{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:00:03Z","timestamp":1787727603480,"version":"build-2784847793"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016350","name":"Sichuan Provincial Administration of Traditional Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019971","name":"Luzhou Science and Technology Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background and purpose<\/jats:title>\n                    <jats:p>\n                      Cerebral ischemia-reperfusion injury disrupts the brain-gut axis, which involves the activation of the toll-like receptor 4 (TLR4)\/myeloid differentiation factor 88 (MyD88)\/nuclear factor-kappa B (NF-\u03baB) pathway and gut microbiota dysregulation.\n                      <jats:italic>Acorus tatarinowii<\/jats:italic>\n                      Schott (AT) and\n                      <jats:italic>Panax notoginseng<\/jats:italic>\n                      saponins are traditional Chinese medicines with neuroprotective potential, yet the mechanism underlying their combined action remains elusive.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      144 Sprague-Dawley rats were divided into groups including: sham, model (transient middle cerebral artery occlusion\/reperfusion, MCAO\/R), and drug-treated groups receiving\n                      <jats:italic>A. tatarinowii<\/jats:italic>\n                      Schott (AT),\n                      <jats:italic>P. notoginseng<\/jats:italic>\n                      saponins (PNS), or their combination (PAT). To evaluate efficacy under heightened inflammatory conditions, parallel groups were pre-treated with lipopolysaccharide (LPS, a TLR4 pathway agonist) before MCAO\/R and subsequent drug administration (e.g., LPS + MCAO\/R, LPS + AT, LPS + PNS, LPS + PAT, etc.). Neurological deficits (Longa score), cerebral infarct volume (TTC staining), intestinal motility, and histopathology (Hematoxylin-eosin staining, transmission electron microscopy) were analyzed. Additionally, levels of tight junction proteins (ZO-1, claudin-5, occludin), TLR4 pathway components, and inflammatory cytokines (TNF-\u03b1, IL-6) were assessed using Western blot and\/or immunohistochemistry. Gut microbiota composition was evaluated via 16S rDNA sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with either monotherapy, the combined AT\u2013PNS treatment produced greater improvements in neurological function, reduced cerebral infarct volume, preserved blood-brain and intestinal barrier integrity, and attenuated TLR4\/MyD88\/NF-\u03baB pathway activation. The combination was also associated with partial normalization of cecal microbiota composition, including an increased Firmicutes\/Bacteroidota ratio and reduced Proteobacteria abundance. These effects were attenuated but remained detectable under LPS-induced inflammatory challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Combined AT\u2013PNS treatment ameliorated brain-gut axis dysfunction after cerebral ischemia-reperfusion injury and showed greater efficacy than either monotherapy in this fixed-dose experimental design. These effects were accompanied by suppression of TLR4\/MyD88\/NF-\u03baB signaling, improved barrier integrity, and associated changes in gut microbiota composition. Because the present study did not include dose-response matrices, a formal dose-response interaction profile and a causal microbiota-TLR4 mechanism remain to be established in future studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1683558","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:26:22Z","timestamp":1782707182000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined treatment with Acorus tatarinowii Schott and Panax notoginseng saponins ameliorates brain\u2013gut axis dysfunction in MCAO\/R rats with suppression of TLR4\/MyD88\/NF-\u03baB signaling and associated gut microbiota changes"],"prefix":"10.3389","volume":"17","author":[{"given":"Lin-Yao","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Peng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Mei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Chou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang-Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.bbi.2021.05.008","article-title":"Stroke affects intestinal immune cell trafficking to the central nervous system","volume":"96","author":"Brea","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41572-019-0118-8","article-title":"Ischaemic stroke","volume":"5","author":"Campbell","year":"2019","journal-title":"Nat. Reviews Dis. Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"112010","DOI":"10.1016\/j.foodres.2022.112010","article-title":"Targeting the gut microbiota to investigate the mechanism of Lactiplantibacillus plantarum 1201 in negating colitis aggravated by a high-salt diet","volume":"162","author":"Chen","year":"2022","journal-title":"Food Res. Int."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.3390\/cells11071239","article-title":"The influence of gut dysbiosis in the pathogenesis and management of ischemic stroke","volume":"11","author":"Chidambaram","year":"2022","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The microbiota-gut-brain axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol. Reviews"},{"key":"B6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3390\/ijms20235972","article-title":"Tight junctions in cell proliferation","volume":"20","author":"D\u00edaz-Cor\u00e1nguez","year":"2019","journal-title":"Int. Journal Molecular Sciences"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5617","DOI":"10.1038\/s41467-022-33313-w","article-title":"Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant enterobacteriaceae","volume":"13","author":"Djukovic","year":"2022","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"845142","DOI":"10.3389\/fcimb.2022.845142","article-title":"Pediococcus acidilactici strain alleviates gluten-induced food allergy and regulates gut microbiota in mice","volume":"12","author":"Fu","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"a002907","DOI":"10.1101\/cshperspect.a002907","article-title":"Molecular basis of the core structure of tight