, and 60 on GA) were collected, and 16S rRNA amplicon sequencing was performed in parallel with immunophenotyping from patients' whole blood (at 1 center only) to validate the expected effects of DMF and GA.…”