{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:26:37Z","timestamp":1791444397576,"version":"4.3.3"},"reference-count":58,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research","award":["2017T8CMCY"],"award-info":[{"award-number":["2017T8CMCY"]}]},{"name":"University of Insubria","award":["2017T8CMCY"],"award-info":[{"award-number":["2017T8CMCY"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Intestinal ischemia and reperfusion (IRI) injury induces acute and long-lasting damage to the neuromuscular compartment and dysmotility. This study aims to evaluate the pathogenetic role of hyaluronan (HA), a glycosaminoglycan component of the extracellular matrix, as a modulator of the enteric neuronal and immune function and of the colonic microbiota during in vivo IRI in the rat small intestine. Methods: mesenteric ischemia was induced in anesthetized adult male rats for 60 min, followed by 24 h reperfusion. Injured, sham-operated and non-injured animals were treated with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU 25 mg\/kg). Fecal microbiota composition was evaluated by Next Generation Sequencing. Neutrophil infiltration, HA homeostasis and toll like receptor (TLR2 and TLR4) expression in the small intestine were evaluated by immunohistochemical and biomolecular approaches (qRT-PCR and Western blotting). Neuromuscular responses were studied in vitro, in the absence and presence of the selective TLR2\/4 inhibitor, Sparstolonin B (SsnB 10, 30 \u00b5M). Results: 4-MU significantly reduced IRI-induced enhancement of potentially harmful Escherichia and Enterococcus bacteria. After IRI, HA levels, neutrophil infiltration, and TLR2 and TLR4 expression were significantly enhanced in the muscularis propria, and were significantly reduced to baseline levels by 4-MU. In the injured, but not in the non-injured and sham-operated groups, SsnB reduced both electrical field-stimulated (EFS, 0.1\u201340 Hz) contractions and EFS-induced (10 Hz) non-cholinergic non-adrenergic relaxations. Conclusions: enhanced HA levels after intestinal IRI favors harmful bacteria overgrowth, increases neutrophil infiltration and promotes the upregulation of bacterial target receptors, TLR2 and TLR4, in the muscularis propria, inducing a pro-inflammatory state. TLR2 and TLR4 activation may, however, underlay a provisional benefit on excitatory and inhibitory neuronal pathways underlying peristalsis.<\/jats:p>","DOI":"10.3390\/cells11213370","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T12:29:45Z","timestamp":1666700985000},"page":"3370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Hyaluronan Regulates Neuronal and Immune Function in the Rat Small Intestine and Colonic Microbiota after Ischemic\/Reperfusion Injury"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5027-880X","authenticated-orcid":false,"given":"Annalisa","family":"Bosi","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Banfi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Bistoletti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Martina","family":"Catizzone","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ospedale di Circolo, ASST-Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3924-2117","authenticated-orcid":false,"given":"Anna Maria","family":"Chiaravalli","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ospedale di Circolo, ASST-Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Moretto","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7002-6367","authenticated-orcid":false,"given":"Elisabetta","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgenia","family":"Karousou","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0634-6390","authenticated-orcid":false,"given":"Manuela","family":"Viola","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0825-7965","authenticated-orcid":false,"given":"Maria Cecilia","family":"Giron","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Crema","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Rossetti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0223-7805","authenticated-orcid":false,"given":"Giorgio","family":"Binelli","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3328-3089","authenticated-orcid":false,"given":"Alberto","family":"Passi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Vigetti","sequence":"additional","affiliation":[{"name":"Department of Medicine 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