{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:41:04Z","timestamp":1790876464182,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82141202"],"award-info":[{"award-number":["82141202"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Qin-Qiao-Xiao-Du (QQXD), a traditional Chinese medicine (TCM) formula, has been used in the clinical treatment of influenza virus pneumonia. However, the effects and mechanisms of QQXD on influenza virus pneumonia remain unknown. Therefore, this study explores the mechanisms of QQXD in the treatment of influenza virus pneumonia from the point of view of intestinal flora and metabolism. The results showed that QQXD was able to reduce mortality, weight loss, lung viral load, lung index, and lung injury in influenza virus mice. A cytokine array found that the QQXD attenuated the expression of serum IL-1\u03b1, IL-4, IL-12(P70), and TNF-\u03b1. Subsequently, 16s rRNA gene sequencing showed that QQXD could increase the relative abundances of Gemmiger, Anaerofustis, Adlercreutzia, and Streptococcus and decrease those of Dehalobacteriu, Burkholderia, Prevotella, Butyrimimonas, Delftia, and others. Meanwhile, targeted metabolic profiling analysis showed that QQXD could regulate nitrogen metabolism, phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis. Correlation analysis demonstrated that the regulatory effect of QQXD on the cyanoamino acid metabolism pathway was associated with changes in the abundance of Parabacteroides, Pediococcus, and Clostridium in influenza mice. In conclusion, our study revealed that QQXD can inhibit influenza virus replication, suppress cytokine storms, and protect mice from influenza virus infection pneumonia. The mechanisms are likely to be related to improved gut microbiota dysbiosis, increased intestinal carbohydrate metabolism, and up-regulated cyanoamino acid metabolism pathways.<\/jats:p>","DOI":"10.3389\/fmed.2022.1032127","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T07:14:34Z","timestamp":1665731674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Qin-Qiao-Xiao-Du formula alleviate influenza virus infectious pneumonia through regulation gut microbiota and metabolomics"],"prefix":"10.3389","volume":"9","author":[{"given":"Bo","family":"Lian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuran","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingquan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"B1","year":"2018","journal-title":"Influenza (Seasonal)."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a038356","article-title":"Human influenza epidemiology.","volume":"11","author":"Ryu","year":"2021","journal-title":"Cold Spring Harb Perspect Med."},{"key":"B3","first-page":"1","article-title":"Technical guidelines for seasonal influenza vaccination in China, 2019-2020.","volume":"6","year":"2019","journal-title":"Chin J Viral Dis."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza.","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat Rev Dis Primers."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd2220","article-title":"COVID-19 and flu, a perfect storm.","volume":"368","author":"Belongia","year":"2020","journal-title":"Science."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1016\/j.ajpath.2014.08.030","article-title":"The role of viral, host, and secondary bacterial factors in influenza pathogenesis.","volume":"185","author":"Kash","year":"2015","journal-title":"Am J Pathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/j.ccc.2013.06.003","article-title":"Influenza and endemic viral pneumonia.","volume":"29","author":"Ramsey","year":"2013","journal-title":"Crit Care Clin."},{"key":"B8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1001\/jama.2012.194139","article-title":"Bacterial coinfection in influenza: a grand rounds review.","volume":"309","author":"Chertow","year":"2013","journal-title":"JAMA."},{"key":"B9","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1080\/00325481.2019.1592400","article-title":"Pulmonary complications of influenza infection: a targeted narrative review.","volume":"131","author":"Daoud","year":"2019","journal-title":"Postgrad Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.cell.2008.02.043","article-title":"Identification of oxidative stress and Toll-Like receptor 4 signaling as a key pathway of acute lung injury.","volume":"133","author":"Imai","year":"2008","journal-title":"Cell."},{"key":"B11","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2009.02.006","article-title":"The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.","volume":"30","author":"Thomas","year":"2009","journal-title":"Immunity."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4864","article-title":"Pathogenic potential of interferon alphabeta in acute influenza infection.","volume":"5","author":"Davidson","year":"2014","journal-title":"Nat Commun."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005572","article-title":"Influenza virus affects intestinal microbiota and secondary Salmonella infection in the gut through type I interferons.","volume":"12","author":"Deriu","year":"2016","journal-title":"PLoS Pathog."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00182","article-title":"Respiratory disease following viral lung infection alters the murine gut microbiota.","volume":"9","author":"Groves","year":"2018","journal-title":"Front Immunol."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-017-0386-z","article-title":"Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis.","volume":"6","author":"Yildiz","year":"2018","journal-title":"Microbiome."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01551","article-title":"The commensal microbiota and viral infection: a comprehensive review.","volume":"10","author":"Li","year":"2019","journal-title":"Front Immunol."