PT  - JOURNAL ARTICLE
AU  - Rebecca Sadler
AU  - Julia V. Cramer
AU  - Steffanie Heindl
AU  - Sarantos Kostidis
AU  - Dene Betz
AU  - Kielen R. Zuurbier
AU  - Bernd H. Northoff
AU  - Marieke Heijink
AU  - Mark P. Goldberg
AU  - Erik J. Plautz
AU  - Stefan Roth
AU  - Rainer Malik
AU  - Martin Dichgans
AU  - Lesca M. Holdt
AU  - Corinne Benakis
AU  - Martin Giera
AU  - Ann M. Stowe
AU  - Arthur Liesz
TI  - Short-chain fatty acids improve post-stroke recovery via immunological mechanisms
AID  - 10.1523/JNEUROSCI.1359-19.2019
DP  - 2019 Dec 30
TA  - The Journal of Neuroscience
PG  - 1359-19
4099  - http://www.jneurosci.org/content/early/2019/12/19/JNEUROSCI.1359-19.2019.short
4100  - http://www.jneurosci.org/content/early/2019/12/19/JNEUROSCI.1359-19.2019.full
AB  - Recovery after stroke is a multicellular process encompassing neurons, resident immune cells and brain-invading cells. Stroke alters the gut microbiome which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut-brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFA), key bioactive microbial metabolites, are the missing link along the gut-brain axis and might be able to modulate recovery after experimental stroke. SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFA induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in spine and synapse densities. RNA-sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional re-modelling. Further analyses confirmed a substantial impact of SCFA on microglial activation, which depended on the recruitment of T cells to the infarcted brain. Our findings identified that microbiota-derived SCFA modulate post-stroke recovery via effects on systemic and brain resident immune cells.SIGNIFICANCE STATEMENTPrevious studies have shown a bi-directional communication along the gut-brain axis after stroke. Stroke alters the gut microbiota composition, and in turn, microbiota dysbiosis has a substantial impact on stroke outcome by modulating the immune response. However, until now the mediators derived from the gut microbiome affecting the gut-immune-brain axis and the molecular mechanisms involved in this process were unknown. Here, we demonstrate that SCFA---fermentation products of the gut microbiome---are potent and pro-regenerative modulators of post-stroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify SCFA as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.