A chemical switch

This common immune response might be behind IBS pain — a new study finds

For some folks with irritable bowel syndrome, targeting histamine may lead to potent pain relief.

Painful digestion IBS or irritable bowel syndrome and intestine pain or Intestinal discomfort inflam...

For millions of people around the world living with irritable bowel syndrome (or IBS), food can often induce anxiety. One bite of something that doesn’t sit well with your body can trigger a host of unpredictable, exhausting, and often debilitating symptoms like constipation, gas, bloating, diarrhea, and abdominal pain.

While there are ways to help with the symptoms that IBS causes, such as eating a diet low in certain carbohydrates (known as FODMAPS) and high in dietary fiber, as well as medications and practicing mindfulness, these interventions don’t get at the root of the problem. What causes this uncomfortable gut disorder, which seems to affect women more than men, is still a bit of a mystery but one thought is that a gut microbiome dominated by “bad” microbes may be the culprit. And according to a study published Wednesday in the journal Science Translational Medicine, some of these microbial bad guys may be causing pain associated with IBS through a chemical well-known to all allergy sufferers: histamine.

What’s new - A team of researchers at McMaster University and Queen’s University in Canada harvested gut bacteria from the poo of patients with IBS who also happen to have high concentrations of histamine in their urine. When these bacteria were transplanted into germ-free mice (basically, mice lacking a gut microbiome), the animals developed hallmarks of the disease such as abdominal sensitivity and pain. But when the animals were given a medication that blocks histamine, their pain got much better.

This research builds off of earlier studies that found when some patients with IBS were placed on a low FODMAP diet – a diet that avoids foods that aren’t easily broken down by the gut – these folks went from high to low levels of histamine in their pee. Histamine is a chemical produced by the immune system, mostly by special cells called mast cells, whenever the body is exposed to foreign particles like dust, pollen, or pet dander, and it also causes inflammation.

“There was a correlation between improvement in pain and then decrease in urinary histamine after starting this [FODMAP] diet and this was also accompanied by changes in the gut microbiota,” Dr. Premysl Bercik, a gastroenterologist at McMaster University who lead the new study, tells Inverse.

Sifting through the collected poo, Bercik and his colleagues found several bacteria capable of producing histamine but found one that was a “superproducer” possessing a high-throughput ability to manufacture the immune chemical. Called Klebsiella aerogenes, it belongs to a family of rod-shaped bacteria that include relatives like Salmonella and E. coli and has been identified in past studies among the gut microbiome of people with IBS.

A diet low in certain carbohydrates, known as FODMAPS, may help manage the debilitating symptoms of IBS.


Why it matters - This study helps us make out what flips the pain switch in IBS, at least for some patients, Dr. Lin Chang, a gastroenterologist and vice-chief of the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, tells Inverse.

“There’s been some data to suggest that mast cells that release histamine are mediators of abdominal pain and IBS,” says Chang, who was not involved in the study.

These prior studies have found that when mast cells get activated – typically by histamine itself floating around in the gut and its surrounding tissues – the histamine they produce in turn leads to activation of neurons involved in pain perception and subsequently abdominal pain. (Interestingly, mast cells are also activated during times of stress or anxiety, which are both recognized triggers for some people with IBS.)

This emerging role of histamine in IBS could lead to treatments that single out the chemical. Medications known as histamine blockers — a class of drugs used to treat conditions like peptic ulcers, gastroesophageal reflux disease, and allergic reactions – might also be considered for IBS, says Chang.

Beyond IBS, these findings could be helpful in illuminating whether histamine is behind chronic abdominal pain for patients with other functional gastrointestinal disorders, which are characterized by persistent or recurring GI symptoms and are usually due to a brain-gut interaction.

Digging into the details - While Bercik and his team identified Klebsiella aerogenes as the major gut microbe producing histamine among the poop samples they collected (the ones transplanted into mice), it may not necessarily be that exact one for all patients with IBS. The microbial superproducer could include other species of gut bacteria capable of spitting out tons of histamine just as efficiently as Klebsiella.

“This is probably what we will have to do in the next set of studies [in finding] the [bacterial] biomarker,” says Bercik. “For example, would it be just measuring Klebsiella aerogenes or finding the biomarker for, let’s say, having several variants of this histidine decarboxylase gene, which is associated with the histamine super-production.”

It’s also not clear whether in the body bacterial histamine is directly involved in activating pain perception neurons, although it seems to be the case in experiments the researchers did in Petri dishes. This distinction could be important when it comes to developing IBS treatments targeting histamine either by blocking the immune chemical’s interaction with mast cells or with neurons, says Bercik.

What’s next - Bercik and his team are currently running a pilot study to see whether what they’ve observed in mice also treks in humans. Through their mouse study, the researchers did uncover a curious phenomenon: gut pH seems to influence histamine production.

“The enzyme histidine decarboxylase works ideally at pH 6.5,” says Bercik, but when intestinal pH spikes above or below that, “histamine production is switched off.”

For folks with IBS following a FODMAP diet, Bercik says, this pH flip could be because the more optimized, tailored nutrition fosters an ecosystem of good, “friendly” bacteria, like Lactobacillus, that produce chemicals like lactic acid, which influence gut pH. Because following a low FODMAP diet can be very complicated for patients (and may sometimes lead to nutritional deficiencies), Bercik believes it may be possible one day to specifically change one’s intestinal pH by targeting specific bacteria involved in histamine production. While that sort of research may be a long way off, we’re at least walking the right path.

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