Diet-induced obesity alters nerochemical code in enteric glial cells and injures enteric plexuses causing intestinal dysfunctions

Objective: Alterations in intestinal motility and in gut mucosal barrier function, two gastrointestinal activities coordinated by the enteric nervous system (ENS), take place in metabolic syndrome. Since derangements in the ENS have not been evaluated in obese subjects, iin this study we investigated the structural and neurochemical alterations in the enteric plexus during dietinduced obesity. Methods: Male C57Bl/6 mice received either regular chow diet (RCD) or high fat diet (HFD) for 9 weeks. Enteric plexus architecture was investigated by immuno-fluorescence on ileal whole mount preparations. Trans-mucosal resistance and neuromuscular contractility of isolated ileal segments were evaluated by Ussing’s chambers and pharmacological/electrical (EFS) stimulation, respectively. Neurochemical code was studied by quantitative RT-PCR in longitudinal muscle myenteric plexus preparations and in cultured enteric glial cells. Results: At the seventh week of diet, mice receiving HFD registered a significant increase in body weight gain and altered glucose tolerance test as compared to mice fed on RCD. HFD administration drastically reduced peripherin and HuC/D expression in the enteric neurons, affecting both neuronal nitric oxide synthase and Chat expression in myenteric and submucosal plexuses. Intestinal mucosal resistance decreased early during HFD administration (P = 0.01 vs RCD at 4 weeks). EFS-induced ileal contractility was significantly reduced at 6 weeks on HFD in a neuronally-mediated manner since contractions were completely abolished by TTX (1 microM). On the second week of HFD, the levels of glia-derived neurotrophic factor (GDNF) mRNA transcript were significantly reduced as compared to RCD fed animals. In cultured enteric glial cells interleukin 6 (10 ng mL)1) and stearic acid (20 micromol) significantly reduced GDNF levels. Conclusion: In summary following HFD administration, changes in ENS integrity and function develop before the occurrence of the metabolic syndrome. We speculate that dietary fatty acids and inflammatory soluble factors alter the neurochemical code in enteric glial cells driving the ENS neuroplasticity in obesity.