Persistent alterations in colonic afferent innervation in a rat model of postinfectious gut dysfunction: Role for changes in peripheral neurotrophic factors.

BACKGROUND: Visceral hypersensitivity in the inflamed gut is related partly to the effects of peripheral neurotrophic factors (NTFs) on local afferent neurons. However, alterations in sensory afferents of distant areas remain unexplored. Using the Trichinella spiralis infection model, which causes a jejunitis, we investigated the remodeling of colonic afferents and the potential role of NTFs. METHODS: Rats were infected with T. spiralis. Inflammatory-like changes, mucosal mast cells (MMCs) dynamics, and expression of nerve growth factor and glial cell line-derived NTFs (glial cell-derived neurotrophic factor, artemin, and neurturin) were determined in the colon up to day 30 postinfection. Functional responses of colonic afferents were determined assessing changes in the expression of sensory-related markers in thoracolumbar (TL)/lumbosacral (LS) dorsal root ganglias (DRGs) following intracolonic capsaicin. KEY RESULTS: Trichinella spiralis induced an inflammatory-like response within the colon, partly resolved at day 30 postinfection, except for a persistent MMC infiltrate. While the jejunum of infected animals showed an up-regulation in the expression of NTFs, a transitory down-regulation was observed in the colon. Overall, T. spiralis effects on DRGs gene expression were restricted to a transient down-regulation of TPRV1. Stimulation with intracolonic capsaicin induced a down-regulation of TRPV1 levels in TL and LS DRGs, an effect enhanced in LS DRGs of infected animals, regardless the postinfection time considered. CONCLUSIONS & INFERENCES: During intestinal inflammation, spread morphological and functional alterations, including remodeling of visceral afferents, are observed outside the primary region affected by the insult. Similar mechanisms might be operating in states of widespread alterations of visceral sensitivity.

Persistent epithelial barrier alterations in a rat model of postinfectious gut dysfunction.

BACKGROUND: Mucosal mast cells (MMCs), epithelial barrier function (EBF) and the enteric nervous system (ENS) are interactive factors in the pathophysiology of functional gastrointestinal disorders. We characterized postinfectious EBF alterations in the Trichinella spiralis infection model of MMC-dependent intestinal dysfunction in rats. METHODS: Sprague-Dawley rats were infected with T. spiralis. 30 ± 2 days postinfection, jejunal EBF (electrophysiological parameters, fluorescein isothiocyanate-dextran fluxes and responses to secretagogues and MMC degranulators) was evaluated (Ussing chamber). In some experiments, participation of secretomotor neurons was examined by tetrodotoxin (TTX) pretreatment. Jejunal histology and MMC count and activity were also assessed. KEY RESULTS: 30 ± 2 days postinfection, when only a low grade inflammation was observed, increased MMC number and activity were associated with altered EBF. EBF alterations were characterized by increased mucosal permeability and ion secretion. In T. spiralis-infected animals, secretory responses to serotonin (5-HT) and immunoglobulin E (IgE)-dependent activation of MMCs were reduced. In contrast, responses to substance P (SP) and capsaicin were similar in infected and noninfected animals. Neuronal blockade with TTX altered secretory responses to SP and capsaicin only in infected rats. CONCLUSIONS & INFERENCES: Trichinella spiralis infection in rats, at late stages, results in persistent postinfectious intestinal barrier dysfunctions and mucosal mastocytosis, with other signs suggestive of a low grade inflammation. The altered permeability and the TTX-independent hyporesponsiveness to 5-HT and IgE indicate epithelial alterations. Changes in responses to SP and capsaicin after neuronal blockade suggest an ENS remodeling during this phase. Similar long-lasting neuro-epithelial alterations might contribute to the pathophysiology of functional and postinfectious gastrointestinal disorders.