{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T16:45:46Z","timestamp":1780591546455,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST)"},{"name":"University of Palermo"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Probiotics are live microorganisms that yield health benefits when consumed, generally by improving or restoring the intestinal flora (microbiota) as part of the muco-microbiotic layer of the bowel. In this work, mice were fed with ethanol alone or in combination with the probiotic Lactobacillus fermentum (L. fermentum) for 12 weeks. The modulation of the NF-\u03baB signaling pathway with the induction of Hsp60, Hsp90, and IkB-\u03b1 by the probiotic occurred in the jejunum. L. fermentum inhibited IL-6 expression and downregulated TNF-\u03b1 transcription. NF-\u03baB inactivation concurred with the restoration of the intestinal barrier, which had been damaged by ethanol, via the production of tight junction proteins, ameliorating the ethanol-induced intestinal permeability. The beneficial effect of the probiotic on the intestine was repeated for the cerebellum, in which downregulation of glial inflammation-related markers was observed in the probiotic-fed mice. The data show that L. fermentum exerted anti-inflammatory and cytoprotective effects in both the small intestine and the cerebellum, by suppressing ethanol-induced increased intestinal permeability and curbing neuroinflammation. The results also suggest that L. fermentum could be advantageous, along with the other available means, for treating intestinal diseases caused by stressors associated with inflammation and dysbiosis.<\/jats:p>","DOI":"10.3390\/biology12111394","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T02:05:07Z","timestamp":1698890707000},"page":"1394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["NF-kB Regulation and the Chaperone System Mediate Restorative Effects of the Probiotic Lactobacillus fermentum LF31 in the Small Intestine and Cerebellum of Mice with Ethanol-Induced Damage"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8037-7761","authenticated-orcid":false,"given":"Letizia","family":"Paladino","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"},{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-5268","authenticated-orcid":false,"given":"Francesca","family":"Rappa","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"},{"name":"Institute of Translational Pharmacology (IFT), Italy National Research Council of Italy (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6491-3640","authenticated-orcid":false,"given":"Rosario","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Macaluso","sequence":"additional","affiliation":[{"name":"Department of SMART Engineering Solutions & Technologies, eCampus University, 22060 Novedrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-8574","authenticated-orcid":false,"given":"Francesco Paolo","family":"Zummo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"David","sequence":"additional","affiliation":[{"name":"Department Surgical, Oncological and Oral Sciences, School of Medicine, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5281-1516","authenticated-orcid":false,"given":"Marta Anna","family":"Szychlinska","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, UKE-Kore University of Enna, Cittadella Universitaria, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Bucchieri","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Everly","family":"Conway de Macario","sequence":"additional","affiliation":[{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy"},{"name":"Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6181-2876","authenticated-orcid":false,"given":"Alberto J. 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Cell. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"604179","DOI":"10.3389\/fimmu.2020.604179","article-title":"The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology","volume":"11","author":"Rutsch","year":"2020","journal-title":"Front Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7792","DOI":"10.3390\/ijms23147792","article-title":"The Chaperone System in Breast Cancer: Roles and Therapeutic Prospects of the Molecular Chaperones Hsp27, Hsp60, Hsp70, and Hsp90","volume":"23","author":"Alberti","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.3390\/app9204324","article-title":"Quantitative Immunomorphological Analysis of Heat Shock Proteins in Thyroid Follicular Adenoma and Carcinoma Tissues Reveals Their Potential for Differential Diagnosis and Points to a Role in Carcinogenesis","volume":"9","author":"Pitruzzella","year":"2019","journal-title":"Appl. