{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T16:32:47Z","timestamp":1754152367618,"version":"3.41.2"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"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:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Helicobacter pylori<\/jats:italic> (HP) is a major gastric pathogen linked to chronic gastritis, peptic ulcers, and gastric cancer. The emergence of antibiotic resistance has prompted the search for alternative treatments. Helile formula, derived from the ancient \u201cTaiping Shenghuifang,\u201d is known to treat various degrees of diarrhea and has potential for treating gastrointestinal disorders. However, the antibacterial efficacy, material basis, and action mechanisms of the helile formula against HP remain undetermined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The chemical constituents were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS\/MS) and high-performance liquid chromatography (HPLC). The <jats:italic>in vitro<\/jats:italic> anti-HP activity and underlying mechanisms were investigated through a series of assays, including the determination of minimum inhibitory concentration (MIC), N-phenyl-1-naphthylamine (NPN) uptake assay, scanning electron microscopy (SEM) to observe morphological changes, cell viability and cell adhesion activity assays, assessment of nitric oxide (NO) production, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for gene expression analysis. For the <jats:italic>in vivo<\/jats:italic> anti-HP infection study and mechanism exploration, techniques such as hematoxylin and eosin (H&amp;amp;E) staining for histological examination, enzyme-linked immunosorbent assay (ELISA) for cytokine and antibody quantification, 16S ribosomal DNA (16S rDNA) sequencing for microbial community profiling, and metabolomics for global metabolite analysis were employed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multiple constituents of helile formula, namely ellagic acid, gallic acid, chebulagic acid, chebulic acid, and corilagin, were identified. <jats:italic>In vitro<\/jats:italic>, helile formula increased bacterial outer-membrane permeability, disrupted HP structure, inhibited toxin-related genes, and suppressed cell adhesion. In male Kunming mice, helile formula effectively reversed HP-induced inflammation. It modulated key metabolites, such as adenine, panaxytriol, 4-hydroxyglutamate semialdehyde, and N-alpha-Acetyl-L-lysine. It influenced the gut microbiota, especially families like <jats:italic>Muribaculaceae<\/jats:italic> and <jats:italic>Lactobacillaceae<\/jats:italic>. Adenine, in particular, repaired HP-caused damage to GES1 cells, reduced HP - mediated cell adhesion, and inhibited HP-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-\u03b1) production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings demonstrated the remarkable anti-HP efficacy of the helile formula <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, suggesting that the helile formula represents a highly promising therapeutic candidate for the management of HP infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1603128","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:30:36Z","timestamp":1753162236000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Helile formula from \u201cTai ping sheng hui fang\u201d: anti-Helicobacter pylori activity, gut microbiota modulation, and inflammatory response regulation"],"prefix":"10.3389","volume":"15","author":[{"given":"Ling","family":"Ou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiyun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haobo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajie","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingchang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meicun","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianhe","family":"Kong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/j.1365-2559.1991.tb00893.x","article-title":"Epithelial damage by Helicobacter pylori in gastric ulcers","volume":"19","author":"Chan","year":"1991","journal-title":"Histopathology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"173267","DOI":"10.1016\/j.ejphar.2020.173267","article-title":"Palmatine ameliorates Helicobacter pylori-induced chronic atrophic gastritis by inhibiting MMP-10 through ADAM17\/EGFR","volume":"882","author":"Chen","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/ajg.2016.563","article-title":"ACG clinical guideline: treatment of helicobacter pylori infection","volume":"112","author":"Chey","year":"2017","journal-title":"Am. J. Gastroenterol."},{"key":"B4","first-page":"115","article-title":"Inhibitory actions of ellagic acid on growth and arylamine N-acetyltransferase activity in strains of Helicobacter pylori from peptic ulcer patients","volume":"93","author":"Chung","year":"1998","journal-title":"Microbios"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1128497","article-title":"Multidrug resistance in Helicobacter pylori infection","volume":"14","author":"Dascalu","year":"2023","journal-title":"Front. Microbiol."},{"key":"B6","first-page":"188","article-title":"Antibacterial activity of 20 kinds of Chinese medicinal materials for Helicobacter pylori in vitro","volume":"24","author":"Du","year":"2001","journal-title":"Zhong Yao Cai"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/S2468-1253(23)00354-0","article-title":"Rising resistance: antibiotic choices for Helicobacter pylori infection","volume":"9","author":"Fauzia","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1355460","article-title":"In vitro anti-Helicobacter pylori activity and the underlining mechanism of an empirical herbal formula - Hezi Qingyou","volume":"15","author":"Feng","year":"2024","journal-title":"Front. Microbiol."},{"key":"B9","first-page":"198","article-title":"Tai ping sheng hui fang (Taiping Holy Prescriptions for Universal Relief) and the compilation during the early Song Dynasty","volume":"40","author":"Han","year":"2010","journal-title":"Zhonghua Yi Shi Za Zhi"},{"key":"B10","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1142\/S0192415X18500155","article-title":"Phytotherapeutic Activities of Sanguisorba officinalis and its Chemical Constituents: A Review","volume":"46","author":"Jang","year":"2018","journal-title":"Am. J. Chin. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.biopha.2017.10.021","article-title":"Quinic acid inhibits vascular inflammation in TNF-alpha-stimulated vascular smooth muscle cells","volume":"96","author":"Jang","year":"2017","journal-title":"BioMed. Pharmacother."