},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1038\/srep26192","article-title":"HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases.","volume":"6","author":"Serrano-Villar","year":"2016","journal-title":"Sci Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1142\/S0192415X20500779","article-title":"Herbal medicine treatment for influenza: a systematic review and meta-analysis of randomized controlled trials.","volume":"48","author":"Choi","year":"2020","journal-title":"Am J Chin Med."},{"key":"B19","first-page":"885","article-title":"Review of mechanism research on anti-influenza virus effects of compound TCM formulas.","volume":"55","author":"Kou","year":"2014","journal-title":"J Tradit Chin Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.phrs.2019.02.024","article-title":"Gut microbiota, a new frontier to understand traditional Chinese medicines.","volume":"142","author":"Feng","year":"2019","journal-title":"Pharmacol Res."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104453","article-title":"Gut microbiota modulation with traditional Chinese medicine: a system biology-driven approach.","volume":"148","author":"Yue","year":"2019","journal-title":"Pharmacol Res."},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2020.104824","article-title":"The interactions between gut microbiota and bioactive ingredients of traditional Chinese medicines: a review.","volume":"157","author":"Gong","year":"2020","journal-title":"Pharmacol Res."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.111047","article-title":"Gut microbiota as a target to limit toxic effects of traditional Chinese medicine: implications for therapy.","volume":"133","author":"Feng","year":"2021","journal-title":"Biomed Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1142\/S0192415X21500130","article-title":"Intestinal flora: a pivotal role in investigation of traditional chinese medicine.","volume":"49","author":"Li","year":"2021","journal-title":"Am J Chin Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.intimp.2015.05.005","article-title":"Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro.","volume":"27","author":"Tao","year":"2015","journal-title":"Int Immunopharmacol."},{"key":"B26","first-page":"966","article-title":"Antiviral effects of the combination of glycyrrhizin and ribavirin against influenza A H1N1 virus infection in vivo.","volume":"50","author":"Chen","year":"2015","journal-title":"Acta Pharm Sin."},{"key":"B27","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1007\/s12272-016-0775-z","article-title":"Protective effects of phillyrin against influenza A virus in vivo.","volume":"39","author":"Qu","year":"2016","journal-title":"Arch Pharm Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.phymed.2018.12.009","article-title":"In vivo effect of quantified flavonoids-enriched extract of Scutellaria baicalensis root on acute lung injury induced by influenza A virus.","volume":"57","author":"Zhi","year":"2019","journal-title":"Phytomedicine."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/v12040373","article-title":"Antiviral effects of menthol on coxsackievirus B.","volume":"12","author":"Taylor","year":"2020","journal-title":"Viruses."},{"key":"B30","author":"Xu","year":"1982","journal-title":"Experimental Methodology of Pharmacology."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.813818","article-title":"Antifungal mechanisms of a Chinese Herbal Medicine, Cao Huang Gui Xiang, against candida species.","volume":"13","author":"Yue","year":"2022","journal-title":"Front Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1093\/aje\/kwm375","article-title":"Time lines of infection and disease in human influenza: a review of volunteer challenge studies.","volume":"167","author":"Carrat","year":"2008","journal-title":"Am J Epidemiol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i6258","article-title":"Influenza.","volume":"355","author":"Ghebrehewet","year":"2016","journal-title":"BMJ."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/82_2019_190","article-title":"ZBP1\/DAI-Dependent cell death pathways in Influenza A virus immunity and pathogenesis.","author":"Thomas","year":"2020","journal-title":"Curr Top Microbiol Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1007\/s00281-017-0636-y","article-title":"New fronts emerge in the influenza cytokine storm.","volume":"39","author":"Guo","year":"2017","journal-title":"Semin Immunopathol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/cmi.2015.74","article-title":"The cytokine storm of severe influenza and development of immunomodulatory therapy.","volume":"13","author":"Liu","year":"2016","journal-title":"Cell Mol Immunol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111998","article-title":"The mechanisms and clinical application of traditional Chinese medicine Lianhua-Qingwen capsule.","volume":"142","author":"Shen","year":"2021","journal-title":"Biomed Pharmacother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/S1875-5364(16)30095-4","article-title":"Screening and evaluation of commonly-used anti-influenza Chinese herbal medicines based on anti-neuraminidase activity.","volume":"14","author":"Han","year":"2016","journal-title":"Chin J Nat Med."