LAUSR

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. Description Bacterial histamine induces visceral hyperalgesia through H4 receptor–dependent pathways in a subset of patients with chronic abdominal pain. A role for bacterial histamine in abdominal pain Gut bacteria have been implicated in the genesis of chronic pain disorders; however, the underlying mechanisms remain unclear. In new work, De Palma and colleagues show that histamine, a known neuroimmune modulator, is produced by gut bacteria and that it induces abdominal pain in a mouse model of irritable bowel syndrome (IBS). Bacterial histamine acts by attracting mast cells to the colon through activation of the histamine 4 receptor. The authors identified Klebsiella aerogenes, present in the gut microbiota of many patients with IBS, as the main bacterial producer of histamine. These results suggest that bacterial histamine may be a therapeutic target for treating chronic abdominal pain.