INVESTIGATING THE ROLE OF BACTERIAL HISTAMINE METABOLISM IN VISCERAL HYPERALGESIA

Abstract

Background: Intestinal microbiota have been implicated in the expression of irritable bowel syndrome (IBS) as patients present with altered gut microbial profiles and metabolic activity. Investigating microbial driven pathways involved in histamine metabolism may be crucial to understanding abdominal pain pathophysiology. We hypothesize that a subset of IBS patients with high histamine-producing microbiota (IBS-HH) exhibit an altered histamine metabolism. Methods: Stool samples from healthy donors and IBS patients were inoculated in a minimal medium with or without excess histidine or histamine. Bacterial histamine production/degradation were assessed in culture supernatants by ELISA. Individual colony’s capacity to degrade histamine was assessed. Germ-free mice were colonized with healthy, IBS-HH, or IBS low-histamine (IBS-LH) producing microbiota and visceromotor responses (VMRs) to colorectal distension (CRD) were measured. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to measure host gene expression of histamine degradation genes in mouse colonic and jejunal tissues. Results: IBS patients were found to possess a higher capacity to produce histamine, with facultative anaerobes potentially playing a major role. Bacterial histamine levels were found highest in IBS patients with higher abdominal pain scores. Diet was found to modulate bacterial histamine production capacity. Individual bacterial colonies from IBS-HH demonstrated a higher capacity to produce/degrade histamine compared to IBS-LH and HC. Microbiota from IBS-HH increased VMRs in colonized mice, and gene expression of diamine oxidase was significantly higher in HC-colonized mice. Conclusion: The microbiota producing high histamine may contribute to higher VMRs to CRD in humanized mice, as well as modify host gene expression. Further research is required to discern whether these changes are due to alterations in certain cell populations or epigenetic modifications, and to provide insight into histamine metabolism in a subset of IBS patients. These data might aid the design of microbiota-directed therapies targeting histamine metabolism in a subset of IBS patients.