junctions","volume":"2","author":"Furuse","year":"2010","journal-title":"Cold Spring Harb. Perspectives Biology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1002\/ptr.2000","article-title":"Antispasmodic effect of Acorus calamus linn. Is mediated through calcium channel blockade","volume":"20","author":"Gilani","year":"2006","journal-title":"Phytotherapy Research PTR"},{"key":"B11","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.jep.2019.112230","article-title":"Best practice in research - overcoming common challenges in phytopharmacological research","volume":"246","author":"Heinrich","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1093\/ecco-jcc\/jjy035","article-title":"Development of reliable, valid and responsive scoring systems for endoscopy and histology in animal models for inflammatory bowel disease","volume":"12","author":"Koelink","year":"2018","journal-title":"J. Crohn\u2019s Colitis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1080\/14728222.2019.1676416","article-title":"Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders","volume":"23","author":"Leitner","year":"2019","journal-title":"Expert Opinion Therapeutic Targets"},{"key":"B14","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1186\/s12967-025-06674-1","article-title":"The pasteurized Weissella cibaria alleviates sepsis-induced acute lung injury by modulation of intestinal mucus barrier and gut microbiota","volume":"23","author":"Li","year":"2025","journal-title":"J. Transl. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"a011247","DOI":"10.1101\/cshperspect.a011247","article-title":"Toll-like receptor signaling","volume":"5","author":"Lim","year":"2013","journal-title":"Cold Spring Harb. Perspectives Biology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3236768","DOI":"10.1155\/2020\/3236768","article-title":"Revealing the pharmacological mechanism of Acorus tatarinowii in the treatment of ischemic stroke based on network pharmacology","volume":"2020","author":"Liu","year":"2020","journal-title":"Evid.Based Complement. Alternat. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1161\/01.str.20.1.84","article-title":"Reversible middle cerebral artery occlusion without craniectomy in rats","volume":"20","author":"Longa","year":"1989","journal-title":"Stroke"},{"key":"B18","doi-asserted-by":"publisher","first-page":"604179","DOI":"10.3389\/fimmu.2020.604179","article-title":"The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology","volume":"11","author":"Rutsch","year":"2020","journal-title":"Front. Immunology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1126\/science.1261833","article-title":"Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin","volume":"347","author":"Saitoh","year":"2015","journal-title":"Sci. (New York, NY)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s11936-019-0778-4","article-title":"Antithrombotic management of ischemic stroke","volume":"21","author":"Sloane","year":"2019","journal-title":"Curr. Treatment Options Cardiovascular Medicine"},{"key":"B21","doi-asserted-by":"publisher","first-page":"32","DOI":"10.13422\/j.cnki.syfjx.20211702","article-title":"Effect of huatan tongluo decoction on gut-brain axis in rats with cerebral ischemia\/reperfusion","volume":"27","author":"Tang","year":"2021","journal-title":"Chin. J. Exp. Tradit. Med. Form."},{"key":"B22","doi-asserted-by":"publisher","first-page":"321","DOI":"10.3390\/nu18020321","article-title":"Gut microbiota and short-chain fatty acids in cardiometabolic HFpEF: mechanistic pathways and nutritional therapeutic perspectives","volume":"18","author":"Vacca","year":"2026","journal-title":"Nutrients"},{"key":"B23","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.jep.2010.06.034","article-title":"The effect of Acorus gramineus on the bioavailabilities and brain concentrations of ginsenosides Rg1, re and Rb1 after oral administration of kai-xin-san preparations in rats","volume":"131","author":"Wang","year":"2010","journal-title":"J. Ethnopharmacology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"114598","DOI":"10.1016\/j.jep.2021.114598","article-title":"Qisheng wan formula ameliorates cognitive impairment of Alzheimer\u2019s disease rat via inflammation inhibition and intestinal microbiota regulation","volume":"282","author":"Xiong","year":"2022","journal-title":"J. Ethnopharmacology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e4115","DOI":"10.1002\/cbf.4115","article-title":"Panax notoginseng saponins ameliorate gamma radiation-mediated damages in human peripheral blood monocytes and Swiss albino mice","volume":"42","author":"Yang","year":"2024","journal-title":"Cell. Biochem. Funct."},{"key":"B26","doi-asserted-by":"publisher","first-page":"130","DOI":"10.13194\/j.issn.1673-842x.2022.04.027","article-title":"Literature review of TCM treatment of ischemic stroke based on \u201cbrain-gut axis\u201d","volume":"24","author":"Zhai","year":"2022","journal-title":"J. Liaoning Univ. Tradit. Chin. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3969\/j.issn.2095-1396.2014.02.008","article-title":"Progress in understanding the multiple organ injury induced by cerebral ischemia-reperfusion","volume":"4","author":"Zhao","year":"2014","journal-title":"Acta Neuropharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s12974-018-1382-3","article-title":"Bidirectional gut-brain-microbiota axis as a potential link between inflammatory bowel disease and ischemic stroke","volume":"15","author":"Zhao","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1093\/ndt\/gfae052","article-title":"IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1 via the TLR4 signaling pathway","volume":"39","author":"Zhu","year":"2024","journal-title":"Nephrol. Dial. Transpl."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1683558\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:26:27Z","timestamp":1782707187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1683558\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":29,"alternative-id":["10.3389\/fphar.2026.1683558"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1683558","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"article-number":"1683558"}}