The trace aminergic system: a gender-sensitive therapeutic target for IBS?

Abstract

Due to a lack of specific or sensitive biomarkers, drug discovery advances have been limited for individuals suffering from irritable bowel syndrome (IBS). While current therapies provide symptomatic relief, inflammation itself is relatively neglected, despite the presence of chronic immune activation and innate immune system dysfunction. Moreover, considering the microgenderome concept, gender is a significant aetiological risk factor. We believe that we have pinpointed a "missing link" that connects gender, dysbiosis, diet, and inflammation in the context of IBS, which may be manipulated as therapeutic target. The trace aminergic system is conveniently positioned at the interface of the gut microbiome, dietary nutrients and by-products, and mucosal immunity. Almost all leukocyte populations express trace amine associated receptors and significant amounts of trace amines originate from both food and the gut microbiota. Additionally, although IBS-specific data are sparse, existing data supports an interpretation in favour of a gender dependence in trace aminergic signalling. As such, trace aminergic signalling may be altered by fluctuations of especially female reproductive hormones. Utilizing a multidisciplinary approach, this review discusses potential mechanisms of actions, which include hyperreactivity of the immune system and aberrant serotonin signalling, and links outcomes to the symptomology clinically prevalent in IBS. Taken together, it is feasible that the additional level of regulation by the trace aminergic system in IBS has been overlooked, until now. As such, we suggest that components of the trace aminergic system be considered targets for future therapeutic action, with the specific focus of reducing oxidative stress and inflammation.

Keywords: Drug discovery; Gut microbiome; Inflammation; Oxidative stress; Trace amine.

Fig. 1

A simplified visualisation of IBS-associated pathology. GI gastrointestinal, EC enterochromaffin, 5-HT serotonin

Fig. 2

Altered trace aminergic homeostasis as a potential aetiological factor in IBS pathogenesis. The predominant risk factor promoting altered trace aminergic signalling in the GIT is functional microbial dysbiosis, which varies TA load. This altered signalling is gender dependent, and results in functional consequences, which manifest as clinical IBS symptoms. TA trace amine, TAAR trace amine associated receptor, IgE immunoglobulin E, IL-4 interleukin 4, GLP-1 glucagon-like peptide-1, PYY peptide tyrosine tyrosine, HPA hypothalamic pituitary axis, 5-HT serotonin, ENS enteric nervous system, GI gastrointestinal, PMN polymorphonuclear cells