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Observational Study
. 2025 Feb 27:16:1514762.
doi: 10.3389/fimmu.2025.1514762. eCollection 2025.

The gut-brain-axis one year after treatment with cladribine tablets in patients with relapsing remitting multiple sclerosis: a pilot study

Jeske van Pamelen  1   2 , Carla Rodriguez-Mogeda  3 , Lynn van Olst  3 , Susanne M A van der Pol  3 , Maarten L Boon  4 , Janet de Beukelaar  5 , Oliver H H Gerlach  6   7 , Andries E Budding  4 , Joep Killestein  2 , Helga E de Vries  3 , Leo H Visser  1
Affiliations
Observational Study

The gut-brain-axis one year after treatment with cladribine tablets in patients with relapsing remitting multiple sclerosis: a pilot study

Jeske van Pamelen et al. Front Immunol. .

Abstract

Introduction: Cladribine tablets are an effective treatment for relapsing remitting multiple sclerosis (RRMS). However, almost half of the treated patients are not free of disease activity after two years. The aim of this study was to describe the changes that cladribine tablets effectuate in the gut and oral microbiota and the peripheral immunological profile between responders and non-responders.

Methods: In this pilot study of the multicenter, prospective, observational BIA (Brain-Immune-Intestine Axis) study, we included patients aged 18 to 55 years with RRMS who were scheduled to start treatment with cladribine tablets. We assessed the clinical status and the immunological and microbiological profile prior to the start of the treatment and after three and twelve months. At twelve months, we assessed the response status, based on clinical relapses, radiological activity and disability progression on the Expanded Disability Status Scale.

Results: The first twenty-five patients of the BIA study were included in this analysis. Ten patients (40%) were responders twelve months after treatment. Three months after treatment we found a significant decline of naïve and transitional B cells and memory B cells, and of CD57+ CD56dim NK cells. After twelve months the values recovered to baseline levels, except for the memory B cells. We did not find significant changes of the microbiological profile over time, except for a decline of the phylum Bacteroidetes in the oral samples twelve months after treatment. Baseline values and changes over time did not significantly differ between responders and non-responders. However, several phyla, genera or species (Bacteroidetes, Prevotella, Faecalibacterium prausnitzii) showed a higher relative abundance, and several phyla, genera or species (Proteobacteria, Escherichia coli) had a lower relative abundance in responders compared to non-responders.

Discussion: After treatment with cladribine tablets, we found significant changes in the immunological landscape. Also, the microbiological profile showed several differences in microbes with known anti- or pro-inflammatory properties between responders and non-responders. Overall, we showed that we can measure a treatment effect from cladribine tablets with our analyses. Future research on data from the BIA study, with a larger sample size and extended follow-up, can possibly confirm the reliability of our findings.

Keywords: 16S-23S rDNA interspace profiling; cladribine tablets; gut-brain-axis; mass cytometry by time-of-flight; microbiota; relapsing remitting multiple sclerosis.

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Conflict of interest statement

JP received a research grant for the BIA study by Merck, and a travel grant for a scientific meeting by Merck, outside the submitted work. MB is an employee of inBiome, the company that developed the IS-pro technology and the Molecular Culture kit used in this study. AB is employee and stockholder of inBiome, the company that developed the IS-pro technique and the Molecular Culture kit used in this study. JK received research grants for multicentre investigator-initiated trials DOT-MS (NCT04260711, ZonMW), Supernext (NCT04225312, Treatmeds) and BLOOMS (NCT05296161, ZonMW and Treatmeds), received consulting fees from F Hoffmann-La Roche, Biogen, Teva, Merck, Novartis, and Sanofi/Genzyme (all payments to institution), reports speaker relationships with F Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis, and Sanofi/Genzyme (all payments to institution), adjudication committee of MS clinical trials of Immunic (payments to institution only) and LV received research grants for research projects, honoraria for lectures and consultancy fees from Merck, Novartis, Janssen-Cilag and Roche The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study timelines. D0: baseline visit. M3: follow-up visit after 3 months. M12: follow-up visit after 12 months. M12 takes places before start of the second cladribine course and can be postponed until M18.
Figure 2
Figure 2
Different repopulation of various immune cells after cladribine treatment. (A) UMAP plot displaying CD45+ immune cells from the blood of cladribine-treated patients at different time points. Colors correspond to PARC-guided clustering. (B) Density UMAP plots showing the proportion of cells assigned to each time point according to each cluster. Color key indicates high (red) and low (blue) percentage of immune cells. (C) Percentage of each annotated cell population out of the total CD45+ immune cells at each time point. Each data point corresponds to each individual, colored by time point. Significant P-values are stated in the graphs. D0: baseline visit; M3: 3 month visit; M12: 12 month visit.
Figure 3
Figure 3
Relative abundance of phyla in oral and fecal samples. Significant P-values are stated in the graphs. FAFV: Firmicutes, Actinobacteria, Fusobacteria and Verrucomicrobia. D0: baseline visit; M3: 3 month visit; M12: 12 month visit. Dots represent outliers and asterixes represent extreme outliers.
Figure 4
Figure 4
Differences in relative abundance of phyla between responders and non-responders. (A) Distribution of relative abundance of different phyla in fecal and oral samples in responders. (B) Distribution of relative abundance of different phyla in fecal and oral samples in non-responders. FAFV: Firmicutes, Actinobacteria, Fusobacteria and Verrucomicrobia. D0: baseline visit; M3: 3 month visit; M12: 12 month visit. Dots represent outliers and asterixes represent extreme outliers.
Figure 5
Figure 5
Differences in relative abundance of fecal species between responders and non-responders. (A) Relative abundance of several bacterial species in fecal samples in responders. (B) Relative abundance of several bacterial species in fecal samples in non-responders. D0: baseline visit; M3: 3 month visit; M12: 12 month visit. Dots represent outliers and asterixes represent extreme outliers.
Figure 6
Figure 6
Differences in relative abundance of oral species between responders and non-responders. (A) Relative abundance of several bacterial species in oral samples in responders. (B) Relative abundance of several bacterial species in oral samples in non-responders. D0: baseline visit; M3: 3 month visit; M12: 12 month visit. Dots represent outliers and asterixes represent extreme outliers.
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