{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:01:12Z","timestamp":1791558072403,"version":"4.3.4"},"reference-count":61,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"San Camillo Hospital Grant, Treviso","award":["UNIPD-DSF-PRID-2023"],"award-info":[{"award-number":["UNIPD-DSF-PRID-2023"]}]},{"name":"AlfaWassermann spa","award":["VC2016SC2019AW"],"award-info":[{"award-number":["VC2016SC2019AW"]}]},{"name":"MUR\/University of Padova PhD Fellowship 2020; Department of Pharmaceutical and Pharmacological Sciences PostDoc Fellowship","award":["ARD-B 2023"],"award-info":[{"award-number":["ARD-B 2023"]}]},{"name":"MUR\/University of Padova PhD Fellowship 2020; Department of Pharmaceutical and Pharmacological Sciences PostDoc Fellowship","award":["ARD-A 2024"],"award-info":[{"award-number":["ARD-A 2024"]}]},{"name":"Department of Pharmaceutical and Pharmacological Sciences PostDoc Fellowship","award":["ARD-B 2020"],"award-info":[{"award-number":["ARD-B 2020"]}]},{"DOI":"10.13039\/100018353","name":"Department of Pharmaceutical and Pharmacological Sciences PostDoc Fellowship","doi-asserted-by":"publisher","award":["ECCO Grant 2022"],"award-info":[{"award-number":["ECCO Grant 2022"]}],"id":[{"id":"10.13039\/100018353","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity is associated with enteric dysfunctions, including gut dysmotility and neurodegeneration, which may involve Toll-like receptor 4 (TLR4) signaling. To investigate this relationship, we examined the impact of TLR4 deficiency on the enteric nervous system (ENS) of the small intestine in a mouse model of high-fat diet (HFD)-induced obesity. Male TLR4\u2212\/\u2212 and wild-type (WT) C57BL\/6J mice were fed either a standard diet (SD; 18% kcal fat) or an HFD (60% kcal fat) for 8 weeks. ENS alterations were evaluated using real-time qPCR and confocal immunofluorescence microscopy on longitudinal muscle\u2013myenteric plexus (LMMP) whole-mount preparations. Alterations in gut motility were evaluated by assessing stool frequency, transit of a fluorescent-labeled marker, and isometric motor responses of ileal preparations to receptor- and non-receptor-mediated stimuli. In WT mice, HFD induced delayed gastrointestinal transit, impaired cholinergic and nitrergic responses, and altered 5-HT-mediated concentration\u2013response curves. These functional deficits were accompanied by neuroglial network disruption, myenteric neurodegeneration, loss of ChAT+ and nNOS+ neurons, and increased 5-HT ileal tissue levels. In contrast, TLR4 deficiency mitigated body weight gain and largely prevented HFD-induced structural and functional alterations. Overall, our findings highlight a key role for TLR4 signaling in modulating small intestine inflammation and ENS remodeling associated with obesity.<\/jats:p>","DOI":"10.3390\/ijms262110710","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T16:18:42Z","timestamp":1762186722000},"page":"10710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Small Intestine Neuromuscular Dysfunctions and Neurogliopathy in a Mouse Model of High-Fat Diet-Induced Obesity: Involvement of Toll-Like Receptor 4"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-2259","authenticated-orcid":false,"given":"Sofia","family":"Faggin","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7099-4475","authenticated-orcid":false,"given":"Silvia","family":"Cerantola","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Bosi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-3441","authenticated-orcid":false,"given":"Cristina","family":"Giaroni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8808-4242","authenticated-orcid":false,"given":"Eleonora","family":"Napoli","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, University of California Davis, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3187-2894","authenticated-orcid":false,"given":"Edoardo Vincenzo","family":"Savarino","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Contran","sequence":"additional","affiliation":[{"name":"Section of Human Anatomy, Department of Neuroscience, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Porzionato","sequence":"additional","affiliation":[{"name":"Section of Human Anatomy, Department of Neuroscience, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2644-5430","authenticated-orcid":false,"given":"Carolina","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Antonioli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7699-702X","authenticated-orcid":false,"given":"Valentina","family":"Caputi","sequence":"additional","affiliation":[{"name":"Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA"}],"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"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Adult BMI Collaborators (2025). 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