The Gut Feeling Behind Autoimmune Encephalitis

The Gut Microbiome Associated with LGI1-Antibody Encephalitis Gilbert E, Binks S, Damato V, Uy C, Colmenero P, Kelly M, Khalil MI, O'Brien M, Claesson MJ, Cryan JF, Delanty N, Irani SR, Cavalleri GL. Epilepsia . 2025;66:4411–4424. Objective: Autoimmune encephalitis is a cause of brain inflammation characterized by auto-antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto-antibodies to leucine-rich glioma-inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto-antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen (HLA) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry-matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods: To investigate this, we studied 42 patients with LGI1-antibody encephalitis (LGI1-Ab-E) and 27 familial/environmentally matched controls and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results: We observed that LGI1-Ab-E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla , which is associated with the dosage of HLA susceptibility allele count in patients with LGI1-Ab-E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short-chain fatty acids (SCFAs) in LGI1-Ab-E patients. Significance: Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1-Ab-E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.