Gut Microbiota in Nervous System Autoimmunity: Molecular Mechanisms of Disease Initiation and Regulation

Project Information

GAMES

Grant agreement ID: 635617

DOI

10.3030/635617

Project closed

EC signature date 18 May 2015

Start date 1 June 2015

End date 31 May 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 946,00

EU contribution

€ 1 499 946,00

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 5 - GAMES (Gut Microbiota in Nervous System Autoimmunity: Molecular Mechanisms of Disease Initiation and Regulation)

Reporting period: 2021-06-01 to 2022-05-31

Summary of the context and overall objectives of the project

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.

Conclusions of the action:Our work unequivocally establishes that the gut microbiome control CNS autoimmune disease development through modulation of immune responses and blood-barrier integrity. Therefore, microbiome modulation is an effective strategy to prevent autoimmunity.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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. 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 or a high salt diet were resistant to developing 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. In the context of a high salt diet, they showed that microbial metabolites reinforced the integrity of the blood-brain barrier thereby controlling CNS autoimmunity. In both cases of dietary interventions, the disease protective effect was observed only if the treatment started before the disease onset but not during later progressive stages of the disease.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our work has established that gut microbes from human MS patients can 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 in affecting 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.

Microbiota-autoimmunity