Abstract TMP25: Short Chain Fatty Acids Mediate the Beneficial Effects of Young Microbiome on Recovery in Aged Mice after Ischemic Stroke

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Introduction: Age is a non-modifiable risk factor for stroke. The elderly have high mortality and delayed recovery after a stroke compared to younger patients, a finding that is recapitulated in murine models. Young animals that received aged biome after stroke had lower short chain fatty acids (SCFAs) in their feces and delayed recovery compared to young mice receiving young biome. SCFAs, generated primarily by gut bacteria are important signaling molecules for gut homeostasis. We hypothesize that fecal transplant from young donor/ SCFA producing bacteria into aged mice will improve recovery compared to mice that received aged biome.Methods: Aged C57BL/6 male mice (18-20 months) were subjected to middle cerebral artery occlusion and randomly assigned to one of two groups, either received: 1. aged biome or 2. young biome. In addition, a separate cohort of aged mice were randomized as above, and divided into two groups: 1. received a cocktail of SCFA producers + Inulin as substrate or 2. received vehicle control group. Mice were tested for motor and cognitive recovery for 14 days. Fecal samples were subjected to 16s sequencing and metabolomics. Tissues were collected at sacrifice and used for flow cytometry and IHC.Results: Aged mice that received young fecal transplants after stroke expressed higher SCFAs in their fecal samples (p<0.05) and demonstrated significantly improved stroke recovery in comparison to mice that received aged biome (n=9-10/grp; p<0.05). Young biome treated mice demonstrated rapid improvement in hang time (54.6±7.9s vs 32.6±3.3s; p<0.05) and better outcomes in open field (p<0.05). Aged mice with young biome had better cognitive outcomes compared to the aged biome group. Consistently, our ongoing studies show that transplanting selected strains of SCFA producing bacteria is sufficient to enhance recovery, as tested in hang wire test (64.7±20.4% vs vehicle 25.0±12.5%; n=4/grp; p<0.05).Conclusions: Metabolites produced by young microbiome improve post-stroke recovery in aged mice, enhance SCFAs, and reduce inflammation. Although SCFA production appears to be a key contributor to recovery, more studies are needed to elucidate the underlying mechanisms in order to develop a therapeutic strategy for the treatment of stroke patients.

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