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

## TL;DR

This study shows that a high-fat diet causes gut and nerve issues in mice, but these problems are reduced when a specific immune receptor, TLR4, is absent.

## Contribution

The study identifies TLR4 as a key mediator of high-fat diet-induced gut dysfunction and neurodegeneration in the small intestine.

## Key findings

- TLR4 deficiency prevents high-fat diet-induced weight gain and gut motility issues in mice.
- HFD leads to neuroglial disruption and loss of specific gut neurons in wild-type mice.
- TLR4 signaling is crucial for obesity-related inflammation and nerve remodeling in the small intestine.

## Abstract

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−/− 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–myenteric 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–response 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.