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. 2025 Apr;182(8):1803-1822.
doi: 10.1111/bph.17439. Epub 2025 Jan 22.

Toll-like receptor 4 deficiency ameliorates experimental ileitis and enteric neuropathy: Involvement of nitrergic and 5-hydroxytryptaminergic neurotransmission

Sofia Faggin  1 , Silvia Cerantola  1 , Valentina Caputi  2 , Angela Tietto  1   3 , Elena Stocco  4   5   6 , Annalisa Bosi  7 , Alessandra Ponti  7 , Antonella Bertazzo  1 , Veronica Macchi  4 , Andrea Porzionato  4 , Edoardo V Savarino  6 , Cristina Giaroni  7 , Maria Cecilia Giron  1
Affiliations

Toll-like receptor 4 deficiency ameliorates experimental ileitis and enteric neuropathy: Involvement of nitrergic and 5-hydroxytryptaminergic neurotransmission

Sofia Faggin et al. Br J Pharmacol. 2025 Apr.

Abstract

Background and purpose: Inflammatory bowel disease (IBD) patients display genetic polymorphisms in toll-like receptor 4 (TLR4) genes, contributing to dysregulate enteric nervous system (ENS) circuits with increased levels of 5-HT and alteration of the neuroimmune crosstalk. In this study, we investigated the impact of TLR4 signalling on mouse ENS dysfunction caused by dextran sulphate sodium (DSS)-induced ileitis.

Experimental approach: Male C57BL/6J (wild-type [WT]) and TLR4-/- mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and then were switched to 3-day regular drinking water. Histological analysis and proinflammatory cytokine mRNA levels were assessed in ileal samples. Gut motility was evaluated by changes in transit of a fluorescent-labelled marker and isometric neuromuscular responses of ileal full-thickness segments to receptor and non-receptor-mediated stimuli. Alterations in ENS architecture were assessed by confocal immunohistochemistry in longitudinal muscle-myenteric plexus whole-mount preparations.

Key results: In WT mice, DSS treatment caused delayed gastrointestinal transit, ileal myenteric neurodegeneration, reactive gliosis and release of proinflammatory cytokines. Enhanced cholinergic and tachykinergic excitatory tone, increased inducible nitric oxide synthase (iNOS)-mediated relaxation, and changes in 5-HT2A and 5-HT3 receptor-mediated responses were observed during ileitis in WT mice. TLR4 deficiency reversed most of the functional and morphological abnormalities.

Conclusion and implications: Our results demonstrate that TLR4 activity influences the severity of ileitis, neuroglial plasticity, gut motility, and nitrergic and 5-HTergic neurotransmissions. The neuroimmune interaction between TLR4 and 5-HT observed in our study appears to be a potential pharmacological target to treat ENS dysfunction implicated in IBD onset/progression.

Keywords: 5‐hydroxytryptamine; enteric nervous system; ileitis; intestinal motility; neuroplasticity; toll‐like receptor 4.

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