},{"key":"B12","first-page":"192","article-title":"Helicobacter pylori and its effects on human health and disease","volume":"14","author":"Kamangar","year":"2011","journal-title":"Arch. Iran Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"257","DOI":"10.5625\/LAR.2010.26.3.257","article-title":"Antibacterial Activity of Sanguisorba officinalis against Helicobacter pylori","volume":"26","author":"Lee","year":"2010","journal-title":"LAR"},{"key":"B14","doi-asserted-by":"publisher","first-page":"106823","DOI":"10.1016\/j.intimp.2020.106823","article-title":"Chebulanin exerts its anti-inflammatory and anti-arthritic effects via inhibiting NF-kappaB and MAPK activation in collagen-induced arthritis mice","volume":"88","author":"Liu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.14715\/cmb\/2023.69.13.5","article-title":"Gallic acid alleviates lipopolysaccharide-induced renal injury in rats by inhibiting cell pro-death and inflammatory response and its mechanism","volume":"69","author":"Luan","year":"2023","journal-title":"Cell Mol. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0924-8579(01)00352-1","article-title":"Antibacterial activity of black myrobalan (Terminalia chebula Retz) against Helicobacter pylori","volume":"18","author":"Malekzadeh","year":"2001","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B17","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1136\/gutjnl-2016-312288","article-title":"Management of Helicobacter pylori infection-the Maastricht V\/Florence Consensus Report","volume":"66","author":"Malfertheiner","year":"2017","journal-title":"Gut"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1016\/S0140-6736(84)91816-6","article-title":"Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration","volume":"1","author":"Marshall","year":"1984","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e15550","DOI":"10.1016\/j.heliyon.2023.e15550","article-title":"Ellagic acid through attenuation of neuro-inflammatory response exerted antidepressant-like effects in socially isolated mice","volume":"9","author":"Mazrooei","year":"2023","journal-title":"Heliyon"},{"key":"B20","doi-asserted-by":"publisher","first-page":"629","DOI":"10.3748\/wjg.v21.i2.629","article-title":"Prevalence of Helicobacter pylori infection and atrophic gastritis in patients with dyspeptic symptoms in Myanmar","volume":"21","author":"Myint","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.1002\/ptr.6702","article-title":"Fruits of Terminalia chebula Retz.: A review on traditional uses, bioactive chemical constituents and pharmacological activities","volume":"34","author":"Nigam","year":"2020","journal-title":"Phytother. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"117428","DOI":"10.1016\/j.jep.2023.117428","article-title":"Terminalia chebula Retz. aqueous extract inhibits the Helicobacter pylori-induced inflammatory response by regulating the inflammasome signaling and ER-stress pathway","volume":"320","author":"Ou","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.3390\/molecules29051161","article-title":"1,3,6-Trigalloylglucose: A Novel Potent Anti-Helicobacter pylori Adhesion Agent Derived from Aqueous Extracts of Terminalia chebula Retz","volume":"29","author":"Ou","year":"2024","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","first-page":"114995","DOI":"10.1016\/j.jep.2022.114995","article-title":"In vitro anti-Helicobacter pylori activity of Syzygium aromaticum and the preliminary mechanism of action","volume":"288","author":"Peng","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"331","DOI":"10.4103\/0974-8520.123139","article-title":"Haritaki (Chebulic myrobalan) and its varieties","volume":"34","author":"Ratha","year":"2013","journal-title":"AYU"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-319-50520-6_1","article-title":"The human stomach in health and disease: infection strategies by helicobacter pylori","volume":"400","author":"Robinson","year":"2017","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"969","DOI":"10.3390\/antibiotics12060969","article-title":"Helicobacter pylori infection: antibiotic resistance and solutions for effective management in africa","volume":"12","author":"Setshedi","year":"2023","journal-title":"Antibiotics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.vph.2018.04.005","article-title":"Chebulagic acid Chebulinic acid and Gallic acid, the active principles of Triphala, inhibit TNFalpha induced pro-angiogenic and pro-inflammatory activities in retinal capillary endothelial cells by inhibiting p38, ERK and NFkB phosphorylation","volume":"108","author":"Shanmuganathan","year":"2018","journal-title":"Vascul. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13020-021-00442-1","article-title":"In vitro anti-bacterial activity and network pharmacology analysis of Sanguisorba officinalis L. against Helicobacter pylori infection","volume":"16","author":"Shen","year":"2021","journal-title":"Chin. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.22038\/IJBMS.2021.59348.13174","article-title":"Corilagin potential in inhibiting oxidative and inflammatory stress in LPS-induced murine macrophage cell lines (RAW 264.7)","volume":"24","author":"Widowati","year":"2021","journal-title":"Iran J. Basic Med. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"11981","DOI":"10.1021\/acs.jafc.2c03711","article-title":"Urolithin A attenuates helicobacter pylori-induced damage in vivo","volume":"70","author":"Yu","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e13016","DOI":"10.1111\/hel.13016","article-title":"Urolithin B alleviates Helicobacter pylori-induced inflammation and oxidative stress in mice","volume":"28","author":"Yu","year":"2023","journal-title":"Helicobacter"},{"key":"B33","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.jep.2013.02.032","article-title":"Anti-Helicobacter pylori compounds from the ethanol extracts of Geranium wilfordii","volume":"147","author":"Zhang","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"5626235","DOI":"10.1155\/2022\/5626235","article-title":"TCM-based therapy as a rescue therapy for re-eradication of helicobacter pylori infection: A systematic review and meta-analysis","volume":"2022","author":"Zhong","year":"2022","journal-title":"Evid. Based. Complement Alternat. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2780","DOI":"10.1080\/14786419.2024.2313183","article-title":"Punicalagin improves inflammation and oxidative stress in rat model of pelvic inflammatory disease","volume":"39","author":"Zoofeen","year":"2025","journal-title":"Nat. Prod. Res."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1603128\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:30:37Z","timestamp":1753162237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1603128\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":35,"alternative-id":["10.3389\/fcimb.2025.1603128"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1603128","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2025,7,22]]},"article-number":"1603128"}}