Intrathecal Anti-Akkermansia muciniphila IgG Responses in Multiple Sclerosis Patients Linked to CSF Immune Cells and Disease Activity

<b>Background/Objectives</b>: Gut microbial dysbiosis, leaky gut, and increased transepithelial translocation of commensal bacteria have been documented in multiple sclerosis (MS). Intrathecal IgGs specific for <i>Akkermansia muciniphila</i>, a gut bacterium, are increased in patients with MS and associated with clinical disability. Our objective here was to explore the putative involvement of intrathecal anti-<i>A. muciniphila</i> IgG in MS pathogenesis by characterizing patients with different anti-<i>A. muciniphila</i> IgG indices. <b>Methods</b>: Serum and intrathecal IgG specific for <i>A. muciniphila</i> and other gut bacteria, as well as routine cerebrospinal fluid (CSF) parameters, were measured in 61 patients with MS. Examination of these patients included immunophenotyping of CSF-infiltrating and paired circulating lymphocytes, intrathecal markers of neurodegeneration and inflammation, and a detailed characterization of demographic, clinical, and magnetic resonance imaging (MRI) features. <b>Results</b>: Plasma blasts (<i>p</i> < 0.01), B cells (<i>p</i> < 0.01), and Th2 cells (<i>p</i> < 0.01), which might be involved in antibody production, were increased in the CSF of these patients, as well as blood pro-inflammatory Th17 cells (<i>p</i> < 0.05). Anti-<i>A. muciniphila</i> IgG indices were negatively associated with blood-brain barrier (BBB) permeability and circulating monocytes (<i>p</i> < 0.001), and positively with brain lesion load (<i>p</i> < 0.01). <b>Conclusions</b>: The differences between patients with low and high anti-<i>A. muciniphila</i> IgG indexes regarding BBB permeability, CSF cell infiltrates, and pro-inflammatory peripheral immune cells, as well as imaging features, support a role of anti-<i>A. muciniphila</i> immune response in MS pathogenesis.