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

Autor:	De Palma G; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Shimbori C; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Reed DE; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Yu Y; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Rabbia V; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Lu J; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Jimenez-Vargas N; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Sessenwein J; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Lopez-Lopez C; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Pigrau M; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Jaramillo-Polanco J; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Zhang Y; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Baerg L; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Manzar A; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Pujo J; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Bai X; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Pinto-Sanchez MI; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Caminero A, Madsen K; University of Alberta, Edmonton, Canada., Surette MG; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Beyak M; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Lomax AE; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Verdu EF; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Collins SM; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada., Vanner SJ; Gastrointestinal Diseases Research Unit, Queens University, Kingston, Canada., Bercik P; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 Jul 27; Vol. 14 (655), pp. eabj1895. Date of Electronic Publication: 2022 Jul 27.
DOI:	10.1126/scitranslmed.abj1895
Abstrakt:	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.
Databáze:	MEDLINE
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