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112097","article-title":"Evaluation of potential herb-drug interactions between oseltamivir and commonly used anti-influenza Chinese medicinal herbs.","volume":"243","author":"Zhang","year":"2019","journal-title":"J Ethnopharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3269","DOI":"10.1007\/s00705-014-2192-2","article-title":"Antiviral activity of baicalin against influenza A (H1N1\/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase.","volume":"159","author":"Ding","year":"2014","journal-title":"Arch Virol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3892\/br.2014.253","article-title":"Baicalin inhibits TLR7\/MYD88 signaling pathway activation to suppress lung inflammation in mice infected with influenza A virus.","volume":"2","author":"Wan","year":"2014","journal-title":"Biomed Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1007\/s12272-018-1022-6","article-title":"The inhibitory effect of sodium baicalin on oseltamivir-resistant influenza A virus via reduction of neuraminidase activity.","volume":"41","author":"Jin","year":"2018","journal-title":"Arch Pharm Res."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/4923062","article-title":"Baicalin downregulates RLRs signaling pathway to control Influenza A virus infection and improve the prognosis.","volume":"2018","author":"Pang","year":"2018","journal-title":"Evid Based Complement Alternat Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.3892\/mmr.2019.10743","article-title":"Baicalin inhibits influenza virus A replication via activation of type I IFN signaling by reducing miR146a.","volume":"20","author":"Li","year":"2019","journal-title":"Mol Med Rep."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.596166","article-title":"Viral infections, the microbiome, and probiotics.","volume":"10","author":"Harper","year":"2020","journal-title":"Front Cell Infect Microbiol."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-019-2539-x","article-title":"Influenza virus-related critical illness: pathophysiology and epidemiology.","volume":"23","author":"Kalil","year":"2019","journal-title":"Crit Care."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12966","article-title":"The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases.","volume":"20","author":"Dumas","year":"2018","journal-title":"Cell Microbiol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184976","article-title":"Lactobacillus paracasei feeding improves immune control of influenza infection in mice.","volume":"12","author":"Belkacem","year":"2017","journal-title":"PLoS One."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1080\/21645515.2015.1009805","article-title":"Dysbiosis of gut microbiota induced the disorder of helper T cells in influenza virus-infected mice.","volume":"11","author":"Yu","year":"2015","journal-title":"Hum Vaccin Immunother."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111896","article-title":"GeGen QinLian decoction alleviate influenza virus infectious Pneumonia through intestinal flora.","volume":"141","author":"Deng","year":"2021","journal-title":"Biomed Pharmacother."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0924-8579(99)00164-8","article-title":"Bacteroides, Prevotella, and Porphyromonas species: a review of antibiotic resistance and therapeutic options.","volume":"15","author":"Falagas","year":"2000","journal-title":"Int J Antimicrob Agents."},{"key":"B52","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.chom.2013.08.006","article-title":"Alterations in the gut microbiota associated with HIV-1 infection.","volume":"14","author":"Lozupone","year":"2013","journal-title":"Cell Host Microbe."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2021.151472","article-title":"Modulation of inflammatory responses by gastrointestinal Prevotella spp. \u2013 from associations to functional studies.","volume":"311","author":"Iljazovic","year":"2021","journal-title":"Int J Med Microbiol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1111\/imm.12760","article-title":"The immune response to Prevotella bacteria in chronic inflammatory disease.","volume":"151","author":"Larsen","year":"2017","journal-title":"Immunology."},{"key":"B55","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.ebiom.2018.06.019","article-title":"Fatty acid metabolism is associated with disease severity after H7N9 infection.","volume":"33","author":"Sun","year":"2018","journal-title":"EBioMedicine."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/srep26076","article-title":"Metabolomics investigation reveals metabolite mediators associated with acute lung injury and repair in a murine model of influenza Pneumonia.","volume":"6","author":"Cui","year":"2016","journal-title":"Sci Rep."},{"key":"B57","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.talanta.2010.09.019","article-title":"GC\/MS-based metabolomics reveals fatty acid biosynthesis and cholesterol metabolism in cell lines infected with influenza A virus.","volume":"83","author":"Lin","year":"2010","journal-title":"Talanta."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1016\/j.celrep.2020.02.013","article-title":"Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered Short-Chain fatty acid production.","volume":"30","author":"Sencio","year":"2020","journal-title":"Cell Rep."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2021.114207","article-title":"Mechanisms of traditional Chinese medicine in modulating gut microbiota metabolites-mediated lipid metabolism.","volume":"278","author":"Li","year":"2021","journal-title":"J Ethnopharmacol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1032127\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T07:14:47Z","timestamp":1665731687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.1032127\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":59,"alternative-id":["10.3389\/fmed.2022.1032127"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.1032127","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]},"article-number":"1032127"}}