The research article by Sander and colleagues¹ in this issue of Gut, reports their results for expression of histamine receptor subtypes in the human intestinal tract from normal individuals and patients with symptoms of the irritable bowel syndrome (IBS) and/or food allergies (see page 498). Work of this nature was overdue because most of the available histological and functional data for histamine receptors in the small and large intestine were obtained from animal models. The authors’ principal findings for the human bowel are in general agreement with the animal literature that reports on expression of the histamine H₁, H₂, and H₄ receptor subtypes in the enteric nervous system (ENS), intestinal musculature, mucosal epithelium, and immune/inflammatory cells. In contrast, the finding by Sander and colleagues¹ that histamine H₃ receptors are not expressed in the human bowel was unexpected in view of the clearcut evidence for functional involvement of the H₃ receptor subtype in the nervous control of motility, secretion, and blood flow in guinea pig intestine, which serves as the primary animal model.^2–5

The authors’ evidence for altered expression of histamine H₁ and H₂ receptor subtypes in mucosal biopsies from the terminal ileum and large intestine of patients with symptoms of food allergy and/or IBS is consistent with current concepts for the involvement of histamine release from enteric mast cells and its paracrine signalling function in the ENS as an underlying factor in these two disorders.^5–8 Histamine is not expressed by enteric neurones and is not a neurotransmitter in the ENS.⁹ Its signalling function is paracrine in nature through release from enteric mast cells and inflammatory granulocytes. Mastocytosis and presumably elevated availability of histamine are present in microscopic colitis, parasitic infections, IBS, and no doubt additional functional gastrointestinal disorders associated with symptoms of cramping abdominal pain, watery diarrhoea, and defecation urgency.^6,8,10–17

The appearance of histamine H₂ receptors in human myenteric ganglia is reminiscent of expression of the H₂ receptor subtype in the guinea pig ENS. Binding of histamine to H₂ receptors on enteric neuronal cell bodies in the guinea pig, either during exogenous application of histamine or by degranulation of neighbouring mast cells, elevates neuronal excitability characterised by firing of longlasting trains of nerve impulses.^18–21 In the case of submucosal secretomotor neurones, elevated firing rates increase the volume of mucosal secretions of electrolytes and H₂O and thereby increase the liquidity of the intestinal contents, which in turn can underlie neurogenic secretory diarrhoea.²² For musculomotor neurones in the myenteric plexus, histamine H₂ evoked firing alters contractile behaviour of the muscularis externa that is coordinated with organised secretory patterns.^23,24 Similar outcomes for release of histamine and its actions at the H₂ neuronal receptors, now reported by Sander and colleagues¹ for human ENS, can be reasonably assumed. Nevertheless, progress in understanding specific pathophysiological malfunctions and therapeutic improvisation requires that future human research be pursued along the lines of what has been done in basic science models.

Excitation of ENS neuronal perikarya is one of the significant actions of histamine at the H₂ receptor subtype. A second important action, which has been well documented in the guinea pig enteric ENS but not in humans, is suppression of synaptic transmission.^2,19,25 Exposure of the ENS to histamine, either by exogenous application in vitro or by release from sensitised mast cells in response to allergins (for example, food proteins or infectious organisms), suppresses neurotransmitter release at four important information transmission nodes in the neural microcircuitry. Which are: (1) fast excitatory nicotinic synapses; (2) slow excitatory synapses where serotonin, substance P, calcitonin gene related peptide, and ATP are among the putative neurotransmitters; (3) slow inhibitory synapses, especially on submucosal secretomotor neurones, where norepinephrine release from the sympathetic innervation and somatostatin released from intrinsic neurons are inhibitory neurotransmitters; and (4) sympathetic neurovascular junctions.

