Stroke and the Microbiome

HomeStrokeVol. 55, No. 3Stroke and the Microbiome Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBStroke and the Microbiome Anik Banerjee, Swati Mohapatra and Louise D. McCullough Anik BanerjeeAnik Banerjee https://orcid.org/0000-0002-1750-928X Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, (A.B., S.M.). The University of Texas, MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston (A.B., S.M.). , Swati MohapatraSwati Mohapatra https://orcid.org/0000-0002-6681-1637 Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, (A.B., S.M.). The University of Texas, MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston (A.B., S.M.). and Louise D. McCulloughLouise D. McCullough Correspondence to: Louise D. McCullough, MD, PhD, Department of Neurology, University of Texas, McGovern Medical School, 6431 Fannin St, Room 7044, Houston, TX 77030. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8050-1686 Department of Neurology, University of Texas, McGovern Medical School, Houston (L.D.M.). Originally published23 Jan 2024https://doi.org/10.1161/STROKEAHA.123.044249Stroke. 2024;55:762–764Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 23, 2024: Ahead of Print Advances in metagenomics and metabolomics have revealed that the gut microbiota plays a crucial role in regulating neuroinflammation, behavior, and cognitive function in the host via a bidirectional microbiota-gut-brain axis that involves both neuronal and nonneuronal mechanisms. With aging, there is a shift in the composition of the gut microbiome, with lower bacterial diversity, reduced abundance of beneficial bacteria, and higher levels of pathogenic and opportunistic bacteria.1 Both host health status and longevity have been associated with distinct compositional patterns of the gut microbiome.2 Multiple studies have shown that stroke results in shifts in the gut microbiota composition, an early loss of host gut integrity, increased bacterial translocation into the host, and alterations in host-microbe metagenomic pathways.3,4 This brief overview highlights the emerging role of the microbiome in the response to ischemic stroke, and the potential of developing novel microbially centered therapies to improve outcomes.IMPACT OF THE MICROBIOME ON THE PREVALENCE OF STROKE RISK FACTORSStroke is the second leading cause of death globally, and in the United States, most strokes are ischemic. To date, therapeutic options for ischemic stroke in the hyperacute phase are limited to thrombolysis and endovascular thrombectomy.5 Many stroke patients are ineligible to receive these treatments due to narrow therapeutic time windows, hemorrhage risk, contraindications to thrombolytic use, or lack of available resources for rapid thrombectomy. Both host-intrinsic (ie, sex, age, and immune senescence)6 and extrinsic factors (ie, environmental and lifestyle factors, medication use, and diet)7 play a critical role in the progression of stroke pathophysiology. Over the past decade, the contribution of circulating metabolites and other molecules (ie, cytokines, immune cells, and senescence factors) from the gut and other peripheral organs (ie, spleen and bone marrow) on the ischemic brain has been increasingly recognized.4,6 Importantly, targeting these peripheral events may lead to newer, more accessible, therapeutic targets than the events occurring within the ischemic brain itself.Metabolic parameters such as obesity, diabetes, and hypertension are well-recognized risk factors for ischemic stroke and are linked to poststroke recovery.8 Metabolites (ie, short-chain fatty acids) produced by the gut microbiome are highly immunoregulatory and dampen both peripheral and central nervous system inflammation. Gut dysbiosis following ischemic stroke, and the reduction in beneficial bacterial strains, such as short-chain fatty acid producers, alter the small intestinal immune compartment resulting in an increase in interleukin (IL)-17+ γδ T