{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:33:44Z","timestamp":1790102024957,"version":"4.0.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by continuous mucosal inflammation of the colon and rectum. The global prevalence of UC has been rising steadily, and accumulating evidence suggests a potential association between proton pump inhibitor (PPIs) use and UC development. Nevertheless, the precise role of PPIs in the pathogenesis and clinical course of UC remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The C57BL\/6J mice were administered saline, omeprazole (OME) and dextran sulfate sodium to establish control, PPIs-treated and UC models, respectively. The fecal samples were subjected to high-throughput sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene. Taxonomic annotation was performed using Mothur software to evaluate microbial diversity and abundance. Principal coordinate analysis, linear discriminant analysis effect size, and functional enrichment analyses were also conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Alpha and beta diversity analyses showed that the richness and diversity of the gut microbiota in the PPI and UC groups were significantly lower than those in the control group (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05). At the family and genus levels, the UC group was dominated by\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      , while the PPIs group exhibited enrichment of\n                      <jats:italic>Eisenbergiella<\/jats:italic>\n                      and\n                      <jats:italic>Prevotella<\/jats:italic>\n                      . Furthermore, functional enrichment analysis demonstrated that the gut microbiota in the PPI group was predominantly enriched in functions related to cell wall and membrane structure biogenesis, whereas the UC group was enriched in energy metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Long-term PPI exposure profoundly alters the gut microbiota, characterized by reduced microbial diversity and enrichment of pro-inflammatory taxa. These findings highlight the contribution of PPIs to gut microbiota dysbiosis and UC pathogenesis, emphasizing the need for further research on microbiota\u2013immunity interactions and for the development of targeted strategies to mitigate PPI-related adverse effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2025.1657865","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T10:24:27Z","timestamp":1761819867000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Proton pump inhibitors and gut microbiota dysbiosis: insights into the pathogenesis of ulcerative colitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Feng","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunsheng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1136\/gutjnl-2021-325096","article-title":"Proton pump inhibitors and risk of colorectal cancer","volume":"71","author":"Abrahami","year":"2022","journal-title":"Gut"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3390\/antibiotics13010030","article-title":"Anti-Salmonella defence and intestinal homeostatic maintenance in vitro of a consortium containing Limosilactobacillus fermentum 3872 and Ligilactobacillus salivarius 7247 strains in human, porcine, and chicken enterocytes","volume":"13","author":"Abramov","year":"2023","journal-title":"Antibiotics (Basel)"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e1385","DOI":"10.1002\/mbo3.1385","article-title":"Relationship between the rod complex and peptidoglycan structure in Escherichia coli","volume":"12","author":"Ago","year":"2023","journal-title":"Microbiology"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1111\/apm.12814","article-title":"The role of bacteria in the inflammatory bowel disease development: a narrative review","volume":"126","author":"Azimi","year":"2018","journal-title":"APMIS"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1471-2172-11-39","article-title":"Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species","volume":"11","author":"Barnett","year":"2010","journal-title":"BMC Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1002\/hep.29822","article-title":"Proton pump inhibitors, Enterococcus, and the liver, oh my!","volume":"68","author":"Carr","year":"2018","journal-title":"Hepatology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.amjmed.2021.09.010","article-title":"Indications for the use of proton pump inhibitors for stress ulcer prophylaxis and peptic ulcer bleeding in hospitalized patients","volume":"135","author":"Clarke","year":"2022","journal-title":"Am. J. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1007\/s12664-023-01430-z","article-title":"Trends of inflammatory bowel disease from the global burden of disease study (1990-2019)","volume":"43","author":"Dharni","year":"2024","journal-title":"Indian J. Gastroenterol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"4470","DOI":"10.1021\/acs.biochem.0c00755","article-title":"Enterococcus NlpC\/p60 peptidoglycan hydrolase SagA localizes to sites of cell division and requires only a catalytic dyad for protease activity","volume":"59","author":"Espinosa","year":"2020","journal-title":"Biochemistry"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1053\/j.gastro.2017.01.031","article-title":"The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association","volume":"152","author":"Freedberg","year":"2017","journal-title":"Gastroenterology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1007\/s00384-014-1850-x","article-title":"NOD2 gene mutations in ulcerative colitis: useless or misunderstood?","volume":"29","author":"Freire","year":"2014","journal-title":"Int. J. Color. Dis."