Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice, 2022, De Palma et al

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.

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.

Open access, https://www.science.org/doi/10.1126/scitranslmed.abj1895

 

Fascinating.......thank you for posting...

 

Press release:
https://sciencesources.eurekalert.org/news-releases/960120

NEWS RELEASE 27-JUL-2022
Histamine-producing gut bacteria can trigger chronic abdominal pain

The discovery has been named Klebsiella aerogenes, the McMaster-Queen (MQ) strain

Peer-Reviewed Publication
MCMASTER UNIVERSITY



CREDIT: MCMASTER UNIVERSITY

Hamilton, ON (July 27, 2022) – Researchers from McMaster University and Queen’s University have discovered a gut bacterial ‘super-producer’ of histamine that can cause pain flare-ups in some patients with irritable bowel syndrome (IBS).



The culprit is what has now been named Klebsiella aerogenes, the McMaster-Queen (MQ) strain, identified in up to 25 per cent of gut microbiota samples from patients with IBS. Researchers examined stool microbiota samples from both Canadian and American patient cohorts.



“We followed up these patients for several months and found high levels of stool histamine at the time when the patients reported severe pain, and low stool histamine when they were pain-free,” said senior author Premysl Bercik, professor of medicine of McMaster’s Michael G. DeGroote School of Medicine and a gastroenterologist.



The McMaster-Queen’s research team pinpointed the bacterium Klebsiella aerogenes as the key histamine producer by studying germ-free mice colonized with gut microbiota from patients with IBS. They also colonized some mice with gut microbiota from healthy volunteers as a control group.



The study found that the bacterium Klebsiella aerogenes converts dietary histidine, an essential amino acid present in animal and plant protein, into histamine, a known mediator of pain.



The bacterial histamine then activates the gut immune system through histamine-4 receptor, which draws immune mast cells into the intestines. These activated mast cells produce even more histamine and other pain-signalling mediators, triggering inflammation and pain.



“Now that we know how the histamine is produced in the gut, we can identify and develop therapies that target the histamine producing bacteria,” said first author Giada de Palma, assistant professor of medicine at McMaster.



The study found that when the mice colonized with histamine producing bacteria were fed a diet low in fermentable carbohydrates, bacterial histamine production dramatically decreased. This was due to change in bacterial fermentation and acidity within the gut, which inhibited the bacterial enzyme responsible for histamine production.



Bercik said that these results explain the beneficial effects of a low fermentable diet observed in patients with IBS.



It is known that patients with IBS have more mast cells in their intestines, and that some of them improve with treatments targeting mast cells or histamine, such as mast cell stabilizers or antihistamines.



“Although mast cell treatment in IBS has been explored, a novel approach based on our research would be targeting the bacterial histamine production or H4R pathways,” Bercik said.



The McMaster-Queen’s study explains why increased mast cells are found in IBS and suggests that H4 receptor pathway plays a major role in this process.



“If we block the H4 receptors, then we can prevent recruitment of mast cells to the colon and subsequently the development of abdominal pain,” said senior co-author Stephen Vanner, professor of medicine at Queen’s University.



“Many but not all IBS patients will benefit from therapies targeting this histamine driven pathway,” said co-first author David Reed, assistant professor of medicine at Queen’s. Reed said that one or more biomarkers of this pathway could be used to find the patients most likely to benefit.



The McMaster-Queens study was funded by the Canadian Institutes of Health Research.



The study was published in the journal Science Translational Medicine on July 27.


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