{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:15:54Z","timestamp":1790403354894,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T00:00:00Z","timestamp":1577059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The resistance of Candida albicans to conventional drug treatments, as well as the recurrence phenomena due to dysbiosis caused by antifungal treatments, have highlighted the need to implement new therapeutic methodologies. The antifungal potential of live biotherapeutic products (LBP) has already been demonstrated using preclinical models (cell cultures, laboratory animals). Understanding their mechanisms of action is strategic for the development of new therapeutics for humans. In this study, we investigated the curative anti-C. albicans properties of Lactobacillus rhamnosus Lcr35\u00ae using the in vitro Caco-2 cell and the in vivo Caenorhabditis elegans models. We showed that Lcr35\u00ae does inhibit neither the growth (p = 0.603) nor the biofilm formation (p = 0.869) of C. albicans in vitro. Lcr35\u00ae protects the animal from the fungal infection (+225% of survival, p &lt; 2 \u00d7 10\u201316) even if the yeast is detectable in its intestine. In contrast, the Lcr35\u00ae cell-free supernatant does not appear to have any antipathogenic effect. At the mechanistic level, the DAF-16\/Forkhead Box O transcription factor is activated by Lcr35\u00ae and genes of the p38 MAP Kinase signaling pathway and genes involved in the antifungal response are upregulated in presence of Lcr35\u00ae after C. albicans infection. These results suggest that the LBM strain acts by stimulating its host via DAF-16 and the p38 MAPK pathway.<\/jats:p>","DOI":"10.3390\/microorganisms8010034","type":"journal-article","created":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T05:56:15Z","timestamp":1577166975000},"page":"34","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Curative Treatment of Candidiasis by the Live Biotherapeutic Microorganism Lactobacillus rhamnosus Lcr35\u00ae in the Invertebrate Model Caenorhabditis elegans: First Mechanistic Insights"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-4390","authenticated-orcid":false,"given":"Cyril","family":"Poupet","sequence":"first","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Veisseire","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Bonnet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Camar\u00e8s","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marylise","family":"Gachinat","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Dausset","sequence":"additional","affiliation":[{"name":"Biose Industrie, 24 avenue Georges Pompidou, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Chassard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Nivoliez","sequence":"additional","affiliation":[{"name":"Biose Industrie, 24 avenue Georges Pompidou, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Bornes","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Clermont Auvergne, INRAE, VetAgro Sup, UMRF, 15000 Aurillac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of Invasive Candidiasis: A Persistent Public Health Problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Presterl, E. (2019). Clinical Syndromes: Candida and Candidosis. Clinically Relevant Mycoses, Springer.","DOI":"10.1007\/978-3-319-92300-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1086\/596757","article-title":"Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America","volume":"48","author":"Pappas","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yano, J., Sobel, J.D., Nyirjesy, P., Sobel, R., Williams, V.L., Yu, Q., Noverr, M.C., and Fidel, P.L. (2019). Current patient perspectives of vulvovaginal candidiasis: Incidence, symptoms, management and post-treatment outcomes. BMC Womens Health, 19.","DOI":"10.1186\/s12905-019-0748-8"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.mib.2011.07.015","article-title":"Inflammation and gastrointestinal Candida colonization Carol","volume":"14","author":"Kumamoto","year":"2011","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Spettel, K., Barousch, W., Makristathis, A., Zeller, I., Nehr, M., Selitsch, B., Lackner, M., Rath, P.M., Steinmann, J., and Willinger, B. (2019). Analysis of antifungal resistance genes in Candida albicans and Candida glabrata using next generation sequencing. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210397"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ajic.2009.06.014","article-title":"Comparison of costs, length of stay, and mortality associated with Candida glabrata and Candida albicans bloodstream infections","volume":"38","author":"Moran","year":"2010","journal-title":"Am. J. Infect. Control"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1128\/CMR.18.4.638-656.2005","article-title":"Antimicrobial Stewardship Programs in Health Care Systems","volume":"18","author":"Polk","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dreher-Lesnick, S.M., Stibitz, S., and Carlson, P.E. (2017). US Regulatory Considerations for Development of Live Biotherapeutic Products as Drugs. Microbiol. Spectr., 5.","DOI":"10.1128\/microbiolspec.BAD-0017-2017"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"O\u2019Toole, P.W., Marchesi, J.R., and Hill, C. (2017). Next-generation probiotics: The spectrum from probiotics to live biotherapeutics. Nat. Microbiol., 2.","DOI":"10.1038\/nmicrobiol.2017.57"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jbiotec.2012.04.005","article-title":"Influence of manufacturing processes on in vitro properties of the probiotic strain Lactobacillus rhamnosus Lcr35\u00ae","volume":"160","author":"Nivoliez","year":"2012","journal-title":"J. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Poupet, C., Saraoui, T., Veisseire, P., Bonnet, M., Dausset, C., Gachinat, M., Camar\u00e8s, O., Chassard, C., Nivoliez, A., and Bornes, S. (2019). Lactobacillus rhamnosus Lcr35 as an effective treatment for preventing Candida albicans infection in the invertebrate model Caenorhabditis elegans: First mechanistic insights. PLoS ONE, 14.","DOI":"10.1101\/612481"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Patrignani, F., Siroli, L., Parolin, C., Serrazanetti, D.I., Vitali, B., and Lanciotti, R. (2019). Use of Lactobacillus crispatus to produce a probiotic cheese as potential gender food for preventing gynaecological infections. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0208906"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/jp.2010.57","article-title":"Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: Incidence of late-onset sepsis and neurological outcome","volume":"31","author":"Romeo","year":"2011","journal-title":"J. Perinatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1097\/CCM.0b013e31826a409c","article-title":"Evaluation of Efficacy of Probiotics in Prevention of Candida Colonization in a PICU\u2014A Randomized Controlled Trial*","volume":"41","author":"Kumar","year":"2013","journal-title":"Crit. Care. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.micpath.2018.02.019","article-title":"Lactobacillus paracasei 28.4 reduces in vitro hyphae formation of Candida albicans and prevents the filamentation in an experimental model of Caenorhabditis elegans","volume":"117","author":"Scorzoni","year":"2018","journal-title":"Microb. Pathog."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.micpath.2018.11.041","article-title":"Probiotic mediated colonization resistance against E. coli infection in experimentally challenged Caenorhabditis elegans","volume":"127","author":"Sharma","year":"2019","journal-title":"Microb. Pathog."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhou, M., Liu, X., Yu, H., Yin, X., Nie, S.-P., Xie, M.-Y., Chen, W., and Gong, J. (2018). Cell Signaling of Caenorhabditis elegans in Response to Enterotoxigenic Escherichia coli Infection and Lactobacillus zeae Protection. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01745"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Schifano, E., Zinno, P., Guantario, B., Roselli, M., Marcoccia, S., Devirgiliis, C., and Uccelletti, D. (2019). The Foodborne Strain Lactobacillus fermentum MBC2 Triggers pept-1-Dependent Pro-Longevity Effects in Caenorhabditis elegans. Microorganisms, 7.","DOI":"10.3390\/microorganisms7020045"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhao, L., Zhao, Y., Liu, R., Zheng, X., Zhang, M., Guo, H., Zhang, H., and Ren, F. (2017). The transcription factor DAF-16 is essential for increased longevity in C. elegans Exposed to Bifidobacterium longum BB68. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-07974-3"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pukkila-Worley, R., Ausubel, F.M., and Mylonakis, E. (2011). Candida albicans infection of Caenorhabditis elegans induces antifungal immune defenses. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002074"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1097\/MCG.0000000000001054","article-title":"Effectiveness of Probiotics in Children with Functional Abdominal Pain Disorders and Functional Constipation A Systematic Review","volume":"52","author":"Wegh","year":"2018","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_23","first-page":"1155","article-title":"Systematic Review: Probiotics for Functional Constipation in Children","volume":"176","author":"Wojtyniak","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jpeds.2017.01.068","article-title":"Lactobacillus casei rhamnosus Lcr35 in the Management of Functional Constipation in Children: A Randomized Trial","volume":"184","author":"Wojtyniak","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1007\/s10096-018-3321-8","article-title":"Comparative phase I randomized open-label pilot clinical trial of Gynophilus\u00ae (Lcr regenerans\u00ae) immediate release capsules versus slow release muco-adhesive tablets","volume":"37","author":"Dausset","year":"2018","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/1471-0307.12286","article-title":"Adherence of probiotic bacteria to human colon epithelial cells and inhibitory effect against enteric pathogens\u2014In vitro study","volume":"69","author":"Nowak","year":"2016","journal-title":"Int. J. Dairy Technol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1111\/1751-7915.12799","article-title":"Interplay between Lactobacillus rhamnosus GG and Candida and the involvement of exopolysaccharides","volume":"10","author":"Allonsius","year":"2017","journal-title":"Microb. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Irazoqui, J.E., Troemel, E.R., Feinbaum, R.L., Luhachack, L.G., Cezairliyan, B.O., and Ausubel, F.M. (2010). Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000982"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1469-0691.2009.02765.x","article-title":"Caenorhabditis elegans as a host model for community-associated methicillin-resistant Staphylococcus aureus","volume":"16","author":"Wu","year":"2010","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Souza, A.C.R., Fuchs, B.B., Alves V de, S., Jayamani, E., Colombo, A.L., and Mylonakis, E. (2018). Pathogenesis of the Candida parapsilosis complex in the model host Caenorhabditis elegans. Genes, 9.","DOI":"10.3390\/genes9080401"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1128\/EC.00163-09","article-title":"Candida albicans hyphal formation and virulence assessed using a Caenorhabditis elegans infection model","volume":"8","author":"Peleg","year":"2009","journal-title":"Eukaryot. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Park, M.R., Ryu, S., Maburutse, B.E., Oh, N.S., Kim, S.H., Oh, S., Jeong, S.Y., Jeong, D.Y., Oh, S., and Kim, Y. (2018). Probiotic Lactobacillus fermentum strain JDFM216 stimulates the longevity and immune response of Caenorhabditis elegans through a nuclear hormone receptor. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25333-8"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1128\/IAI.06350-11","article-title":"Caenorhabditis elegans immune conditioning with the probiotic bacterium Lactobacillus acidophilus strain ncfm enhances gram-positive immune responses","volume":"80","author":"Kim","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_34","unstructured":"Dausset, C. (2015). D\u00e9termination des m\u00e9canismes d\u2019inhibition de souches de lactobacilles. Influence du proc\u00e9d\u00e9 industriel sur leurs caract\u00e9ristiques probiotiques, AgroParisTech."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4507","DOI":"10.1073\/pnas.1620432114","article-title":"Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans","volume":"114","author":"Graham","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, M., Lee, K., Hsu, M., Nau, G., Mylonakis, E., and Ramratnam, B. (2017). Lactobacillus-derived extracellular vesicles enhance host immune responses against vancomycin-resistant enterococci. BMC Microbiol., 17.","DOI":"10.1186\/s12866-017-0977-7"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10522-012-9411-6","article-title":"Mechanism underlying prolongevity induced by bifidobacteria in Caenorhabditis elegans","volume":"14","author":"Komura","year":"2013","journal-title":"Biogerontology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35580","DOI":"10.1074\/jbc.M109.060905","article-title":"Regulation of DAF-16-mediated Innate Immunity in Caenorhabditis elegans","volume":"284","author":"Singh","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_39","first-page":"323","article-title":"Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture","volume":"47","author":"Pinto","year":"1983","journal-title":"Biol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hellemans, J., Mortier, G., De Paepe, A., Speleman, F., and Vandesompele, J. (2007). qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome. Biol., 8.","DOI":"10.1186\/gb-2007-8-2-r19"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nmeth.1495","article-title":"Rapid selection of transgenic C. elegans using antibiotic resistance","volume":"7","author":"Semple","year":"2010","journal-title":"Nat. Methods."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hoogewijs, D., Houthoofd, K., Matthijssens, F., Vandesompele, J., and Vanfleteren, J.R. (2008). Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans. BMC Mol. Biol., 9.","DOI":"10.1186\/1471-2199-9-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/acel.12431","article-title":"Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans","volume":"15","author":"Nakagawa","year":"2016","journal-title":"Aging Cell"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Fatima, S., Haque, R., Jadiya, P., Shamsuzzama Kumar, L., and Nazir, A. (2014). Ida-1, the Caenorhabditis elegans orthologue of mammalian diabetes autoantigen IA-2, potentially acts as a common modulator between Parkinson\u2019s disease and diabetes: Role of Daf-2\/Daf-16 insulin like signalling pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0113986"},{"key":"ref_46","unstructured":"R Core Team (2018). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_47","unstructured":"Therneau, T.M. (2019, September 10). A Package for Survival Analysis in R. Available online: https:\/\/github.com\/therneau\/survival."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kassambara, A., and Kosinski, M. (2019, September 10). Survminer: Drawing Survival Curves using \u201cggplot2.\u201d 2017. Available online: http:\/\/www.sthda.com\/english\/rpkgs\/survminer\/.","DOI":"10.32614\/CRAN.package.survminer"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/1\/34\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:44:57Z","timestamp":1760190297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/1\/34"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,23]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["microorganisms8010034"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms8010034","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,23]]}}}