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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - GAMES (Gut Microbiota in Nervous System Autoimmunity: Molecular Mechanisms of Disease Initiation and Regulation)

Teaser

Summary

Multiple Sclerosis (MS), an autoimmune disease, causes tremendous disability in young adults and inflicts a huge economic burden on society. The incidence of MS is steadily increasing in many countries arguing for environmental factors driven changes in disease induction. How and which environmental factors contribute to disease initiation and progression is unknown. Using a spontaneous mouse model of MS, we have shown that the gut microbiota is essential in triggering CNS autoimmunity. In contrast to the mice housed in conventional housing conditions, germ-free mice, devoid of gut bacteria, were protected from spontaneous experimental autoimmune encephalomyelitis (sEAE). The GAMES project studies how and which gut bacteria influence autoimmune responses and which molecular pathways are involved in disease development. Knowing the basic processes leading to disease would aid the establishment of therapeutic strategies targeting gut microbiota to limit the development of inflammatory processes during CNS autoimmunity.

Work performed

During the first 4.5 years, GAMES researchers investigated the impact of gut microbes on CNS autoimmunity by combining germ-free (GF) mouse models, knock out mouse strains, antibiotic treatments and dietary manipulation strategies to learn the mechanisms by which gut microbes impact CNS autoimmunity. They specifically worked towards defining the importance of microbial flora in the causal role of CNS autoimmunity. They showed that gut microbiota from human MS patients triggers disease in experimental animals suggesting a potential causal role of human gut microbiota in disease pathogenesis. This part of the work was published in scientific reports (Berer, K et al. PNAS 2017). In a follow up of this work, they also found differential immune responses induced by specific species of microbiota from human MS patients compared to controls. Further, they used dietary interventions to modulate microbiota in models of CNS autoimmunity. They showed that mice fed a fiber-rich diet were resistant to develop spontaneous CNS autoimmunity. The disease resistance was a result of changes in the gut microbiota and metabolites. They showed that metabolites, in particular, long-chain fatty acids were responsible for the decrease of pro-inflammatory responses and increase of anti-inflammatory immune responses. Further effects of specific microbial metabolites on intestinal and blood-brain barrier permeability are currently being explored.

Final results

Our work in the past 4.5 years has established that the gut microbes from human MS patients are able to trigger autoimmunity in mouse models. These pioneer studies establish a novel model system to directly test the role of human gut microbes in experimental animals. Further, these results show that humans MS microbiomes lack microbial factors that are necessary for disease suppression. In addition, we have investigated various strategies to modulate the microbiome for therapeutic purposes. Our results indicate that dietary interventions could be used for preventing autoimmunity. Our results identify dietary metabolites as novel targets to prevent autoimmune disease. We anticipate that microbial metabolites are involved not only affect immune responses but also affect the immune cell entry into the CNS. Thus, these specific pathways could be exploited for the control of CNS autoimmunity. We anticipate that these results are not only relevant for MS but also applicable to other CNS diseases.