{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:02:57Z","timestamp":1792789377442,"version":"4.5.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T00:00:00Z","timestamp":1717459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Donato-Venturi","award":["2023"],"award-info":[{"award-number":["2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intestinal epithelium renewal strictly depends on fine regulation between cell proliferation, differentiation, and apoptosis. While murine intestinal microbiota has been shown to modify some epithelial cell kinetics parameters, less is known about the role of the human intestinal microbiota. Here, we investigated the rate of intestinal cell proliferation in C3H\/HeN germ-free mice associated with human flora (HFA, n = 8), and in germ-free (n = 15) and holoxenic mice (n = 16). One hour before sacrifice, all mice were intraperitoneally inoculated with 5-bromodeoxyuridine (BrdU), and the number of BrdU-positive cells\/total cells (labelling index, LI), both in the jejunum and the colon, was evaluated by immunohistochemistry. Samples were also observed by scanning electron microscopy (SEM). Moreover, the microbiota composition in the large bowel of the HFA mice was compared to that of of human donor\u2019s fecal sample. No differences in LI were found in the small bowels of the HFA, holoxenic, and germ-free mice. Conversely, the LI in the large bowel of the HFA mice was significantly higher than that in the germ-free and holoxenic counterparts (p = 0.017 and p = 0.048, respectively). In the holoxenic and HFA mice, the SEM analysis disclosed different types of bacteria in close contact with the intestinal epithelium. Finally, the colonic microbiota composition of the HFA mice widely overlapped with that of the human donor in terms of dominant populations, although Bifidobacteria and Lactobacilli disappeared. Despite the small sample size analyzed in this study, these preliminary findings suggest that human intestinal microbiota may promote a high proliferation rate of colonic mucosa. In light of the well-known role of uncontrolled proliferation in colorectal carcinogenesis, these results may deserve further investigation in a larger population study.<\/jats:p>","DOI":"10.3390\/ijms25116182","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T05:17:30Z","timestamp":1717478250000},"page":"6182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intestinal Microbiota Increases Cell Proliferation of Colonic Mucosa in Human-Flora-Associated (HFA) Mice"],"prefix":"10.3390","volume":"25","author":[{"given":"Giovanni","family":"Brandi","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy"},{"name":"Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-9698","authenticated-orcid":false,"given":"Simona","family":"Tavolari","sequence":"additional","affiliation":[{"name":"Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Bridonneau","sequence":"additional","affiliation":[{"name":"INRAe, AgroParisTech, Micalis Institute, Universit\u00e9 Paris-Saclay, 78350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Raibaud","sequence":"additional","affiliation":[{"name":"INRAe, AgroParisTech, Micalis Institute, Universit\u00e9 Paris-Saclay, 78350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Liguori","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-3274","authenticated-orcid":false,"given":"Muriel","family":"Thomas","sequence":"additional","affiliation":[{"name":"INRAe, AgroParisTech, Micalis Institute, Universit\u00e9 Paris-Saclay, 78350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Di Battista","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Gaboriau-Routhiau","sequence":"additional","affiliation":[{"name":"INRAe, AgroParisTech, Micalis Institute, Universit\u00e9 Paris-Saclay, 78350 Jouy-en-Josas, France"},{"name":"Laboratory of Intestinal Immunity, Imagine Institute, INSERM UMR1163, Universit\u00e9 Paris Cit\u00e9, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Langella","sequence":"additional","affiliation":[{"name":"INRAe, AgroParisTech, Micalis Institute, Universit\u00e9 Paris-Saclay, 78350 Jouy-en-Josas, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/nrc3744","article-title":"Stem cell dynamics in homeostasis and cancer of the intestine","volume":"14","author":"Vermeulen","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1080\/10408398.2012.732126","article-title":"Effects of dietary components on cancer of the diges-tive system","volume":"55","author":"Zanini","year":"2015","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_3","first-page":"234","article-title":"Reversing the Warburg effect to control cancer: A review of di-et-based solutions","volume":"2","author":"Bahrami","year":"2022","journal-title":"J. Curr. Oncol. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Clemente-Su\u00e1rez, V.J., Beltr\u00e1n-Velasco, A.I., Redondo-Fl\u00f3rez, L., Mart\u00edn-Rodr\u00edguez, A., and Tornero-Aguilera, J.F. (2023). Global Impacts of Western Diet and Its Effects on Metabolism and Health: A Narrative Review. Nutrients, 15.","DOI":"10.3390\/nu15122749"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrmicro3552","article-title":"Gut biogeography of the bacterial microbiota","volume":"14","author":"Donaldson","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature23889","article-title":"Strains, functions and dynamics in the expanded Human Microbiome Project","volume":"550","author":"Mahurkar","year":"2017","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6ra14","DOI":"10.1126\/scitranslmed.3000322","article-title":"The effect of diet on the human gut micro-biome: A metagenomic analysis in humanized gnotobiotic mice","volume":"1","author":"Turnbaugh","year":"2009","journal-title":"Sci. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature12820","article-title":"Diet rapidly and reproducibly alters the human gut micro-biome","volume":"505","author":"David","year":"2014","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8787","DOI":"10.3748\/wjg.v21.i29.8787","article-title":"Role of the normal gut microbiota","volume":"21","author":"Jandhyala","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1136\/gutjnl-2015-309990","article-title":"The gut microbiota and host health: A new clinical frontier","volume":"65","author":"Marchesi","year":"2016","journal-title":"Gut"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41579-023-00973-4","article-title":"The microbial landscape of colorectal cancer","volume":"22","author":"White","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/s41575-019-0209-8","article-title":"Gut microbiota in colorectal cancer: Mechanisms of action and clinical applications","volume":"16","author":"Wong","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Afzaal, M., Saeed, F., Shah, Y.A., Hussain, M., Rabail, R., Socol, C.T., Hassoun, A., Pateiro, M., Lorenzo, J.M., and Rusu, A.V. (2022). Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.999001"},{"key":"ref_14","first-page":"69","article-title":"Human flora-associated (HFA) animals as a model for studying the role of intestinal flora in human health and disease","volume":"6","author":"Hirayama","year":"2005","journal-title":"Curr. Issues Intest. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/202884a0","article-title":"Generation cycle in the duodenal crypt cells of germ-free and conventional mice","volume":"202","author":"Lesher","year":"1964","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"G348","DOI":"10.1152\/ajpgi.00384.2009","article-title":"Microbiota matures colonic epithelium through a coordinated induction of cell cycle-related proteins in gnotobiotic rat","volume":"299","author":"Cherbuy","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.immuni.2009.08.020","article-title":"The key role of segmented filamentous bacteria in the coordi-nated maturation of gut helper T cell responses","volume":"31","author":"Rakotobe","year":"2009","journal-title":"Immunity"},{"key":"ref_18","first-page":"207","article-title":"Early proliferative changes in gastrointestinal neoplasia","volume":"77","author":"Deschner","year":"1982","journal-title":"Am. J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chen, B., Chen, H., Shu, X., Yin, Y., Li, J., Qin, J., Chen, L., Peng, K., Xu, F., and Gu, W. (2018). Presence of Segmented Filamentous Bacteria in Human Children and Its Potential Role in the Modulation of Human Gut Immunity. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.01403"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lagier, J.C., Million, M., Hugon, P., Armougom, F., and Raoult, D. (2012). Human gut microbiota: Repertoire and variations. Front. Cell Infect. Microbiol., 2.","DOI":"10.3389\/fcimb.2012.00136"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1111\/1469-0691.12023","article-title":"Microbial culturomics: Paradigm shift in the human gut microbiome study","volume":"18","author":"Lagier","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/0016-5085(87)90021-7","article-title":"Abnormal pattern of cell proliferation in the entire colonic mucosa of patients with colon adenoma or cancer","volume":"92","author":"Terpstra","year":"1987","journal-title":"Gastroenterology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/BF02054982","article-title":"Regional proliferative patterns in the colon of patients at risk for hereditary nonpolyposis colorectal cancer","volume":"40","author":"Patchett","year":"1997","journal-title":"Dis. Colon Rectum"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1007\/BF02237224","article-title":"High proliferative activity is associated with dysplasia in ulcerative colitis","volume":"43","author":"Shinozaki","year":"2000","journal-title":"Dis. Colon Rectum"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.2337\/db13-0035","article-title":"Overnutrition stimulates intestinal epithelium proliferation through \u03b2-catenin signaling in obese mice","volume":"62","author":"Mao","year":"2013","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.toxlet.2014.10.011","article-title":"Diet supplementation with cholic acid promotes intestinal epithelial proliferation in rats exposed to \u03b3-radiation","volume":"232","author":"Hagio","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/intimm\/dxae003","article-title":"A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations","volume":"36","author":"Shiratori","year":"2024","journal-title":"Int. Immunol."},{"key":"ref_28","first-page":"609","article-title":"Colorectal carcinogenesis in germ-free and conventionally reared rats: Different intestinal environments affect the systemic immunity","volume":"32","author":"Vannucci","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8727","DOI":"10.1038\/ncomms9727","article-title":"Gut mucosal microbiome across stages of colorectal carcinogenesis","volume":"6","author":"Nakatsu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1757-4749-5-2","article-title":"Diversified pattern of the human colorectal cancer microbiome","volume":"5","author":"Geng","year":"2013","journal-title":"Gut Pathog."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sommer, F., Nookaew, I., Sommer, N., Fogelstrand, P., and B\u00e4ckhed, F. (2015). Site-specific programming of the host epithelial transcriptome by the gut micro-biota. Genome Biol., 16.","DOI":"10.1186\/s13059-015-0614-4"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.chom.2010.06.006","article-title":"Bacterial interactions with the host epithelium","volume":"8","author":"Kim","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_33","first-page":"568","article-title":"Microflora of the digestive system of the rat. I. Technics of study and proposed culture media","volume":"110","author":"Raibaud","year":"1966","journal-title":"Ann. Inst. Pasteur"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41571-023-00766-x","article-title":"Gut microbiota in colorectal cancer development and therapy","volume":"20","author":"Wong","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Salvi, P.S., and Cowles, R.A. (2021). Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease. Cells, 10.","DOI":"10.3390\/cells10071775"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/mi.2012.32","article-title":"Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice","volume":"5","author":"Derrien","year":"2012","journal-title":"Mucosal Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1093\/ajcn\/33.11.2440","article-title":"Implantation of bacteria from the digestive tract of man and various animals into gnotobiotic mice","volume":"33","author":"Raibaud","year":"1980","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","unstructured":"Brandi, G., Pisi, A.M., and Biasco, G. (1996). Ultrastructure et Micro-\u00c9cologie du Canal Alimentaire, Edra Medical Publishing & New Media."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1574-6968.2004.tb09568.x","article-title":"Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces","volume":"235","author":"Lepercq","year":"2004","journal-title":"FEMS Microbiol. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:53:23Z","timestamp":1760108003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,4]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25116182"],"URL":"https:\/\/doi.org\/10.3390\/ijms25116182","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,4]]}}}