Inhibition of neurotransmission in each of these cases is presynaptic. Stimulation of presynaptic inhibitory receptors by histamine suppresses the release of neurotransmitter from the presynaptic axonal terminal and thereby inhibits transmission of neural signals. Inhibition of transmission at the multitude of nicotinic synapses in the enteric neural networks would be expected to prevent “call-up” of selective behavioural programmes or to selectively activate a specific programme in the ENS library of programmes (for example, intestinal defence).⁵ Suppression of slow excitatory transmission, either at selective slow synapses or in combination with suppression of fast nicotinic transmission, is probably also involved in generation of the pattern of defensive intestinal behaviour, which can be demonstrated during exposure to sensitising antigens in previously sensitised animals. Slow inhibitory postsynaptic potentials (IPSPs) in submucosal secretomotor neurones impose a braking action on neurogenic secretion that is removed when histamine is applied experimentally or released from enteric mast cells in sensitised animals. Removal of the sympathetic brake from secretomotor neurones is a factor underlying the diarrhoeal states associated with allergic responses and mucosal inflammation.² Suppression of norepinephrine release at submucosal neurovascular junctions removes the sympathetic braking action on blood flow, which in effect supports stimulation of neurogenic mucosal secretion.⁴

Several types of presynaptic inhibitory receptors are expressed in the ENS, one of which is a histaminergic receptor. The presynaptic histaminergic inhibitory receptor in the guinea pig ENS belongs to the histamine H₃ receptor subtype. The slow IPSPs in guinea pig secretomotor neurones, which are mediated by release of norepinephrine and somatostatin, are suppressed by histamine.² Selective histamine H₃ agonists, but not histamine H₁ or H₂ agonists, act presynaptically to suppress IPSPs, and selective H₃ antagonists, but not H₁ or H₂ antagonists, block both the effects of exogenously applied histamine and the effects of histamine released from mast cells in sensitised animal preparations.^2,19–21,25 Likewise, suppression of excitatory neurotransmission at other neural synapses and neurovascular junctions reflects histamine H₃ mediated inhibition of neurotransmitter release.⁴

Absence of the histamine H₃ receptor subtype from human bowel, as reported by Sander and colleagues,¹ was unexpected and is paradoxical in view of the evidence in the literature for its expression and importance in the animal model. Data to explain the paradox are not readily available. On the one hand, failure to find the human receptor with any of three valid methods (that is, immunohistochemistry, western blot, or reverse transcription-polymerase chain reaction) strongly supports the conclusion that the H₃ receptor is not expressed in human bowel. On the other hand, evidence from physiological studies convincingly supports expression and important functional significance of the receptor in the guinea pig model. This is a dilemma raised by Sander and colleagues.¹

The importance of histamine release from enteric mast cells in terms of intestinal symptoms, which are associated with human allergy, IBS and brain-gut interactions in stress is widely supported and convincing.^12–15,26 Symptoms of watery diarrhoea, urgency, cramping abdominal pain, and intestinal hypersensitivity to distension in humans appear in general to have a counterpart in animal models, whether it is a guinea pig, rat, or canine model.^5,6 These symptoms are perceived as side effects of the “running” of a specific ENS neural programme that has evolved as a defensive mechanism for rapid expulsion from the intestine of a threat to the integrity of the whole animal. If this is indeed the case, then the mechanisms of histaminergic call-up of programmed intestinal defence are not expected to differ much across mammalian species. Most of the results reported by Sander and colleagues¹ are consistent with this concept, except for the absence of the histamine H₃ receptor subtype. Histaminergic presynaptic inhibition that removes the sympathetic brake on secretion and mucosal blood flow would seem to be a necessary requirement in the “running” of the secretory component of the neural defence programme that “flushes” threatening agents and organisms from the mucosa and maintains them in suspension in a fluid filled intestine awaiting clearance by powerful propulsive motility.

In view of the importance of immune/inflammatory cells and histamine signalling in the ENS, thorough understanding for the human gut is imperative. A credible start in this direction has been made by Sander and colleagues.¹ Now, neurogastroenterological research must determine whether presynaptic inhibition in the ENS has the same significance for the common symptoms of food allergy, mucosal inflammation, and brain-gut interactions in stress in humans, as is known to exist in animal models. If this proves to be the case, then additional investigation will be needed to determine if it might be mediated by a histamine receptor other than the H₃ subtype.