Stool GFAP Is Elevated in Progressive MS, Is Associated with Disability, and Predicts Disease Worsening
Luke Schwerdtfeger1, Federico Montini2, Millicent Ekwudo1, Bonnie Glanz1, Tanuja Chitnis1, Laura Cox1, Howard Weiner1
1Neurology, Brigham and Women's Hospital, Harvard Medical School, 2Vita-Salute San Raffaele University
Objective:
Investigate stool protein biomarkers as predictive of disease worsening in multiple sclerosis (MS).
Background:
The gut microbiome is abnormal in MS and can influence disease via many pathways. Serum NfL and GFAP are elevated in MS and are linked to neuronal and glial abnormalities in the brain. The gut is a prime target for biomarker discovery given that the gut contains enteric glia which express glial fibrillary acidic protein (GFAP) and regulate enteric nervous and immune function.
Design/Methods:
Stool was analyzed from 26 healthy controls (HC), 61 RRMS and 28 progressive MS (ProgMS) subjects via enzyme linked immunosorbent assay (ELISA) to GFAP. Subjects had clinical follow-up 2-years after stool donation, including EDSS, symbol digit modality testing (SDMT), and NeuroQoL measurement.
Results:
Stool GFAP was significantly higher in ProgMS subjects by 86.9% and 103.1% compared to RRMS and HCs respectively (F(2,112) = 29.08, p < 0.0001). Further, stool GFAP level was positively correlated with baseline EDSS (rho = 0.589, p < 0.0001) and with an increased EDSS at 2-years (rho = 0.268, p < 0.05). Stsool GFAP levels were significantly correlated with worsening in seven NeuroQoL domains: upper and lower extremity function, ability to participate in and satisfaction with social roles, stigma, cognitive function, and anxiety. GFAP trended towards a negative correlation with baseline SDMT score (rho = -0.23, p = 0.052), which was significant at 2-years (rho = -0.26, p < 0.05). Neither stool NfL nor multiple inflammatory markers were altered in MS.
Conclusions:
Stool GFAP is a biomarker for ProgMS with prognostic value for EDSS, SDMT, and NeuroQoL, and may serve as biomarker linked to disease stage and course. Enteric glial signaling is a novel avenue for the study of the role of the microbiome in MS and may be linked to peripheral immune activation.