According to a new study published in the July 27, 2022, issue of Science Translational Medicine, a lower intake of fermentable carbohydrates produces changes in the intestinal microbiota that decrease histamine production reducing chronic abdominal pain in patients with irritable bowel syndrome (IBS). Unlike in healthy people, the abundance of the bacteria Klebsiella aerogenes, with a variant of the histidine decarboxylase gene, would be related to a higher production of histidine in IBS patients and the origin of visceral pain.

Researchers at McMaster University in Hamilton have concluded this after examining the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity in germ-free mice transplanted with fecal microbiota from IBS patients. It was already known that intestinal bacteria could contribute to abdominal pain in those organs that are in contact with the external environment and, therefore, exposed to interaction with microbiota microorganisms. But there was no data about what kind of compounds cause the pain or how are the mechanisms that explain it.

Visceral abdominal pain, sometimes accompanied by nausea and vomiting, occurs in patients with IBS, interstitial cystitis (painful bladder syndrome) or vulvodynia. Visceral pain or abdominal discomfort is often chronic in IBS patients and, according to the International Foundation for Gastrointestinal Disorders, affects between 5-10% of the world's population. These patients often have visceral hypersensitivity, the perception of normal physiological stimuli as a pain sensation.

Histamine control could relieve the pain of IBS patients. This compound attracts mast cells, which trigger an allergic response. Therefore, researchers designed several experiments to understand the origin of pain, to see the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity.

The importance of the microbiome in pain perception comes by the fact that the microbiota favors the excitability of intestinal sensory neurons. Furthermore, it is known that, compared to normal mice, mice that do not have a commensal microbiota do not show a high sensitivity to pain.

Thus, researchers used germ-free mice transplanted with fecal microbiota from IBS patients. To measure the visceral sensitivity of mice, the authors recorded their visceromotor responses to colorectal distention using an adapted ambulatory harness equipped with an electromyogram and barostat.

There are other bacterial metabolites, such as butyrate and propionate, that could affect intestinal neuroimmune function and thus influence visceral sensitivity. However, in this study they found no differences in the cecum of mice with respect to these short-chain fatty acids.

Mice with high urine histamine levels developed visceral hyperalgesia and mast cell activation. The investigators then reduced fermentable carbohydrates in their diet, observing less visceral hypersensitivity and a decreased accumulation of mast cells in the colon. This did not occur, for example, in mice transplanted with microbiota from healthy people or from patients with IBS but low urinary histamine levels. Reducing fermentable carbohydrates in their diet had no effect on these animals.

Since visceral hypersensitivity seems related to high histamine levels, the authors used pharmacological histamine H4 receptor blockade in the transplanted mice. This way, they reduced visceral hypersensitivity and the accumulation of mast cells in the colon, finding a possible therapeutic strategy to avoid chronic pain in patients with IBS.

By in vitro experiments, researchers found that cultures of fecal microbiota from IBS patients with high levels of histamine in urine produced, in turn, a high amount of histamine. They also observed that histamine came from the most common strains in three of the IBS patient cohorts: the bacterium K. aerogenes, which carried a variant of the histidine decarboxylase gene.

Now, the focus is on the type of diet, the composition of the microbiota and, above all, how to prevent excessive histamine production. "The data in our paper suggest that altering the acidity in the gut, which is mainly determined by the bacterial fermentation of fiber/carbohydrates, can affect histamine production as the enzyme histidine decarboxylase is pH sensitive," Premysl Bercik, professor of medicine at McMaster University, told BioWorld Science.

"We are currently conducting a pilot study to examine effects of treatment with probiotic lactobacilli, which by producing lactic acid in the gut may affect histamine production," Bercik explained. As another step, he remarked that it would be important "to determine which patients have these histamine-producing bacteria, and what are the best biomarkers to identify these patients."

Patients suffering from other disorders, such as interstitial cystitis, could benefit from these findings. "This condition may co-exist with IBS," Bercik said. In fact, other studies show that mast cells are implicated in the genesis of interstitial cystitis. "Whether these mast cells are recruited and activated by the bacterial histamine originating in the gut remains to be determined," he commented