Scientists from McMaster University and Queen’s University, both in Ontario, Canada, have identified a gut bacterial ‘super-producer’ of histamine that can trigger pain flare-ups in some irritable bowel syndrome (IBS) patients.
The offender has been named Klebsiella aerogenes, the McMaster-Queen (MQ) strain, and it appears in up to 25 percent of gut microbiota samples from patients with IBS. The research team examined stool microbiota samples from both Canadian and American patient cohorts.
“We followed up with 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 study authors pinpointed the bacterium Klebsiella aerogenes as the key histamine producer by examining germ-free mice colonized with gut microbiota from IBS patients. To establish a control group, the researchers also colonized some mice with gut microbiota from healthy volunteers.
Scientists found that Klebsiella aerogenes converts dietary histidine, an essential amino acid 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.
A “Low Fermentable Diet” Helps
When 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.
“In conclusion, our study establishes that visceral hypersensitivity can be shaped by an individual’s gut microbial community, through a specific diet-microbial interaction involving histamine production. Our results provide evidence that bacterial histamine may lead to intestinal mast cell hyperplasia and activation through an H4 receptor–dependent pathway, triggering visceral hyperalgesia. In agreement with clinical trial data, our findings suggest that gas production with bowel distension is not the primary nociceptive trigger in patients with IBS consuming a high fermentable diet and may help to explain why only some patients respond clinically to a low fermentable diet. Identifying those patients will be crucial as the low microbial diversity in Western populations, which has been linked to many chronic diseases, can further decrease when restriction of dietary fiber is recommended. The identification of K. aerogenes, or bacteria with similar hdc activity, as a source of histamine in the gut may guide dietary recommendations, microbiota-directed therapies, or use of H4 receptor antagonists in a subset of patients with IBS with chronic abdominal pain.”