Research summary: Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor

The background

Astrocytes are the most common cell type in the central nervous system (CNS) and perform a wide variety of functions, including modulating transmission of nerve signals, controlling the blood-brain barrier (BBB) and CNS development and repair. Studies have implied that astrocytes are most likely important in the pathogenesis, or development, of multiple sclerosis (MS). It is also known that the function of astrocytes can be impacted by factors inside and outside the CNS.

One such factor, that hasn’t been fully explored, is the role of diet and gut microbiota on astrocytes. It is known that the microorganisms within the gut can affect immune system dependent inflammation. Improving our knowledge of these factors may help provide a better understanding of MS and lead to new therapeutic approaches.

The study

In this study, by researchers at the Brigham and Women’s Hospital, the link between diet, metabolism and inflammation in the CNS was investigated. In order to achieve this, the gene expression of astrocytes was assessed in healthy mice and those with EAE (the animal model of MS). Following this, the metabolism of dietary tryptophan was analysed in mice with EAE, as well as the effect of antibiotic treatment on this process. Lastly, gene expression and the presence of important metabolic products was investigated using human brain tissue and blood samples respectively.

The findings

The experiments conducted in this study led to a number of key findings, including:

The identification that gene expression was altered in the astrocytes of mice with EAE compared to healthy mice. The majority of the genes affected were associated with the signaling pathway of an important regulator of the immune system, interferon-1. It was shown that the interferon-1 pathway is important in reducing inflammation, as without it the mice developed more severe disease.

The discovery of the importance of dietary tryptophan in regulating the severity of EAE in mice. It was found that mice that received a diet deficient in tryptophan developed worse EAE, which could be treated by re-introducing tryptophan into their food source. It is thought that the breakdown of tryptophan by gut bacteria produces a number of compounds that regulate the interferon-1 pathway described previously. Antibiotic treatment designed to target the bacteria that metabolise tryptophan resulted in impaired disease recovery.

The finding that these important tryptophan-derived compounds are lower in abundance in the blood of people with MS compared to healthy controls.

The outcomes

Whilst we are aware that environmental factors can play an important role in the development of MS, it remains unclear as to what they are and how they are involved. This study has shown that the metabolism of dietary tryptophan by microflora in the gut impacts on pathways that control inflammation in the central nervous system. Gaining a better understanding of this mechanism will not only help improve our knowledge of MS, but also provide new potential treatment targets.

The abstract for this article can be viewed here.