Histamine-Producing Bacteria: The Missing Link in Irritable Bowel Syndrome?

De Palma G, Shimbori C, Reed DE, et al. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med 2022;14(655):eabj1895. The interaction between diet, intestinal microbiota, and host plays a role in the pathophysiology of irritable bowel syndrome (IBS). A key mediator in the development of visceral hypersensitivity in IBS is histamine, with its release acting on nociceptive afferents and generating pain signals. Although it is generally thought that histamine is derived from mucosal mast cells in IBS patients, De Palma et al provide evidence for a different source of histamine in the gut: bacteria. In an elegant series of mechanistic experiments, performed using germ-free mice colonized with fecal microbiota from patients with IBS, Klebsiella aerogenes was identified as a major producer of histamine by the activity of a histidine decarboxylase gene specific to these species. K aerogenes was abundant in the fecal microbiota of patients with IBS, particularly in those with high and not low urinary histamine concentrations. In addition, Klebsiella-derived histamine led to visceral hypersensitivity in mice colonized with microbiota from IBS patients with high urinary histamine. These effects were mediated by H4-receptor–dependent signaling; an H4-antagonist reduced visceromotor responses to colonic distension in mice. Furthermore, an increase in mast cells was also seen in these animals, similarly to mice monocolonized with a single bacterial strain of K aerogenes, capable of producing high amounts of histamine. Notably, K aerogenes derives its name from its ability to produce gas, in particular hydrogen, and can metabolize different sugars, including lactose and fructose. This could also explain why its abundance decreased when patients with high urinary histamine ate a low–fermentable carbohydrate diet, as observed by reanalyzing fecal samples from a previous study (Gut 2017;66:1241-1251). Could urinary histamine profile be used to select IBS patients harboring the histamine-producing K. aerogenes to increase efficacy of therapies such as the low-FODMAP diet? What remains unclear is how bacterial histamine from the lumen can reach high concentrations in urine without any concurrent increase in intestinal permeability or any other mechanism at operation allowing transepithelial passage of large amounts of histamine. Alternatively, high urinary histamine could be the result of endogenous rather than bacterial histamine production due to the increased influx of mucosal mast cells, which can be induced by the chemo-attractive effects of K aerogenes. Although the novel disease mechanism presented here is particularly intriguing, the fecal microbiota used for the mechanistic studies was derived from just 2 patients with IBS (one with high and the other with low urinary histamine, with different IBS subtypes and different sexes) and a healthy control subject. Whether such a mechanism is operating in a broader group of patients warrants further investigation, and if confirmed, it could represent a true breakthrough in mechanism-driven treatment in IBS.