Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signalling in mice

WHAT DO WE ALREADY KNOW ABOUT THIS SUBJECT?

Gut microbiota has been implicated in the pathophysiology of some chronic pain disorders, including pain associated with irritable bowel syndrome (IBS) and fibromyalgia [2]. This assumption is largely based on studies reporting an association between pain levels and changes in the composition of gut microbiota, on differences in pain thresholds between conventionally bred and germ-free mice, which return to normal after bacterial colonisation, and on the ability of bacteria to produce neuroactive metabolites in vitro [3]. However, there is a lack of data demonstrating causality, the precise mechanisms involved in visceral pain induced by the gut microbiota, or identifying the specific bacterial species involved. The authors of this article previously reported that abdominal pain in IBS patients improved after restriction of fermentable carbohydrate intake. This improvement was associated with changes in gut microbiota profiles and lower concentrations of urinary histamine [2], a known mediator implicated in visceral hypersensitivity [4]. In this article, the authors investigated gut microbiota functions triggering histamine production and visceral hypersensitivity using germ-free mice colonised with the faecal microbiota of IBS patients or healthy individuals.

WHAT ARE THE MAIN INSIGHTS FROM THIS STUDY?

A positive correlation was first observed between visceral pain severity and urinary histamine concentration in a cohort of IBS patients.

Visceral hypersensitivity and gut mechanosensation, evaluated using action potential measurements in colonic afferent nerves, was higher in germ-free mice colonised with faecal microbiota from IBS patients with high urinary histamine levels compared with mice colonised with microbiota associated with low urinary histamine levels. It was shown that the microbiota was responsible for the production of histamine in IBS patients with high urinary levels of this metabolite (Figure 1). In addition, a diet low in fermentable carbohydrates reduced histamine-mediated visceral hypersensitivity.

Using culturomics, Klebsiella bacteria were then identified as the main producer of histamine in IBS patients with elevated urinary levels of this molecule.

Compared with healthy subjects, IBS patients had a higher prevalence of K. aerogenes and a higher relative abundance of the histidine decarboxylase (hdc) gene, responsible for histamine production. Mechanistically, histamine produced by K. aerogenes was implicated in mast cell recruitment, which plays a role in the pain phenotype in mice. H4R (histamine receptor 4) expression was elevated in the colon of mice colonised with the faecal microbiota of IBS patients with high levels of urinary histamine. In vitro, H4R blockade blocked mast-cell chemotaxis. Finally, in vivo, H4R blockade reduced visceral-motor responses to colorectal distension in mice colonised with the faecal microbiota of IBS patients with high levels of urinary histamine.

WHAT ARE THE CONSEQUENCES IN PRACTICE?

This study reveals the specific role of histamine production by some bacteria in the gut microbiota in the painful symptoms suffered by a subgroup of IBS patients, in the context of a diet rich in fermentable carbohydrates. It suggests that gut distension related to gas production is not the main nociceptive trigger in these patients. Identifying K. aerogenes, or other histamine- producing bacteria, could help guide dietary recommendations as well as therapies targeting the microbiota or the use of H4 receptor antagonists in this subgroup of IBS patients.