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s12192-016-0721-5","article-title":"Quantitative patterns of Hsps in tubular adenoma compared with normal and tumor tissues reveal the value of Hsp10 and Hsp60 in early diagnosis of large bowel cancer","volume":"21","author":"Rappa","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3390\/nu10060683","article-title":"Dietary nutrients and bioactive substances modulate heat shock protein (HSP) expression: A Review","volume":"10","author":"Moura","year":"2018","journal-title":"Nutrients"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"C1018","DOI":"10.1152\/ajpcell.00131.2005","article-title":"Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells","volume":"290","author":"Tao","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_9","first-page":"163","article-title":"Alcohol and gut-derived inflammation","volume":"38","author":"Bishehsari","year":"2017","journal-title":"Alcohol Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1080\/10408398.2019.1688250","article-title":"Lactobacillus fermentum: A bacterial species with potential for food preservation and biomedical applications","volume":"60","author":"Naghmouchi","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.3390\/nu12010124","article-title":"Effects of Probiotics on Metabolic Syndrome: A Systematic Review of Randomized Clinical Trials","volume":"12","author":"Gil","year":"2020","journal-title":"Nutrients"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"He, M., and Shi, B. (2017). Gut microbiota as a potential target of metabolic syndrome: The role of probiotics and prebiotics. Cell Biosci., 7.","DOI":"10.1186\/s13578-017-0183-1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00384-005-0773-y","article-title":"Lactobacillus fermentum, a probiotic capable to release glutathione, prevents colonic inflammation in the TNBS model of rat colitis","volume":"21","author":"Peran","year":"2006","journal-title":"Int. J. Color. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e138","DOI":"10.1038\/ctg.2015.66","article-title":"Alcoholic liver disease: A mouse model reveals protection by Lactobacillus fermentum","volume":"7","author":"Barone","year":"2016","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Carr, R.M., Peralta, G., Yin, X., and Ahima, R.S. (2014). Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097118"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/acer.12075","article-title":"Temporal effects of ethanol consumption on energy homeostasis, hepatic steatosis, and insulin sensitivity in mice","volume":"37","author":"Carr","year":"2013","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_17","first-page":"e21328","article-title":"Sex-based differences after a single bout of exercise on PGC1\u03b1 isoforms in skeletal muscle: A pilot study","volume":"35","author":"Macaluso","year":"2021","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1093\/alcalc\/agw098","article-title":"The Role of NF\u03baB in Drug Addiction: Beyond Inflammation","volume":"52","author":"Nennig","year":"2017","journal-title":"Alcohol Alcohol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9407","DOI":"10.3390\/ijms21249407","article-title":"The impact of acute or chronic alcohol intake on the NF-\u03baB signaling pathway in alcohol-related liver disease","volume":"21","author":"Nowak","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41467-019-08581-8","article-title":"Intestinal non-canonical NF\u03baB signaling shapes the local and systemic immune response","volume":"10","author":"Ramakrishnan","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1136\/gutjnl-2015-310585","article-title":"Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease","volume":"65","author":"Llopis","year":"2016","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/j.ajpath.2013.09.001","article-title":"TNF-\u03b1 modulation of intestinal epithelial tight junction barrier is regulated by ERK1\/2 activation of Elk-1","volume":"183","author":"Guo","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ruder, B., Atreya, R., and Becker, C. (2019). Tumour necrosis factor alpha in intestinal homeostasis and gut related diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081887"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1186\/s12974-018-1328-9","article-title":"Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression","volume":"15","author":"Lowe","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/hep.23009","article-title":"Endotoxemia and gut barrier dysfunction in alcoholic liver disease","volume":"50","author":"Rao","year":"2009","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E4485","DOI":"10.1073\/pnas.1415174111","article-title":"Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity","volume":"111","author":"Leclercq","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.alcohol.2018.08.009","article-title":"Comparative study on the effects of cigarette smoke exposure, ethanol consumption and association: Behavioral parameters, apoptosis, glial fibrillary acid protein and S100\u03b2 immunoreactivity in