Diet-induced obesity is associated with changes in gastrointestinal function and induction of a mild inflammatory state. Serotonin (5-HT) containing enterochromaffin (EC) cells within the intestine respond to nutrients and are altered by inflammation. Thus, our aim was to characterize the uptake and release of 5-HT from EC cells of the rat ileum in a physiologically relevant model of diet-induced obesity. In chow-fed (CF) and Western diet–fed (WD) rats electrochemical methods were used to measure compression evoked (peak) and steady state (SS) 5-HT levels with fluoxetine used to block the serotonin reuptake transporter (SERT). The levels of mRNA for tryptophan hydroxylase 1 (TPH1) and SERT were determined by quantitative PCR, while EC cell numbers were determined immunohistochemically. In WD rats, the levels of 5-HT were significantly increased (SS: 19.2±3.7 μm; peak: 73.5±14.1 μm) compared with CF rats (SS: 12.3±1.8 μm; peak: 32.2±7.2 μm), while SERT-dependent uptake of 5-HT was reduced (peak WD: 108% of control versus peak CF: 212% control). In WD rats, there was a significant increase in TPH1 mRNA, a decrease in SERT mRNA and protein, and an increase in EC cells. In conclusion, our data show that foods typical of a Western diet are associated with an increased 5-HT availability in the rat ileum. Increased 5-HT availability is driven by the up-regulation of 5-HT synthesis genes, decreased re-uptake of 5-HT, and increased numbers and/or 5-HT content of EC cells which are likely to cause altered intestinal motility and sensation in vivo.

Background and purpose:  ATP, released from urothelial cells, modulates afferent nerve firing from the urinary bladder. Here, we have characterized ATP release from the rat bladder mucosa in response to acid, capsaicin, electrical field stimulation (EFS) and stretch, using agonists and antagonists at transient receptor potential vanilloid receptor 1 (TRPV1) and acid‐sensing ion channels (ASICs).Experimental approach:  Rat mucosal strips (containing urothelium and lamina propria) in Perspex microbaths were superfused with Krebs solution. ATP was measured after exposure of matched strips to acid (pH 6.6–5.0), capsaicin (0.1–10 µM), EFS or stretch (150% of original length).Key results:  Median basal ATP release was 3.46 nmol·g⁻¹. The mucosal strips responded to stimuli with potency order (median, IQR): acid (pH 5.6–6.0) 286 (103–555) > 10 µM capsaicin 188 (117–431) > 10 Hz EFS 63.0 (13.3–96.4) > stretch 24.4 (6.73–55.1) nmol ATP g⁻¹. ATP release in response to acid was pH dependent (P < 0.05). Responses to capsaicin did not desensitize nor were they concentration dependent. TRPV1 antagonist, capsazepine (10 µM) abolished capsaicin‐evoked ATP release, and reduced acid‐evoked (pH 6.5) release to 30% (P < 0.001). The ASIC channel antagonists gadolinium (0.1 mM) and amiloride (0.3 µM) reduced (P < 0.05) the acid‐evoked (pH 6.5) release to 40 and 6.5% respectively. ASIC (ASIC1, ASIC2a, ASIC2b, ASIC3) and two TRPV1 gene products were detected in mucosal and detrusor extracts.Conclusions and implications:  Capsaicin (at TRPV1) and acid (at both TRPV1 and ASIC) induce ATP release from the rat bladder mucosa. This ATP appears to be principally of urothelial origin. This study highlights the importance of ATP and acid as signalling molecules in modulating bladder function.

Purinergic receptors play an important role in inflammation, and can be activated by ATP released via pannexin channels and/or connexin hemichannels. The purinergic P2X7 receptor (P2X7R) is of interest since it is involved in apoptosis when activated. Most studies focus on the influence of pannexin-1 (Panx1) and connexin 43 (Cx43) on ATP release and how it affects P2X7R function during inflammation. Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation within the gastrointestinal system. At present, the pathophysiology of this disease remains largely unknown but it may involve the interplay between P2X7R, Panx1 and Cx43. There are two main types of IBD, ulcerative colitis and Crohn’s disease, that are classified by their location and frequency of inflammation. Current research suggests that alterations to normal functioning of innate and adaptive immunity may be a factor in disease progression. The involvement of purinergic receptors, connexins and pannexins in IBD is a relatively novel notion in the context of gastrointestinal inflammation, and has been explored by various research groups. Thus, the present review focuses on the current research involving connexins, pannexins and purinergic receptors within the gut and enteric nervous system, and will examine their involvement in inflammation and the pathophysiology of IBD.