{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:05:49Z","timestamp":1789729549917,"version":"4.0.1"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Periodontal disease is an independent risk indicator for the progression of liver fibrosis, yet the underlying mechanisms remain incompletely defined. Emerging evidence suggests that the \u201coral-gut-liver axis\u201d plays a critical role. This review aims to systematically synthesize the molecular mechanisms that may plausibly contribute to the pathogenesis of liver fibrosis via this axis and to propose a novel spatiotemporal framework to guide future research and therapeutic strategies. We propose a three-phase framework that temporally dissects the fibrogenic process into initiation, amplification, and maintenance phases\u2014a distinction that, to our knowledge, has not been systematically applied to the oral-gut-liver axis in previous literature. This framework is proposed as a working hypothesis based on integrating current preclinical and observational evidence and is intended to guide future mechanistic and interventional studies. In the initiation phase, periodontal pathogens and their virulence factors disseminate haematogenously or via the intestinal route to the liver, where, in animal models, they have been shown to activate Toll-like receptor (TLR)\/nuclear factor-\u03baB (NF-\u03baB) signaling and trigger the initial inflammatory response. In the amplification phase, hepatic inflammatory cytokines disrupt the intestinal barrier, leading to a \u201cleaky gut\u201d and massive endotoxin translocation into the liver, theoretically establishing a self-perpetuating positive feedback loop that may drive Kupffer cell M1 polarization and hepatic stellate cell (HSC) activation. In the maintenance phase, even after the oral trigger subsides, liver-intrinsic mechanisms\u2014including HSC autocrine TGF-\u03b2 signaling, epigenetic reprogramming, extracellular matrix crosslinking, liver sinusoidal endothelial cell capillarization, and bile acid\u2013farnesoid X receptor (FXR)\/Takeda G protein-coupled receptor 5 (TGR5) dysregulation\u2014are hypothesized to sustain and contribute to the aggravation of fibrosis, based largely on preclinical evidence. Despite promising preclinical and observational evidence, translation to clinical practice remains hampered by the lack of high-quality randomized controlled trials with histological reversal as a hard endpoint. Future research should integrate multi-omics analysis, organoid and humanized animal models, and rigorously designed interventional trials to validate the oral-gut-liver axis as a therapeutic target. This review provides an integrated mechanistic framework that may inform future opportunities for early prevention and multidisciplinary management of periodontal disease-associated liver fibrosis.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1942882","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:41:43Z","timestamp":1789728103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms underlying the role of the oral-gut-liver axis in the promotion of liver fibrosis by periodontal disease: an interacting network of inflammation, microbiota, and barrier function"],"prefix":"10.3389","volume":"16","author":[{"given":"Shuxin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Shengjing Hospital, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/dj10020016","article-title":"Oral health and liver disease: bidirectional associations-a narrative review","volume":"10","author":"\u00c5berg","year":"2022","journal-title":"Dent. 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