Butyrate promotes post-stroke outcomes in aged mice via interleukin-22

Aging increases the risk of stroke, may exacerbate neuroinflammatory responses, reduce angiogenesis, and promote white matter damage post-stroke, all of which contribute to long-term functional recovery. Butyric acid, an important gut microbial metabolite, showed the highest correlation with the outcomes of ischemic stroke, and butyrate was selected as an effective treatment for aged stroke mice. Here, we tested the neurorestorative effect and potential therapeutic mechanisms of butyrate in aged mice with stroke. Aged male C57BL/6 J mice (17-19 months) were subjected to photothrombotic stroke. We performed butyrate supplementation in the drinking water for 3 weeks before surgery until 14 days after the stroke. At 14 days after ischemic stroke, white matter damage, leukocyte infiltration, and blood-brain barrier permeability were all decreased in the aged stroke mice that received the butyrate treatment, which also improved neurological outcomes by stimulating angiogenesis. Stroke reduces the level of interleukin-22 (IL-22) and butyrate treatment significantly enhanced IL-22 expression in the brain. To further validate the mechanisms of butyrate promoting neurological function after stroke, monoclonal antibodies were used to block IL-22 in aged stroke mice when butyrate treatment was provided. Blocking IL-22 in butyrate-treated aged stroke fails to improve functional outcomes and attenuated butyrate-induced angiogenesis, increased axon/white matter density and blood-brain barrier (BBB) integrity, but has no effect on inflammatory cells infiltration. In conclusion, butyrate improves outcomes in aged mice after stroke by promoting angiogenesis and BBB integrity and reducing leukocyte infiltration. To some extent, IL-22 may contribute to butyrate treatment induced vascular remodeling and increased BBB integrity responses in aged stroke mice.