Small Intestine Neuromuscular Dysfunctions and Neurogliopathy in a Mouse Model of High-Fat Diet-Induced Obesity: Involvement of Toll-Like Receptor 4

Obesity is associated to enteric dysfunctions, such as gut dysmotility and neurodegeneration, potentially involving Toll-like receptor 4 (TLR4) signaling. Therefore, we assessed the impact of TLR4 deficiency on small intestine enteric nervous system (ENS) in a mouse model of high-fat diet (HFD)-induced obesity.TLR4-/- and wild-type (WT) C57BL/6J male mice (aged 9±1 weeks) were fed with standard-diet (SD; 18% kcal fat) or HFD (60% kcal fat) for 8 weeks. ENS sufferance was studied by real-time qPCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations. Alterations in gut motility were evaluated by stool frequency, transit of a fluorescent-labelled marker and isometric motor responses of ileal preparations to receptor and non-receptor-mediated stimuli. In WT mice, HFD caused delayed gastrointestinal transit, impairment of both cholinergic- and nitrergic-mediated responses and changes in concentration-effect curve to exogenous 5-HT. These functional alterations were associated with disrupted neuroglial network, myenteric neurodegeneration, loss of ChAT+ and nNOS+ neurons and increased 5-HT ileal tissue levels. TLR4 deficiency protected against body weight gain and prevented mostly ENS morpho-functional anomalies following HFD. Our study further supports the involvement of TLR4 in the modulation of small intestine inflammation and ENS morpho-functional changes associated with obesity.