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

Abstract

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified Klebsiella aerogenes , carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

Irritable bowel syndrome: treatment based on pathophysiology and biomarkers

“…For example, the bacterial metabolite, tryptamine, which stimulates colonic mucosal secretion, was increased in patients with IBS-D and was associated with an enrichment in inflammation-related pathways56; however, the studies were conducted in small numbers of patients with flares in IBS and require replication. Another example is the demonstration that a Klebsiella aerogenes strain, carrying a histidine decarboxylase gene variant, produces high amounts of histamine leading to mastocytosis and to mast cell activation via histamine-H4 receptors leading to the release of histamine and proteases that induce visceral hypersensitivity 57…”

Docosapentaenoic Acid (DPA, 22:5n-3) Alleviates Ulcerative Colitis via Modification of Gut Microbiota and Their Metabolism

“…Many tissues, especially the mast cells of the skin, lungs, and intestinal mucosa, contain a large amount of histamine, which can be released when the tissue is damaged or when inflammation or allergic reactions occur. Histamine and its metabolites are closely related to the occurrence and development of UC [ 37 , 38 , 39 ]. An in vivo study showed that the expression of histamine and histamine 4 receptor significantly increased in mice with UC [ 40 ].…”

Applications of human organoids in the personalized treatment for digestive diseases

“…Thus, while antibiotic treatment provides an inexpensive and easy-to-use alternative to sterile models, the results obtained by these protocols have the potential for off-target drug effects, as well as incomplete or inconsistent ablation of microbes. 212 – 214 Germ-free (GF) mice represent a system that allows the study of animals completely devoid of microbes, in which researchers introduce microbes into GF mice individually or sequentially and evaluate the effects of individual bacteria or known bacterial communities on host function impact. 204 GF animal models are powerful tools for studying microbe-host interactions in health and disease.…”