different regions of the rat hippocampus","volume":"77","author":"Huf","year":"2019","journal-title":"Alcohol"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"132","DOI":"10.5114\/fn.2017.68580","article-title":"Neuronal vacuolation and spinocerebellar degeneration associated with altered neurotransmission","volume":"55","author":"Giannakopoulou","year":"2017","journal-title":"Folia Neuropathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fnmol.2018.00078","article-title":"Molecular neuropathology of astrocytes and oligodendrocytes in alcohol use disorders","volume":"11","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1744-313X.2008.00819.x","article-title":"A comparative analysis of the products of GROEL-1 gene from Chlamydia trachomatis serovar D and the HSP60 var1 transcript from Homo sapiens suggests a possible autoimmune response","volume":"36","author":"Campanella","year":"2009","journal-title":"Int. J. Immunogenet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Scalia, F., Marino Gammazza, A., Conway de Macario, E., Macario, A.J.L., and Cappello, F. (2019). Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy. Brain Sci., 9.","DOI":"10.3390\/brainsci9110297"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/S0016-5085(03)00215-4","article-title":"Enteric flora and lymphocyte-derived cytokines determine expression of heat shock proteins in mouse colonic epithelial cells","volume":"124","author":"Kojima","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1053\/j.gastro.2004.09.001","article-title":"Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition","volume":"127","author":"Petrof","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"148","DOI":"10.4161\/gmic.1.3.11712","article-title":"Probiotics-host communication: Modulation of signaling pathways in the intestine","volume":"1","author":"Thomas","year":"2010","journal-title":"Gut Microbes."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, Y., Wu, Y., Wang, Y., Xu, H., Mei, X., Yu, D., Wang, Y., and Li, W. (2017). Antioxidant properties of probiotic bacteria. Nutrients, 9.","DOI":"10.3390\/nu9050521"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1002\/ibd.20930","article-title":"Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-\u03baB pathways and inhibits proteasome function","volume":"15","author":"Petrof","year":"2009","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm2083","article-title":"Integrating cell-signalling pathways with NF-\u03baB and IKK function","volume":"8","author":"Perkins","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1517\/14728220903431069","article-title":"The NF-\u03baB activation pathways, emerging molecular targets for cancer prevention and therapy","volume":"14","author":"Lin","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lawrence, T. (2009). The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb. Perspect. Biol., 1.","DOI":"10.1101\/cshperspect.a001651"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41392-020-00312-6","article-title":"Targeting NF-\u03baB pathway for the therapy of diseases: Mechanism and clinical study","volume":"5","author":"Yu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2008.01.020","article-title":"Shared principles in NF-\u03baB signaling","volume":"132","author":"Hayden","year":"2008","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.freeradbiomed.2009.07.033","article-title":"Lactobacillus rhamnosus blocks inflammatory signaling in vivo via reactive oxygen species generation","volume":"47","author":"Lin","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1128\/IAI.72.9.5308-5314.2004","article-title":"Live Lactobacillus rhamnosus [corrected] is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression","volume":"72","author":"Ma","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1093\/jn\/135.7.1752","article-title":"Alive and dead Lactobacillus rhamnosus GG decrease tumor necrosis factor-alpha-induced interleukin-8 production in Caco-2 cells","volume":"135","author":"Zhang","year":"2005","journal-title":"J. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1136\/gut.52.7.988","article-title":"Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC)","volume":"52","author":"Barrett","year":"2003","journal-title":"Gut"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Plaza-D\u00edaz, J., Ruiz-Ojeda, F.J., Vilchez-Padial, L.M., and Gil, A. (2017). Evidence of the Anti-Inflammatory Effects of Probiotics and Synbiotics in Intestinal Chronic Diseases. Nutrients, 9.","DOI":"10.3390\/nu9060555"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Phillippi, D.T., Daniel, S., Nguyen, K.N., Penaredondo, B.A., and Lund, A.K. (2022). Probiotics Function as Immunomodulators in the Intestine in C57Bl\/6 Male Mice Exposed to Inhaled Diesel Exhaust Particles on a High-Fat Diet. 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