Reevaluation of the gastrointestinal methanogenic archaeome in multiple sclerosis and its association with treatment

The role of the gut archaeal microbiome (archaeome) in health and disease remains poorly understood. Methanogenic archaea have been linked to multiple sclerosis (MS), but prior studies were limited by small cohorts and inconsistent methodologies. To address this, we re-evaluated the association between methanogenic archaea and MS using metagenomic data from the International Multiple Sclerosis Microbiome Study. We analyzed gut microbiome profiles from 115 MS patients and 115 healthy household controls across Buenos Aires (27.8%), Edinburgh (33.9%), New York (10.4%), and San Francisco (27.8%). Metagenomic sequences were taxonomically classified using kraken2/bracken and a curated profiling database to detect archaea, specifically Methanobrevibacter species. Most MS patients were female (80/115), aged 25-72 years (median: 44.5), and 70% were undergoing treatment, including dimethyl fumarate (n = 21), fingolimod (n = 20), glatiramer acetate (n = 14), interferon (n = 18), natalizumab (n = 6), or ocrelizumab/rituximab (n = 1). We found no significant differences in overall archaeome profiles between MS patients and controls. However, treated MS patients exhibited higher abundances of Methanobrevibacter smithii and M. sp900766745 compared to untreated patients. Notably, M. sp900766745 abundance correlated with lower disease severity scores in treated patients. Our results suggest that gut methanogens are not directly associated with MS onset or progression but may reflect microbiome health during treatment. These findings highlight potential roles for M. smithii and M. sp900766745 in modulating treatment outcomes, warranting further investigation into their relevance to gut microbiome function and MS management.IMPORTANCEMultiple sclerosis (MS) is a chronic neuroinflammatory disease affecting the central nervous system, with approximately 2.8 million people diagnosed worldwide, mainly young adults aged 20-30 years. While recent studies have focused on bacterial changes in the MS microbiome, the role of gut archaea has been less explored. Previous research suggested a potential link between methanogenic archaea and MS disease status, but these findings remained inconclusive. Our study addresses this gap by investigating the gut archaeal composition in MS patients and examining how it changes in response to treatment. By focusing on methanogens, we aim to uncover novel insights into their role in MS, potentially revealing new biomarkers or therapeutic targets. This research is crucial for enhancing our understanding of the gut microbiome's impact on MS and improving patient management.