Short-Chain Fatty Acids Improve Poststroke Recovery via Immunological Mechanisms.

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 (SCFAs), 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 SCFAs 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 remodeling. Further analyses confirmed a substantial impact of SCFAs on microglial activation, which depended on the recruitment of T cells to the infarcted brain. Our findings identified that microbiota-derived SCFAs modulate poststroke recovery via effects on systemic and brain resident immune cells.SIGNIFICANCE STATEMENT Previous studies have shown a bidirectional 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 short-chain fatty acids, fermentation products of the gut microbiome, are potent and proregenerative modulators of poststroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify short-chain fatty acids as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.

Axon sprouting in adult mouse spinal cord after motor cortex stroke.

Functional reorganization of brain cortical areas occurs following stroke in humans, and many instances of this plasticity are associated with recovery of function. Rodent studies have shown that following a cortical stroke, neurons in uninjured areas of the brain are capable of sprouting new axons into areas previously innervated by injured cortex. The pattern and extent of structural plasticity depend on the species, experimental model, and lesion localization. In this study, we examined the pattern of axon sprouting in spinal cord after a localized lesion which selectively targeted the primary motor cortex in adult mice. We subjected mice to a stereotaxic-guided photothrombotic stroke of the left motor cortex, followed 2 weeks later by an injection of the neuronal tracer biotinylated dextran amine (BDA) into the uninjured right motor cortex. BDA-positive axons originating from the uninjured motor cortex were increased in the gray matter of the right cervical spinal cord in stroke mice, compared to sham control mice. These results show that axon sprouting can occur in the spinal cord of adult wild-type mice after a localized stroke in motor cortex.