cells and a reduction of regulatory T cells via altered dendritic cell antigenic presentation in the lamina propria.3 The ability of the microbiome to produce neuroactive gut microbiota-derived metabolites is also altered after stroke.9 Thus, studies examining alterations in the gut microbiome composition and resulting metabolomic shifts seen following stroke could lead to new therapeutic interventions to restore gut homeostasis and improve outcomes.HOST FACTORS AFFECTING GUT MICROBIOME IN POSTSTROKE OUTCOMESExtrinsic factors such as diet, medications, and lifestyle factors can dramatically alter the gut microbiome and its metabolites10 (Figure). Germ-free mice supplemented with gut microbiota from human donors that consume a high-fat and high-sugar diet developed diet-induced obesity after a high-fat diet challenge. In contrast, Germ-free mice reconstituted with the microbiome from individuals that ate a low-fat and plant polysaccharide-rich diet were resistant to obesity.11 In clinical populations, higher total dietary fiber intake was associated with a lower stroke risk even after accounting for sex, metabolic dysfunction, and other comorbid illnesses that are risk factors for stroke.12 In a recent meta-analysis, individuals who consumed a vegetarian-based diet had a significantly lower incidence of stroke compared with individuals predominantly on protein-based diets.13 Thus, exposure to external factors (antibiotics and diet) can shape the microbiome composition regulating host immunity, longevity, and metabolism all of which contribute to poststroke outcomes.14Download figureDownload PowerPointFigure. Extrinsic and intrinsic factors affect poststroke outcomes that are regulated by the host gut microbiome. A recent emerging avenue is to understand the role of gut microbiome mediated through the microbiota-gut-liver-brain axis. The communication between the gut and the brain is regulated through the top-down and bottom-up signaling pathways regulated via liver metabolism which remains understudied. CXCL1 indicates C-X-C motif chemokine ligand 1; CXCL2, C-X-C motif chemokine ligand 2; DCs, dendritic cells; FMT, fecal microbiota transfer; IL, interleukin; MCAO, middle cerebral artery occlusion; mLN, mesenteric lymph node; PMN, polymorphonuclear leukocytes; SCFA, short-chain fatty acid; SI-LP, small intestinal lamina propria; and Treg, regulatory T cells.Host intrinsic factors, including aging and sex, have a major impact on both stroke incidence and poststroke recovery. Once thought to be a nonmodifiable risk factor for stroke and cognitive decline, there has been growing recognition that some of the detrimental effects of aging can be reversed by manipulating the gut-brain axis. Aging contributes to poorer outcomes after stroke, and as noted above, aging also leads to changes in the gut microbiome composition. Aged animals exhibit gut epithelial barrier disruption both at baseline and after injury, which leads to translocation of intestinal bacteria into the liver, triggering sepsis,15 and likely contributes to the higher incidence of poststroke infections seen in the elderly. Fecal microbiota transfers from aged mice into young mice before an experimental stroke led to poor outcomes and reduced survival in young mice, conversely, a young fecal microbiota transfers into an aged donor significantly reduced neurological deficits and improved recovery.1,4 This appears to be mediated by specific microbially derived metabolites, as a probiotic cocktail enriched with short-chain fatty acids producers, given with the prebiotic inulin (a fiber-based substrate), improved gut barrier integrity, reduced T-cell-mediated inflammation, and decreased neurological deficits in aged mice, even when administered 3 days after stroke.4Sex differences exist in the composition of the gut microbiome and in outcomes after stroke.16 A study incorporating cross-sex fecal microbiota transfers demonstrated that a female-like biological