Exploring the lung-brain axis in MS


An emerging concept in MS research is the role of the lung microbiome in promoting disease severity, with preliminary evidence showing that pulmonary micro-organisms can regulate autoimmunity in the central nervous system (reviewed in Chen et al. Int J Mol Sci 2023;24:2170).

While the healthy lung was traditionally considered to be a sterile site, new non-culture-based techniques (e.g. 16S RNA gene sequencing) have shown that lungs are chronically colonized by a low biomass of micro-organisms (~106 organisms). A further suggestion is that this lung microbiome, like the gut microbiome, may contribute to MS pathogenesis.

Evidence for this hypothesis largely derives from a series of animal studies. The first study examined entry of T cell blasts into the CNS across the blood-brain barrier (BBB) in a Lewis rat model of experimental autoimmune encephalomyelitis (EAE) (Odoardi et al. Nature 2012;488:675-679). T cell blasts generally did not directly cross the BBB. Instead, T cell blasts in lung tissue entered bronchial lymphoid tissue and mediastinal lymph nodes before entering the circulation and crossing the BBB. A similar migratory pattern was seen in effector T cells administered to the airways.

In the pulmonary lymphoid organs, the gene expression of T cells was reprogrammed. The most noteworthy alteration was the upregulation of cellular locomotion molecules and adhesion receptors, changes that facilitated passage across the BBB. The authors suggested that the lungs may serve as an initiating site for autoimmunity, activating autoreactive T cells and enabling their entry into the CNS.

The second study examined how lung microbiome changes affected EAE severity (Hosang et al. Nature 2022;603:138-144). Intratracheal administration of neomycin altered the bacterial diversity of the lung microbiome (dysbiosis) and reduced EAE severity. Similarly, EAE severity was reduced after microbiome transplantation in which animals received a bronchoalveolar lavage fluid (BALF) microbiome from neomycin-treated rats. Dysbiosis did not affect T cell trafficking. Instead, neomycin shifted the microbiome in favour of lipopolysaccharide (LPS)-enriched phyla (e.g. Bacteroidetes); LPS is a component of the bacterial cell wall that induces a type I interferon response. LPS enrichment stimulated a type I-interferon response in microglia and impaired their response to type II-interferons. The result was a reduction in the inflammatory response, a decrease in macrophage recruitment and an amelioration of clinical signs. Similar effects were seen when LPS was injected into the lungs. Conversely, administration of polymyxin B, which neutralizes LPS, increased EAE severity.

Neomycin-induced dysbiosis was also shown to reduce relapses in animals with established EAE, according to an update presented earlier this year (Odoardi F. ECTRIMS-ACTRIMS 2023, session 14:1). These findings suggest that the lung may play a previously unrecognized role in autoimmunity, and may help to explain how pulmonary factors (e.g. smoking, air pollution) may contribute to MS susceptibility and disease severity.

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