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Short-Chain Fatty Acids Improve Poststroke Recovery via Immunological Mechanisms
Abstract
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.
Introduction
Stroke induces a multiphasic pathophysiological cascade, which consists of an initial excitotoxicity followed by a longer neuroinflammatory phase within the brain (Dirnagl et al., 1999; Iadecola and Anrather, 2011). Moreover, stroke can be regarded as a systemic disease affecting also remote organ function, including the lung (Austin et al., 2019), heart (Bieber et al., 2017), and immune system and intestinal function (Singh et al., 2016). Recently, it has been shown that a dysbiotic gut microbiota is correlated with a worsened outcome in patients (Xia et al., 2019), and that these changes are evident up until 3 weeks after hospitalization (Swidsinski et al., 2012). We have previously demonstrated an important role of the gut microbiome on stroke outcome in proof-of-principle experiments using germ-free and recolonized mice (Singh et al., 2018). Further experimental studies in rodent stroke models have identified a key role for the immune system, particularly brain-invading lymphocytes originating from the intestinal immune compartment, in mediating along the gut–brain axis (Benakis et al., 2016; Singh et al., 2016).
The gut microbiome produces a large number of bioactive metabolites which may affect brain function via modulating the immune system or afferent neuronal pathways (Kau et al., 2011; Cryan and Dinan, 2012). In particular, the metabolite group of short-chain fatty acids (SCFAs) acetate, butyrate, and propionate have been shown to readily cross the blood–brain barrier (Frost et al., 2014; Morrison and Preston, 2016) and affect brain function in development, health, and disease. For example, SCFA treatment improved the disease course in experimental autoimmune encephalitis by promoting anti-inflammatory mechanisms and reducing axonal damage (Haghikia et al., 2015). In mouse models of chronic stress, mice that received SCFA treatment exhibited significant improvements in antidepressant and anxiolytic behaviors, which was accompanied by reduced plasma corticosterone levels and differential gene regulation (van de Wouw et al., 2018).
More recently, the role of SCFAs in modulating the immune system has been studied in great detail. Through these investigations, they have been shown to play a role in the polarization of T cells in the intestinal immune compartment and inducing anti-inflammatory T-cell subset (Smith et al., 2013; Tan et al., 2016). Other studies have shown a critical role for microbiota-derived SCFAs in the maturation of microglial cells, the brain's resident immune cells (Erny et al., 2015). However, SCFAs can have far-reaching pleiotropic effects also beyond the immune system, including a direct effect on neuronal function through their potent function as histone deacetylase inhibitors (Bourassa et al., 2016). Accordingly, the importance of SCFA function has been implicated in neurodegenerative diseases and even in postischemic neurogenesis (Chuang et al., 2009; Kim et al., 2009).
Despite the key contribution of the gut microbiome to stroke outcome and the identification of SCFA as one of the microbiome's primary bioactive mediators, the role of SCFAs and their potential therapeutic use for poststroke recovery in the chronic phase after brain ischemia have not yet been investigated. In this study, we comprehensively investigated the effect of SCFA administration on poststroke recovery using advanced behavior analyses, in vivo wide-field calcium imaging, transcriptomic studies, and histological analyses to study and link SCFA-mediated recovery mechanisms from the molecular level up to behavior.
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