Contributions
Abstract: P960
Type: Poster Sessions
Abstract Category: Therapy - Others
Introduction: Recent data suggest that patients with multiple sclerosis (MS) have a distinct gut microbiota profile. Delayed-release dimethyl fumarate (DMF) is an orally administered drug for relapsing-remitting MS (RRMS), which has been associated with initial gastrointestinal (GI) side-effects in some patients.
Objectives: To determine if DMF alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with GI side-effects.
Methods: In this study (NCT02471560), 36 patients with RRMS (72% female) from 8 study sites received either DMF (n=27) or an injectable MS disease-modifying therapy (n=9) for 12 weeks. GI-symptoms rating scale (GSRS) and stool samples were collected at baseline, 2 and 12 weeks. A two-point increase in GSRS was classified as a worsening of GI-symptoms. Stool samples were analyzed by sequencing of the V3-V4 region of the 16s rRNA gene. We included 165 healthy individuals (63% female) as controls.
Results: At baseline, 17 microbial genera were significantly altered in MS patients compared with healthy controls, including a decline in the abundance of Faecalibacterium in MS patients (P=0.001), as previously reported in MS and other chronic inflammatory diseases. Intra-individual microbial (alpha) diversity was similar in patients and controls.
In the DMF-treated group, a worsening of GI-symptoms compared with baseline was observed at 2 weeks (P=0.04), but not at 12 weeks (P=0.25). At 2 weeks, we observed a reduction of Actinobacteria (median abundance reduced from 2.0% to 1.2%,P=0.03) mainly driven by a reduction of Bifidobacterium (1.1% to 0.7%,P=0.06). The abundance of Bifidobacterium at 2 weeks was numerically lower in patients with a worsening of GI-symptoms from baseline (0.5% vs. 0.8%,P=0.44).
At 12 weeks, the DMF-treated patients experienced an increased abundance of Firmicutes (P=0.02), mostly driven by Faecalibacterium (4.4% to 6.7%,P=0.01). Similar alterations were not observed in the injectable drug group.
Conclusions: A 12-week treatment with DMF was associated with alterations in the gut microbiota profile, including a near-normalization of the low abundance of the butyrate-producing Faecalibacterium seen in MS patients. It could therefore be speculated that direct effects on the gut microbiome are part of the therapeutic actions of DMF. Short term depletion of Bifidobacterium was observed after initiation of DMF; however, the study was underpowered to firmly link microbiota changes to GI-symptoms.
Disclosure:
Biogen Norway has provided the financial support for this study. CS: nothing to disclose. KM: has received speakers honaria, participated in clinical trials, received unrestricted research grants or attended advisory meatings for one or more of the following companies last three years; Almirall, Biogen, Sanofi Genzyme, Merck, Novartis, Roche or Teva. KM is the president for the academic council for the Norwegian MS-association, norwegian representative of MS International federation (MSIF) and EAN Scientific Panel Multiple sclerosis. EF: has participated in advisory boards and received lecture honoraria from Biogen, Genzyme, Novartis, and Merck. Unrestricted research grant from Novartis. RM: has served on scientific advisory boards for Novartis Norway and Merck Norway and has received travel funding and/or speaker honoraria from Biogen, Novartis Norway, Sanofi Genzyme. KN: nothing to disclose. LB: nothing to disclose. PB: has received funding for travel or speaker's fees from Novartis, UCB and Teva. AB: nothing to disclose. KH: nothing to disclose. LF: previous employee at Biogen. EB: Biogen employee. JH: reports research funding from Biogen in conjunction with the present study. TH: has received speakers honoraria, and/or served on advisory board, and/or received unrestricted research grants from Biogen, Roche, Merck, Novartis, and Genzyme.
Abstract: P960
Type: Poster Sessions
Abstract Category: Therapy - Others
Introduction: Recent data suggest that patients with multiple sclerosis (MS) have a distinct gut microbiota profile. Delayed-release dimethyl fumarate (DMF) is an orally administered drug for relapsing-remitting MS (RRMS), which has been associated with initial gastrointestinal (GI) side-effects in some patients.
Objectives: To determine if DMF alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with GI side-effects.
Methods: In this study (NCT02471560), 36 patients with RRMS (72% female) from 8 study sites received either DMF (n=27) or an injectable MS disease-modifying therapy (n=9) for 12 weeks. GI-symptoms rating scale (GSRS) and stool samples were collected at baseline, 2 and 12 weeks. A two-point increase in GSRS was classified as a worsening of GI-symptoms. Stool samples were analyzed by sequencing of the V3-V4 region of the 16s rRNA gene. We included 165 healthy individuals (63% female) as controls.
Results: At baseline, 17 microbial genera were significantly altered in MS patients compared with healthy controls, including a decline in the abundance of Faecalibacterium in MS patients (P=0.001), as previously reported in MS and other chronic inflammatory diseases. Intra-individual microbial (alpha) diversity was similar in patients and controls.
In the DMF-treated group, a worsening of GI-symptoms compared with baseline was observed at 2 weeks (P=0.04), but not at 12 weeks (P=0.25). At 2 weeks, we observed a reduction of Actinobacteria (median abundance reduced from 2.0% to 1.2%,P=0.03) mainly driven by a reduction of Bifidobacterium (1.1% to 0.7%,P=0.06). The abundance of Bifidobacterium at 2 weeks was numerically lower in patients with a worsening of GI-symptoms from baseline (0.5% vs. 0.8%,P=0.44).
At 12 weeks, the DMF-treated patients experienced an increased abundance of Firmicutes (P=0.02), mostly driven by Faecalibacterium (4.4% to 6.7%,P=0.01). Similar alterations were not observed in the injectable drug group.
Conclusions: A 12-week treatment with DMF was associated with alterations in the gut microbiota profile, including a near-normalization of the low abundance of the butyrate-producing Faecalibacterium seen in MS patients. It could therefore be speculated that direct effects on the gut microbiome are part of the therapeutic actions of DMF. Short term depletion of Bifidobacterium was observed after initiation of DMF; however, the study was underpowered to firmly link microbiota changes to GI-symptoms.
Disclosure:
Biogen Norway has provided the financial support for this study. CS: nothing to disclose. KM: has received speakers honaria, participated in clinical trials, received unrestricted research grants or attended advisory meatings for one or more of the following companies last three years; Almirall, Biogen, Sanofi Genzyme, Merck, Novartis, Roche or Teva. KM is the president for the academic council for the Norwegian MS-association, norwegian representative of MS International federation (MSIF) and EAN Scientific Panel Multiple sclerosis. EF: has participated in advisory boards and received lecture honoraria from Biogen, Genzyme, Novartis, and Merck. Unrestricted research grant from Novartis. RM: has served on scientific advisory boards for Novartis Norway and Merck Norway and has received travel funding and/or speaker honoraria from Biogen, Novartis Norway, Sanofi Genzyme. KN: nothing to disclose. LB: nothing to disclose. PB: has received funding for travel or speaker's fees from Novartis, UCB and Teva. AB: nothing to disclose. KH: nothing to disclose. LF: previous employee at Biogen. EB: Biogen employee. JH: reports research funding from Biogen in conjunction with the present study. TH: has received speakers honoraria, and/or served on advisory board, and/or received unrestricted research grants from Biogen, Roche, Merck, Novartis, and Genzyme.