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1016\/j.chom.2022.08.002","article-title":"Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway","volume":"30","author":"Gao","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1126\/science.abc9113","article-title":"Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy","volume":"373","author":"Griffin","year":"2021","journal-title":"Science"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/s41416-021-01606-4","article-title":"Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150","volume":"126","author":"Hopkins","year":"2022","journal-title":"Br. J. 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Proteins"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"107224","DOI":"10.1016\/j.intimp.2020.107224","article-title":"Paeoniflorin ameliorates experimental colitis by inhibiting gram-positive bacteria-dependent MDP-NOD2 pathway","volume":"90","author":"Luo","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1111\/apt.15604","article-title":"Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract-evidence from next-generation sequencing studies","volume":"51","author":"Macke","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"781","DOI":"10.3390\/pathogens11070781","article-title":"Gut microbiota composition associated with Clostridioides difficile colonization and infection","volume":"11","author":"Martinez","year":"2022","journal-title":"Pathogens"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1159\/000481813","article-title":"Intestinal dysbiosis secondary to proton-pump inhibitor use","volume":"97","author":"Naito","year":"2018","journal-title":"Digestion"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1126\/science.6387911","article-title":"Shiga-like toxin-converting phages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea","volume":"226","author":"O'Brien","year":"1984","journal-title":"Science"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e1004911","DOI":"10.1371\/journal.ppat.1004911","article-title":"Surface-associated lipoproteins link Enterococcus faecalis virulence to colitogenic activity in IL-10-deficient mice independent of their expression levels","volume":"11","author":"Ocvirk","year":"2015","journal-title":"PLoS Pathog."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"146","DOI":"10.3164\/jcbn.23-87","article-title":"Crosstalk between NOD2 and TLR2 suppresses the development of TLR2-mediated experimental colitis","volume":"74","author":"Okai","year":"2024","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1126\/science.aaf3552","article-title":"A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens","volume":"353","author":"Rangan","year":"2016","journal-title":"Science"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1186\/s13059-019-1879-9","article-title":"Gut-derived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host","volume":"20","author":"Seishima","year":"2019","journal-title":"Genome Biol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1159\/000455008","article-title":"Gastric acid suppression is associated with an increased risk of adverse outcomes in inflammatory bowel disease","volume":"95","author":"Shah","year":"2017","journal-title":"Digestion"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1093\/ibd\/izad017","article-title":"Proton pump inhibitor use before and after a diagnosis of inflammatory bowel disease","volume":"29","author":"Singh","year":"2023","journal-title":"Inflamm. Bowel Dis."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1053\/j.gastro.2011.05.035","article-title":"Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation","volume":"141","author":"Steck","year":"2011","journal-title":"Gastroenterology"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e13841","DOI":"10.1111\/nmo.13841","article-title":"Proton pump inhibitors enhance intestinal permeability via dysbiosis of gut microbiota under stressed conditions in mice","volume":"32","author":"Takashima","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"5033","DOI":"10.1128\/IAI.71.9.5033-5041.2003","article-title":"An Enterococcus faecium secreted antigen, SagA, exhibits broad-spectrum binding to extracellular matrix proteins and appears essential for E. faecium growth","volume":"71","author":"Teng","year":"2003","journal-title":"Infect. Immun."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.devcel.2021.12.016","article-title":"Bacterial peptidoglycan muropeptides benefit mitochondrial homeostasis and animal physiology by acting as ATP synthase agonists","volume":"57","author":"Tian","year":"2022","journal-title":"Dev. 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