Irritable bowel syndrome (IBS) is defined as a functional gastrointestinal disorder, whose main symptoms are recurrent abdominal pain, changes in the frequency or characteristics of stool and abdominal distension. As a functional gastrointestinal disorder, IBS does not have a morphologic, metabolic, or neurologic aetiology. It is diagnosed using Rome IV clinical parameters. IBS can be classified in 4 different subtypes according to patient’s bowel habit: IBS with predominant constipation (IBS-C), IBS with predominant diarrhoea (IBS-D) and mixed-IBS which alternates between diarrhoea and constipation (IBS-M). Another type of IBS is called unclassified (IBS-U) [1], where individuals who do not fall into the other intestinal pattern categories are included.

IBS is considered the most prevalent gastrointestinal disorder; its prevalence is estimated to be around 10% to 15% of the population in Europe and North America. Despite its high prevalence, the physiopathology of IBS is still unknown. There are many hypotheses about IBS aetiology: psychosocial disorders, microbiotic alterations, hypersensitivity to some food, intestinal motility disorders, changes in visceral pain perception, or neurotransmitter alterations, creating a complex disorder of the gut-brain axis [2]. This axis is composed of intestinal microbiota, the intestinal epithelial barrier, neurotransmitters, the central nervous system (CNS), enteric nervous system (ENS), autonomic nervous system, and the hypothalamic-pituitary-adrenal axis. Together, all these components communicate bidirectionally (mainly through neurotransmitters), so intestinal signals can influence brain functions and vice versa. In fact, IBS patients show differences in brain activation areas in response to rectal distension and pain compared with healthy controls; suggesting that IBS patients lack central activation of descending inhibitory pathways [3]. Recent studies have reported alterations in brain networks and networks of interacting systems in the gut in IBS patients, evidencing a potential role of neurotransmitters on IBS pathophysiology [4]. On the other hand, psychosocial factors such as stress, anxiety, or depression, where neurotransmitters can play a key role, are considered risk factors for IBS and may even contribute to an exacerbation of IBS symptoms [5].

In recent years, many studies have focused on the association between IBS and changes in gut microbiota [6]. Gut microbiota can modulate host production of different neurotransmitters, as well as produce some neurotransmitters themselves [7]. Gut microbiota could play a role in the aetiology of IBS as they influence intestinal motility, gastrointestinal physiology, neurotransmitter levels, and behaviour. Actually, germ-free rats display a delay in intestinal peristalsis and that can be reverted by colonization with Lactobacillus acidophilus or Bifidobacterium bifidum [8]. IBS patients show perturbed microbiota composition, although there is no common microbiotic signature among IBS patients [9]. An increase of Firmicutes, especially Clostridium and Ruminococcaceae with a decrease of Bacteroidetes, particularly Bifidobacteria can be obtained in several mucosal and faecal samples from IBS patients [10]. Moreover, preliminary data suggest correlations of regional brain structural differences with gut microbial taxa [4].

The pathophysiology of IBS is incompletely understood, but it is well established that alterations in the gut-brain axis, altered CNS processing, motility disturbances and visceral hypersensitivity contribute to IBS aetiology. Other, less relevant or less studied mechanisms involved in IBS include genetic associations, alterations in gastrointestinal microbiota, cultural factors, and disturbances in mucosal and immune function [11]. Alterations in the gut-brain axis and differences in brain function are major contributing factors to IBS aetiology; however, the implications of key neurotransmitters such as norepinephrine (NE), serotonin, glutamate, GABA, and acetylcholine (ACh) in IBS are still unknown. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore its potential therapeutic treatment. The Rome IV criteria for the diagnosis of IBS consist of abdominal pain associated with an alteration in either stool form or frequency, occurring for at least 6 months. Neurotransmitter dysfunctions could contribute to IBS and some of its most prevalent symptoms used for its diagnosis, grouped into two main aspects, visceral hypersensitivity and altered motility (Figure 1), although they may also be involved in other symptoms such as diet-related digestive disturbances, psychosocial disturbances, anxiety, depression, fatigue, hypertension, dyslipidaemia, etc. Therefore, targeting those dysfunctions may open novel lines for IBS management, taking into account, that these symptoms may also be indirect effects mediated by other biological and psychological factors.

Noradrenaline (NE) is a key catecholamine with multiple physiological and homeostatic functions, key in the sympathetic nervous system. It is involved in excitation and the alert state during awake time, and in sensory signal detection. Secondarily, NE plays a role in behaviour, memory, attention, and learning. In fact, NE depletion in rats triggers distractibility and attentional deficits [12]. NE also has a leading role in spatial working, and memory functions, and its level is correlated with cognitive performance.

3. Serotonin