microbial community reduced the levels of systemic proinflammatory cytokines following ischemic stroke17 by lowering the number of inflammatory macrophages and neutrophils infiltrating into the ischemic brain. El-Hakim et al demonstrated that males exhibited greater mortality, worse gut permeability, and detrimental changes in the gut villi architecture following stroke compared with females, and this was primarily driven by sex-specific effects on the gut epithelium.18 Lee et al recently demonstrated that estradiol replacement before stroke increased mucin expression in the colonic epithelial cells and increased the presence of Lactobacillus and Bifidobacterium in the gut microbiome.16 Thus, sex hormones can shape the gut microbiome composition, leading to alterations in host gut epithelial-specific defense mechanisms following stroke.FUTURE HORIZON OF EMERGING STROKE THERAPIESOngoing studies utilizing fecal microbiota transfers from stroke and healthy human samples to germ-free mice will help us further understand the role of gut dysbiosis and microbial metabolites on poststroke outcomes. Assessing the effects of administration of beneficial microbiota or their derived metabolites is likely on the horizon for poststroke intervention. Host extrinsic factors including race and ethnicity also play a major role in modulating the gut microbiome; however, only 3 ethnic populations have been extensively studied (Chinese, the Netherlands, and Japanese populations) clinically. Incorporating a more diverse subset of patients from distinct backgrounds is essential as the microbiome composition is shaped by multiple host factors (ie, host genetics, environment, medication, and diet). In summary, understanding the link between immune and neuronal components in the brain and gut will help elucidate novel regulatory components of the gut-brain axis that can be developed as cost effective and widely accessible therapies for stroke.ARTICLE INFORMATIONAcknowledgmentsA. Banerjee, S. Mohapatra, and Dr McCullough wrote the article.Sources of FundingThis work was supported by the American Heart Association Grant No. 23PRE1027421 and the Dr John J. Kopchick Research Award (to A. Banerjee), the Cancer Prevention and Research Institute of Texas (CPRIT) Research Training Grant No. RP210028 and Schissler Foundation Fellowship (to S. Mohapatra). National Institutes of Health (NIH)/National Institute on Aging and National Institute of Neurological Disorders and Stroke (NINDS): NIH/NINDS R01-NS103592 (Detrimental Effects of Age-Related Dysbiosis to Dr McCullough), and NIH/AG058463 (Dynamic non-neuronal interactions between the gut microbiota and the brain in aging to L.D. McCullough).Disclosures None.FootnotesThe American Heart Association celebrates its 100th anniversary in 2024. This article is part of a series across the entire AHA Journal portfolio written by international thought leaders on the past, present, and future of cardiovascular and cerebrovascular research and care. To explore the full Centennial Collection, visit https://www.ahajournals.org/centennial.*A. Banerjee and S. Mohapatra contributed equally.For Sources of Funding and Disclosures, see page 764.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Louise D. McCullough, MD, PhD, Department of Neurology, University of Texas, McGovern Medical School, 6431 Fannin St, Room 7044, Houston, TX 77030. Email louise.d.mccullough@uth.tmc.eduREFERENCES1. Spychala MS, Venna VR, Jandzinski M, Doran SJ, Durgan DJ, Ganesh BP, Ajami NJ, Putluri N, Graf J, Bryan RM, et al. Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome.Ann Neurol. 2018; 84:23–36. doi: 10.1002/ana.25250CrossrefMedlineGoogle Scholar2. Barcena C, Valdes-Mas R, Mayoral P, Garabaya C, Durand S, Rodriguez F, Fernandez-Garcia MT, Salazar N, Nogacka AM, Garatachea N, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.Nat Med. 2019; 25:1234–1242. doi: 10.1038/s41591-019-0504-5CrossrefGoogle Scholar3. Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta t cells.Nat Med. 2016; 22:516–523. doi: 10.1038/nm.4068CrossrefMedlineGoogle Scholar4. Lee J, d'Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, Hassan A, Graf J, Petrosino J, Putluri N, et al. Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice.Circ Res. 2020; 127:453–465. doi: 10.1161/CIRCRESAHA.119.316448LinkGoogle Scholar5. Marko M, Posekany A, Szabo S, Scharer S, Kiechl S, Knoflach M, Serles W, Ferrari J, Lang W, Sommer P, et al; Austrian Stroke Unit Registry Collaborators. Trends of r-tpa (recombinant tissue-type plasminogen activator) treatment and treatment-influencing factors in acute ischemic stroke.Stroke. 2020; 51:1240–1247. doi: 10.1161/STROKEAHA.119.027921LinkGoogle Scholar6. Ritzel RM, Lai YJ, Crapser JD, Patel AR, Schrecengost A, Grenier JM, Mancini NS, Patrizz A, Jellison ER, Morales-Scheihing D, et al. Aging alters the immunological response to ischemic stroke.Acta Neuropathol. 2018; 136:89–110. doi: 10.1007/s00401-018-1859-2CrossrefMedlineGoogle Scholar7. Banerjee A, Chokkalla AK, Shi JJ, Lee J, Venna VR, Vemuganti R, McCullough LD. Microarray profiling reveals distinct circulating miRNAs in aged male and female mice subjected to post-stroke social isolation.Neuromolecular Med. 2021; 23:305–314. doi: 10.1007/s12017-020-08622-2CrossrefGoogle Scholar8. Shi H, Zhang B, Abo-Hamzy T, Nelson JW, Ambati CSR, Petrosino JF, Bryan RM, Durgan DJ. Restructuring the gut microbiota by intermittent fasting lowers blood pressure.Circ Res. 2021; 128:1240–1254. doi: 10.1161/CIRCRESAHA.120.318155LinkGoogle Scholar9. Parker A, Fonseca S, Carding SR. Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health.Gut Microbes. 2020; 11:135–157. doi: 10.1080/19490976.2019.1638722CrossrefMedlineGoogle Scholar10. Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly.Proc Natl Acad Sci U S A. 2011; 108:4586–4591. doi: 10.1073/pnas.1000097107CrossrefMedlineGoogle Scholar11. Wang S, Huang M, You X, Zhao J, Chen L, Wang L, Luo Y, Chen Y. Gut microbiota mediates the anti-obesity effect of calorie restriction in mice.Sci Rep. 2018; 8:13037. doi: 10.1038/s41598-018-31353-1CrossrefMedlineGoogle Scholar12. Li DB, Hao QQ, Hu HL. The relationship between dietary fibre and stroke: a meta-analysis.J Stroke Cerebrovasc Dis. 2023; 32:107144. doi: 10.1016/j.jstrokecerebrovasdis.2023.107144CrossrefGoogle Scholar13. Guo N, Zhu Y, Tian D, Zhao Y, Zhang C, Mu C, Han C, Zhu R, Liu X. Role of diet in stroke incidence: an umbrella review of meta-analyses of prospective observational studies.BMC Med. 2022; 20:194. doi: 10.1186/s12916-022-02381-6CrossrefGoogle Scholar14. Lynn MA, Eden G, Ryan FJ, Bensalem J, Wang X, Blake SJ, Choo JM, Chern YT, Sribnaia A, James J, et al. The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life.Cell Rep. 2021; 36:109564. doi: 10.1016/j.celrep.2021.109564CrossrefGoogle Scholar15. Tran L, Greenwood-Van Meerveld B. Age-associated remodeling of the intestinal epithelial barrier.J Gerontol A Biol Sci Med Sci. 2013; 68:1045–1056. doi: 10.1093/gerona/glt106CrossrefGoogle Scholar16. Lee J, Peesh P, Quaicoe V, Tan C, Banerjee A, Mooz P, Ganesh BP, Petrosino J, Bryan RM, McCullough LD, et al. Estradiol mediates colonic epithelial protection in aged mice after stroke and is associated with shifts in the gut microbiome.Gut Microbes. 2023; 15:2271629. doi: 10.1080/19490976.2023.2271629CrossrefGoogle Scholar17. Wang J, Zhong Y, Zhu H, Mahgoub OK, Jian Z, Gu L, Xiong X. Different gender-derived gut microbiota influence stroke outcomes by mitigating inflammation.J Neuroinflammation. 2022; 19:245. doi: 10.1186/s12974-022-02606-8CrossrefGoogle Scholar18. El-Hakim Y, Mani KK, Eldouh A, Pandey S, Grimaldo MT, Dabney A, Pilla R, Sohrabji F. Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult sprague-dawley rats.Biol Sex Differ. 2021; 12:14. doi: 10.1186/s13293-020-00352-1CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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