{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:49:41Z","timestamp":1791528581522,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,11]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background and Aims<\/jats:title>\n \n Resmetirom has emerged as a major advance in MASH pharmacotherapy as the first approved liver\u2010targeted THR\u2010\u03b2 agonist; however, variable therapeutic efficacy and adverse responses may limit its clinical benefits. This study investigated whether\n \n C. butyricum<\/jats:italic>\n <\/jats:styled-content>\n could provide additional therapeutic benefits when combined with resmetirom and attenuate nausea\/vomiting\u2010like responses in association with changes across the gut\u2013liver\u2013brain axis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study, we established a high\u2010fat diet\u2010induced MASH mouse model and administered\n \n C. butyricum<\/jats:italic>\n <\/jats:styled-content>\n , resmetirom, or their combination. Comprehensive biochemical, histological, molecular, 16S rRNA sequencing\u2010based microbiome profiling, and gut\u2013brain axis\u2010related analyses were performed to evaluate the effects of combination therapy on hepatic metabolism, inflammation, fibrosis, intestinal barrier integrity, gut microbiota remodelling, microbial metabolites, and resmetirom\u2010associated adverse responses.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Combined treatment with\n \n C. butyricum<\/jats:italic>\n <\/jats:styled-content>\n and resmetirom produced additional therapeutic benefits compared with either monotherapy, markedly improving hepatic steatosis, lipid accumulation, insulin resistance, inflammation, oxidative stress, and fibrosis in MASH mice. At the molecular level, combination treatment was associated with increased hepatic THR\u2010\u03b2 expression and coordinated changes in AMPK\u2010related lipid metabolism, NRF2\/HO\u20101 antioxidant, and TLR4\/MyD88\/NF\u2010\u03baB inflammatory markers. Furthermore, combination therapy restored intestinal barrier integrity, alleviated MASH\u2010associated gut microbial dysbiosis, increased beneficial bacterial taxa, and increased faecal butyrate levels. Notably,\n \n C. butyricum<\/jats:italic>\n <\/jats:styled-content>\n attenuated resmetirom\u2010induced nausea\/vomiting\u2010like responses, accompanied by reduced colonic and cerebral 5\u2010HT\/SP signalling, decreased brain\n Htr3a<\/jats:italic>\n and\n Tacr1<\/jats:italic>\n mRNA expression, and suppressed neuronal FOS activation. Faecal butyrate levels were inversely associated with hepatic lipid burden and brain 5\u2010HT\/SP levels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n \n C. butyricum<\/jats:italic>\n <\/jats:styled-content>\n combined with resmetirom provides additional therapeutic benefits and attenuates nausea\/vomiting\u2010like responses in MASH, accompanied by coordinated changes across the gut\u2013liver\u2013brain axis. This combination strategy provides a potential microbiota\u2010based adjunctive approach for optimizing the therapeutic benefits of resmetirom in MASH.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/liv.70905","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:59:46Z","timestamp":1791525586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\n C. butyricum<\/i>\n <\/scp>\n Combined With Resmetirom Provides Therapeutic Benefits in\n MASH<\/scp>\n Associated With Gut\u2013Liver\u2013Brain Axis Modulation"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5694-3858","authenticated-orcid":false,"given":"Kaige","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"},{"name":"Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"},{"name":"National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4165-0504","authenticated-orcid":false,"given":"Yuyu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The First Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0558-8368","authenticated-orcid":false,"given":"Jianhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Queen Mary School, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Huan Kui Academy, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqiang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Third Affiliated Hospital (The First Hospital of Nanchang), Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0506-8536","authenticated-orcid":false,"given":"Tingtao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"},{"name":"Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"},{"name":"National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College Nanchang University Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"issue":"18","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI186420","article-title":"MASH: The Nexus of Metabolism, Inflammation, and Fibrosis","volume":"135","author":"Steinberg G. 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M.","year":"2016","journal-title":"Hepatology"},{"issue":"9","key":"e_1_2_11_6_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.gastha.2025.100709","article-title":"A Real\u2010World Experience With Resmetirom: Tolerability and Access","volume":"4","author":"Shuaibi S.","year":"2025","journal-title":"Gastro Hep Advances"},{"issue":"6","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH With Liver Fibrosis","volume":"390","author":"Harrison S. A.","year":"2024","journal-title":"New England Journal of Medicine"},{"issue":"11","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41579-023-00904-3","article-title":"The Gut\u2010Liver Axis and Gut Microbiota in Health and Liver Disease","volume":"21","author":"Hsu C. L.","year":"2023","journal-title":"Nature Reviews. 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A.","year":"2019","journal-title":"Lancet"},{"issue":"12","key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s42255-021-00501-9","article-title":"Non\u2010Alcoholic Fatty Liver Disease: The Interplay Between Metabolism, Microbes and Immunity","volume":"3","author":"Tilg H.","year":"2021","journal-title":"Nature Metabolism"},{"issue":"3","key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s11605-021-05188-7","article-title":"The Role of Gut\u2010Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases","volume":"26","author":"An L.","year":"2022","journal-title":"Journal of Gastrointestinal Surgery"},{"issue":"11","key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 Enhances TGF\u2010Beta Signaling and Hepatic Fibrosis","volume":"13","author":"Seki E.","year":"2007","journal-title":"Nature Medicine"},{"issue":"7","key":"e_1_2_11_28_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI186423","article-title":"Metabolic Dysfunction\u2010Associated Steatotic Liver Disease and the Gut Microbiome: Pathogenic Insights and Therapeutic Innovations","volume":"135","author":"Schnabl B.","year":"2025","journal-title":"Journal of Clinical Investigation"},{"issue":"1","key":"e_1_2_11_29_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41522-022-00338-4","article-title":"Rational Consideration of \n Akkermansia muciniphila\n Targeting Intestinal Health: Advantages and Challenges","volume":"8","author":"Luo Y.","year":"2022","journal-title":"npj Biofilms and Microbiomes"},{"issue":"4","key":"e_1_2_11_30_1","doi-asserted-by":"crossref","DOI":"10.3390\/nu12041107","article-title":"The Effect of Probiotics on the Production of Short\u2010Chain Fatty Acids by Human Intestinal Microbiome","volume":"12","author":"Markowiak\u2010Kope\u0107 P.","year":"2020","journal-title":"Nutrients"},{"issue":"8","key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41577-024-01014-8","article-title":"Short\u2010Chain Fatty Acids: Linking Diet, the Microbiome and Immunity","volume":"24","author":"Mann E. R.","year":"2024","journal-title":"Nature Reviews. Immunology"},{"key":"e_1_2_11_32_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.crfs.2026.101354","article-title":"Clostridium butyricum\n \u2010Derived Antimicrobial Peptides Remodel SCFA\u2010Producing Gut Symbionts to Alleviate Inflammation and Enhance Gut Barrier Integrity Through Microbial Crosstalk","volume":"12","author":"Chen Y.","year":"2026","journal-title":"Current Research in Food Science"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.00277","article-title":"Short Chain Fatty Acids (SCFAs)\u2010Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases","volume":"10","author":"Parada Venegas D.","year":"2019","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"e_1_2_11_34_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41522-025-00824-5","article-title":"Role of Intestinal SCFAs Homeostasis in the Hepatoprotective Effect of \n Clostridium butyricum\n in T2DM","volume":"11","author":"Yan M.","year":"2025","journal-title":"npj Biofilms and Microbiomes"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70905","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.70905","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70905","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:59:52Z","timestamp":1791525592000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.70905"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":33,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1111\/liv.70905"],"URL":"https:\/\/doi.org\/10.1111\/liv.70905","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70905"}}