Dylan Grote

Introduction: Multiple sclerosis is the most common chronic inflammatory CNS disease affecting over two million people worldwide.¹ MS is more common in western countries and dietary habits have been suggested as a potential factor contributing to its epidemiology.² Diet is an important determinant of the gut microbial composition.² Gut dysbiosis is seen in human patients with MS and is reported to be linked with its pathogenesis.³ Studies have found reduced overall gut microbiome diversity and increased prevalence of species like Acinetobacter calcoaceticus.⁴ Treg cells play an important anti-inflammatory role by dampening inappropriate Th response by releasing anti-inflammatory cytokines.² MS is associated with a decrease in Tregs and an increase Th1 and Th17 cells, creating a pro-inflammatory state.² Pro-inflammatory myelin-reactive Th1 and Th17 cells migrate across the blood-brain barrier, causing inflammation in the CNS.⁵ This leads to oligodendrocyte loss, axonal demyelination, and neuronal injury, leading to the clinical symptoms of MS.⁵  Methods: Stool samples from MS patients and healthy controls were transplanted into a germ-free mouse model for MS (EAE). Clinical progression of MS was assessed and mesenteric lymph nodes (MLNs) were examined for Treg induction. Germ free EAE mice were monocolonized with the MS associated bacterial species A. calcoaceticus. Human peripheral blood mononuclear cells (PBMCs) extracted from healthy volunteers were exposed to MS associated heat-killed A. calcoaceticus extracts in vitro. Flow cytometry was used to evaluate T cell differentiation and proliferation.  Results: Fecal transplant from human donors with MS into germ free EAE mice demonstrated more severe symptoms and quicker disease progression than mice who received a fecal transplant from control donors (P < 0.0001). MLNs of MS microbiome colonized mice also showed decreased Tregs (P<0.01) compared to mice colonized with control microbiome. Monocolonization with A. calcoaceticus promoted Th1 proliferation (P<0.05), and inhibited Treg differentiation (P<0.01), creating a pro-inflammatory state. PBMCs exposed to extracts from A. calcoaceticus showed decreased Treg proliferation (P<0.05) and increased Th1 proliferation (P<0.01), creating a pro-inflammatory state.⁴ Conclusions: MS associated bacterial species such as A. calcoaceticus can cause a decrease in proliferation of anti-inflammatory Treg cells and an increase in proliferation of pro-inflammatory Th1 cells. Auto-reactive Th1 cells cross the blood-brain barrier and destroy myelin, increasing disease severity in mice. These findings support a role of the gut microbiome in modulating disease activity in multiple sclerosis. Microbiome manipulation should be investigated as an adjunctive therapy in multiple sclerosis.

1.  Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. New England Journal of Medicine. 2018;378(2):169-180. doi:10.1056/nejmra1401483
2. Cignarella F, Cantoni C, Ghezzi L, et al. Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota. Cell Metabolism. 2018;27(6):1222-1235. doi:10.1016/j.cmet.2018.05.006
3. Werbner M, Barsheshet Y, Werbner N, et al. Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells. mSystems. 2019;4(4):e00292-18. doi:10.1128/mSystems.00292-18
4. Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proceedings of the National Academy of Sciences. 2017;114(40):10713-10718. doi:10.1073/pnas.1711235114
5. Al-Ghezi ZZ, Busbee PB, Alghetaa H, Nagarkatti PS, Nagarkatti M. Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain, Behavior, and Immunity. 2019;82:25-35. doi:10.1016/j.bbi.2019.07.028