Juneyoung Lee1, John d'Aigle1, Louise Atadja1, Victoria Quaicoe1, Pedram Honarpisheh1, Bhanu P Ganesh1, Ahmad Hassan2, Joerg Graf2, Joseph Petrosino3, Nagireddy Putluri4, Liang Zhu5, David J Durgan6, Robert M Bryan6, Louise D McCullough1, Venugopal Reddy Venna1. 1. From the Department of Neurology, McGovern Medical School (J.L., J.d'A., L.A., V.Q., P.H., B.P.G., L.D.M., V.R.V.), The University of Texas Health Science Center at Houston. 2. Department of Molecular and Cell Biology, Institute of Systems Genomics, The University of Connecticut, Storrs (A.H., J.G.). 3. Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (J.P.). 4. Department of Molecular and Cellular Biology, Dan L. Duncan Comprehensive Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery (N.P.), Baylor College of Medicine, Houston, TX. 5. Biostatistics and Epidemiology Research Design Core, Center for Clinical and Translational Sciences (L.Z.), The University of Texas Health Science Center at Houston. 6. Department of Anesthesiology (D.J.D., R.M.B.), Baylor College of Medicine, Houston, TX.
Abstract
RATIONALE: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown. OBJECTIVE: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy. METHODS AND RESULTS: Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion. We performed fecal transplant gavage 3 days after middle cerebral artery occlusion using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged stroke mice receiving young fecal transplant gavage had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected 4 SCFA-producers (Bifidobacterium longum, Clostridium symbiosum, Faecalibacterium prausnitzii, and Lactobacillus fermentum) for transplantation. These SCFA-producers alleviated poststroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged stroke mice. CONCLUSIONS: This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via poststroke bacteriotherapy following the replenishment of youthful gut microbiome via modulation of immunologic, microbial, and metabolomic profiles in the host.
RATIONALE: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown. OBJECTIVE: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy. METHODS AND RESULTS: Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion. We performed fecal transplant gavage 3 days after middle cerebral artery occlusion using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged strokemice receiving young fecal transplant gavage had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected 4 SCFA-producers (Bifidobacterium longum, Clostridium symbiosum, Faecalibacterium prausnitzii, and Lactobacillus fermentum) for transplantation. These SCFA-producers alleviated poststroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged strokemice. CONCLUSIONS: This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via poststroke bacteriotherapy following the replenishment of youthful gut microbiome via modulation of immunologic, microbial, and metabolomic profiles in the host.
Authors: Dragana Stanley; Linda J Mason; Kate E Mackin; Yogitha N Srikhanta; Dena Lyras; Monica D Prakash; Kulmira Nurgali; Andres Venegas; Michael D Hill; Robert J Moore; Connie H Y Wong Journal: Nat Med Date: 2016-10-03 Impact factor: 53.440
Authors: Po-Wah So; Antigoni Ekonomou; Kim Galley; Leigh Brody; Meliz Sahuri-Arisoylu; Ivan Rattray; Diana Cash; Jimmy D Bell Journal: Int J Nanomedicine Date: 2019-03-18
Authors: Marlies Elderman; Bruno Sovran; Floor Hugenholtz; Katrine Graversen; Myrte Huijskes; Eva Houtsma; Clara Belzer; Mark Boekschoten; Paul de Vos; Jan Dekker; Jerry Wells; Marijke Faas Journal: PLoS One Date: 2017-09-12 Impact factor: 3.240
Authors: Aleah Holmes; Carson Finger; Diego Morales-Scheihing; Juneyoung Lee; Louise D McCullough Journal: Transl Res Date: 2020-08-02 Impact factor: 7.012