Hamilton, ON (July 27, 2022) — Researchers from McMaster University and Queen’s University have discovered a gut bacterial “superproducer” of histamine that can trigger pain attacks 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 percent of gut microbiota samples from patients with IBS. Researchers examined stool microbiota samples from both Canadian and US patient cohorts.
“We followed these patients for several months and found high levels of histamine in the stool when the patients reported severe pain, and low histamine in the stool when they were pain-free,” said senior author Premysl Bercik, professor of medicine at McMaster’s Michael. G. DeGroote School of Medicine and a gastroenterologist.
The McMaster-Queen’s research team has located the bacteria Klebsiella aerogenes as the major 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 bacteria Klebsiella aerogenes converts dietary histidine, an essential amino acid present in animal and vegetable proteins, into histamine, a known mediator of pain.
The bacterial histamine then activates the gut immune system via the histamine-4 receptor, which attracts immune mast cells into the gut. These activated mast cells produce even more histamine and other pain-signaling mediators, causing inflammation and pain.
“Now that we know how 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 decreased dramatically. This was due to change in bacterial fermentation and acidity in the gut, which inhibited the bacterial enzyme responsible for producing histamine.
Bercik said these results explain the beneficial effects of a low-fermentation diet seen in patients with IBS.
Patients with IBS are known to have more mast cells in their gut and some of them improve with treatments that target mast cells or histamine, such as mast cell stabilizers or antihistamines.
“While mast cell treatment in IBS has been explored, a novel approach based on our research would target the bacterial histamine production or H4R pathways,” Bercik said.
The McMaster-Queen’s study explains why elevated mast cells are found in IBS and suggests that the H4 receptor pathway plays an important role in this process.
“If we block the H4 receptors, we can prevent the recruitment of mast cells to the colon and subsequently the development of abdominal pain,” said co-senior author Stephen Vanner, a professor of medicine at Queen’s University.
“Many, but not all IBS patients will benefit from therapies that target this histamine-driven pathway,” said co-first author David Reed, assistant professor of medicine at Queen’s. Reed said one or more biomarkers of this pathway could be used to find the patients most likely to benefit from it.
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.
Editors: Photos of Premysl Bercik and Stephen J. Vanner can be found at https://bit.ly/3ODJcuY
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Science Translational Medicine
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Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice
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Competing Interests: SC is a paid member of the Microbiome Advisory Board for Norgine. The other authors declare that they have no competing interests. Availability of Data and Materials: All data associated with this study is contained in the paper or supplemental materials. The 16S rRNA sequencing data has been deposited with the National Center for Biotechnology Information BioProject No. PRJNA542489.
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