New Study Finds Link Between Gut Hormone GLP-1 and NMOSD Symptoms, Paving Way for Targeted Treatments

A poster presented at the 150^th Annual Meeting of the American Neurological Association (ANA) found that GLP-1 and GLP-1 receptor (GLP-1 R) contributes to brain inflammation and nerve overactivity, leading to area postrema syndrome (APS), a hallmark feature for patients with neuromyelitis optica spectrum disorder (NMOSD). The first-of-its-kind study has brought light to the link between gut hormones and brain inflammation, opening conversations about more targeted treatments for patients with NMOSD.^1,

Led by Lingfei Yang, PhD, a physician at the First Affiliated Hospital of Zhengzhou University, China, the study comprised 248 patients with NMOSD, including 57 with APS, who had GLP-1 and GLP-1R measurements compared with 164 people without NMOSD or APS. Compared with healthy controls and non-APS attacked NMOSD, APS-attacked patients with the disease demonstrated significantly elevated GLP1/GLP1R levels in plasma and cerebrospinal fluid (CSF) and gradually decreased after immunotherapy.

Using Spearman correlation analysis, findings showed a positive correlation between CSF GLP-1/GLP-1R levels and Expanded Disability Status Scale (EDSS) scores, a measure of disease progression, in patients with NMOSD. Changes in these levels also correlated with NMOSD PUQE scores, an obstetric, validated tool that assess the severity of nausea and vomiting.

"We found that this hormone, which is usually helpful in other conditions, can actually make things worse for people with APS by overstimulating certain brain cells," Yang said in a statement.¹ "However, our findings don’t mean that GLP-1 drugs are automatically harmful or cause inflammation on their own. Instead, they may trigger stronger reactions in people who already have inflammation in the brain, like those with NMOSD. We need more research to understand whether these drugs should be used with caution in these patients—or if they could even be adapted to help with more targeted treatment."

In the study, investigators observed significantly upregulated expression of GLP-1 and GLP-1R, as well as neuronal activity markers of c-FOS and RAB5, in AP neurons. Using an EAE model with APS-like symptoms, mimicking NMOSD-APS pathology, metabolomic analyses revealed a significant increase in anaerobic glycolysis metabolites with elevated lactate levels in AP neurons, while patch-clamp electrophysiology demonstrated a concurrent reduction in their postsynaptic membrane action potential threshold.

In the EAE model, GLP-1R signaling was inhibited by intracerebroventricular injection of exendin (9-39), and the effects of AP neuronal activity were assessed through western blot and immunofluorescence. Following administration of exendin (9-39), the expression of GLP-1 and GLP-1R in AP neurons decreased, and neuronal excitability was significantly reduced, leading to relief of APS-like symptoms in the preclinical model.

READ MORE: Investigational BAT4406F Performs in Phase 2/3 Study of NMOSD, Leading to Early Enrollment Termination

Over the years, there has been a cumulating amount of research on the role of the gut microbiome in the pathophysiology of NMOSD, with some reports suggesting it can serve as a biomarker for disease onset and progression as a disease-modifying therapy. One recently published case report examined a 29-year-old woman who developed seronegative NMOSD coinciding with the use of semaglutide (Ozempic), an FDA-approved GLP-1 receptor agonist for weight loss.

The report, published in Brain Disorders, concluded that gut microbiome alterations from GLP-1 RAs may influence immune dysregulation in NMOSD. Led by a group of study investigators from King Saud University, the authors hypothesized that semaglutide may contribute to NMOSD either indirectly through gut microbiome-mediated immune dysregulation or directly via GLP-1 receptor activity on astrocytes and central nervous system regions.³

"Although this case does not establish a definitive causal relationship, it underscores the need for further research to elucidate the underlying mechanisms and ensure the safe use of GLP-1RAs in patients at risk for autoimmune conditions," the study authors wrote.

Liraglutide, another GLP-1 receptor agonist, has also been shown to increase lactobacillus and oscillospira, microbes linked to worse outcomes in NMOSD. These microbes may trigger immune responses that worsen NMOSD by activating pro-inflammatory cytokines, particularly through Th17 pathways and NF-kb signaling. A first-ever study in 2017 highlighted GLP-1 agonist-associated changes in the human microbiome using liraglutide, as well as demonstrated its differentiating effects to metformin, a first-line therapy for type 2 diabetes.⁴

REFERENCES
1. First-of-Its-Kind Study Links Gut Hormone GLP-1 to Brain Inflammation in Neurological Disorder. News release. American Neurological Association. September 15, 2025. Accessed September 16, 2025. https://www.newswise.com/articles/first-of-its-kind-study-links-gut-hormone-glp-1-to-brain-inflammation-in-neurological-disorder/?article_id=835153
2. Hao Q, Li Q, Qin H, et al. The pathological mechanism of GLP1/GLP1R-mediated glycolytic reprogramming in area postrema neurons involved in APS-attacked NMOSD. Presented at: ANA Annual Meeting; September 13-16. Abstract M151.
3. Aldraihem MO, Shareefi G, AlYami W, et al. Neuromyelitis optica spectrum disorder-like presentation following semaglutide therapy: A case report. Brain Disorders. 2025;19:100249. doi:10.1016/j.dscb.2025.100249
4. Wang Z, Saha S, Van Horn S, et al. Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects. Endocrinology, Diabetes, & Metabolism. 2018;1(1):e00009. doi:10.1002/edm2.9