Luca Antonioli1,2, Valentina Caputi3,4,5, Matteo Fornai6, Carolina Pellegrini1, Daniela Gentile1, Maria Cecilia Giron3, Genny Orso7, Nunzia Bernardini1, Cristina Segnani1, Chiara Ippolito1, Balázs Csóka2, György Haskó2, Zoltán H Németh2,8, Carmelo Scarpignato9, Corrado Blandizzi1, Rocchina Colucci3. 1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 2. Department of Anesthesiology, Columbia University, New York, NY, 10032, USA. 3. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. 4. San Camillo Hospital, Treviso, Italy. 5. APC Microbiome Ireland, University College Cork, T12YT20 Cork, Ireland. 6. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. mfornai74@gmail.com. 7. Scientific Institute IRCCS Eugenio Medea, Bosisio Parini-, Lecco, Italy. 8. Department of Surgery, Morristown Medical Center, Morristown, NJ, 07960, USA. 9. Laboratory of Clinical Pharmacology, University of Parma, Parma, Italy.
Abstract
BACKGROUND: The murine model of high fat diet (HFD)-induced obesity is characterized by an increment of intestinal permeability, secondary to an impairment of mucosal epithelial barrier and enteric inflammation, followed by morphofunctional rearrangement of the enteric nervous system. The present study investigated the involvement of abdominal macrophages in the mechanisms underlying the development of enteric dysmotility associated with obesity. METHODS: Wild type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD, 18% kcal from fat) for 8 weeks. Groups of mice fed with NCD or HFD were treated with clodronate encapsulated into liposomes to deplete abdominal macrophages. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. Substance P distribution was examined by confocal immunohistochemistry. The density of macrophages in the colonic wall was examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay) and IL-1β (ELISA assay) levels were also evaluated. RESULTS: MDA and IL-1β levels were increased in colonic tissues from HFD-treated animals. In colonic preparations, electrically evoked tachykininergic contractions were enhanced in HFD mice. Immunohistochemistry displayed an increase in substance P immunoreactivity in myenteric ganglia, as well as in the muscular layers of colonic cryosections from obese mice. Macrophage depletion in HFD mice was associated with a significant reduction of colonic inflammation. In addition, the decrease in macrophage density attenuated the morphofunctional alterations of tachykininergic pathways observed in obese mice. CONCLUSION: Obesity elicited by HFD determines a condition of colonic inflammation, followed by a marked rearrangement of motor excitatory tachykininergic enteric nerves. Macrophage depletion counteracted the morphofunctional changes of colonic neuromuscular compartment, suggesting a critical role for these immune cells in the onset of enteric dysmotility associated with obesity.
BACKGROUND: The murine model of high fat diet (HFD)-induced obesity is characterized by an increment of intestinal permeability, secondary to an impairment of mucosal epithelial barrier and enteric inflammation, followed by morphofunctional rearrangement of the enteric nervous system. The present study investigated the involvement of abdominal macrophages in the mechanisms underlying the development of enteric dysmotility associated with obesity. METHODS: Wild type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD, 18% kcal from fat) for 8 weeks. Groups of mice fed with NCD or HFD were treated with clodronate encapsulated into liposomes to deplete abdominal macrophages. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. Substance P distribution was examined by confocal immunohistochemistry. The density of macrophages in the colonic wall was examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay) and IL-1β (ELISA assay) levels were also evaluated. RESULTS: MDA and IL-1β levels were increased in colonic tissues from HFD-treated animals. In colonic preparations, electrically evoked tachykininergic contractions were enhanced in HFD mice. Immunohistochemistry displayed an increase in substance P immunoreactivity in myenteric ganglia, as well as in the muscular layers of colonic cryosections from obese mice. Macrophage depletion in HFD mice was associated with a significant reduction of colonic inflammation. In addition, the decrease in macrophage density attenuated the morphofunctional alterations of tachykininergic pathways observed in obese mice. CONCLUSION: Obesity elicited by HFD determines a condition of colonic inflammation, followed by a marked rearrangement of motor excitatory tachykininergic enteric nerves. Macrophage depletion counteracted the morphofunctional changes of colonic neuromuscular compartment, suggesting a critical role for these immune cells in the onset of enteric dysmotility associated with obesity.
Authors: D Le Pluart; J-M Sabaté; M Bouchoucha; S Hercberg; R Benamouzig; C Julia Journal: Aliment Pharmacol Ther Date: 2015-03-01 Impact factor: 8.171
Authors: R L Bertrand; S Senadheera; I Markus; L Liu; L Howitt; H Chen; T V Murphy; S L Sandow; P P Bertrand Journal: Endocrinology Date: 2010-11-10 Impact factor: 4.736
Authors: Yan Y Lam; Connie W Y Ha; Craig R Campbell; Andrew J Mitchell; Anuwat Dinudom; Jan Oscarsson; David I Cook; Nicholas H Hunt; Ian D Caterson; Andrew J Holmes; Len H Storlien Journal: PLoS One Date: 2012-03-23 Impact factor: 3.240