Serotonin, which is a derivative of the exogenous amino acid tryptophane is synthesized and stored in the enteric enterochromaffin (EC) cells located in the intestinal mucosa. In the human gastrointestinal (GI) tract EC cells are the most abundant in the duodenum and rectum and the scarcest in the ileum. On the other hand activated mast cells may also contribute to the synthesis and secretion of serotonin. The concentration of serotonin is relatively low in the duodenum and ileum (1.4 and 0.6 nmol/mg protein, respectively) and gradually rises in the colon reaching 45 nmol/mg protein in the rectum [1]. The synthesis of serotonin in the gut requires tryptophan hydroxylase 1 (TPH1), which is a rate limiting enzyme in this process [2]. In neurons serotonin is synthesized by an isoform of tryptophan hydroxylase, TPH2 [3]. Additionally Moreover, the availability of serotonin in the GI tract is locally regulated by the serotonin-selective reuptake transporter (SERT) which removes it from the interstitial space following the release by EC cells. SERT is expressed by all epithelial cells of the intestinal mucosa [2]. Noteworthy, the expression of SERT is decreased in the gut of IBS patients [4].

Serotonin receptors are distributed on enteric neurons, extrinsic nerve fibers, smooth muscle cells, goblet cells and enterocytes [2]. They can exert excitatory and/or inhibitory activities depending on the receptor type. Serotonin secreted by the EC cells mediates various GI functions including those involved in the pathophysiology of IBS such as peristalsis, electrolyte secretion and absorption, vasodilatation, as well as perception of pain (for comprehensive review, see Mawe et al. [2]). Moreover, it has been shown that the plasma 5-HT concentration correlates with colonic motility under both fasting and fed conditions [1]. Hence, perhaps not surprisingly, serotonin system has been recognized as one of the most promising targets for anti-IBS drugs and stimulation of serotonin receptors has been clinically validated for the treatment of disorders manifested by disturbed intestinal motility and pain.

Chloride ion channels (ClC) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. To date several types of ClC have been identified, including ClC-0, ClC-1, ClC-2, ClC-4 and ClC-5 [5]. CICs are involved in the regulation of the excitability of neurones, smooth muscle cells, cell volume control and transepithelial salt transport.

ClC-2 is a member of the ClC family that is ubiquitously expressed in mammalian tissues and has been found in both small and large intestinal epithelial cells as well as on GI parietal cells [6]. In the physiological membrane conditions the channel is closed; however, it may be activated by hyperpolarisation, cell swelling as well as acidic extracellular pH [5]. Chloride secretion is responsible for maintenance of mucosal hydration throughout the GI tract, and chloride transport is also pivotal in the regulation of fluid secretion into the intestinal lumen [6]. Activation of ClC-2 enables translocation of chloride ions across the membrane followed by the release of sodium and water into the gut lumen. The influx of fluid into the intestine promotes GI motility and increases the colonic transit together with the number of spontaneous bowel movements. The surplus of water is absorbed by the colonic epithelial tissue what limits the emergence of diarrhea [6]. Taken together, ClC-2 has been validated as a target for the treatment of chronic idiopathic constipation as well as constipation-predominant IBS (IBS-C) [7].

GC-C is a transmembrane enzyme, belonging to the protein family synthesizing one of the most common and important secondary messengers—cyclic guanosine monophosphate (cGMP) [8]. There are seven members of the GC family (GC-A–G); however, only GC-C has been validated as a pharmacological target for the treatment of GI pathologies. The endogenous activators of GC-C include peptides, guanylin and uroguanylin which play important function in the maintenance of gut homeostasis. Moreover, GC-C is known as a target protein for heat-stable enterotoxins produced by numerous enteric pathogens that colonize intestines, including Escherichia coli, Citrobacter freundii, Vibrio cholerae and Yersinia enterocolitica [8, 9]. GC-C is expressed on the brush border of intestinal cells along the small and large intestine. Its expression is regulated by intestine-specific transcription factor Cdx2 and is higher in the crypt of the colonic mucosa compared to the crypt of the small intestine [10, 11].

Activation of GC-C leads to the increase of the intracellular level of cGMP, what causes activation of the cGMP-dependent protein kinase II (PKG II). PKG II by phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel induces secretion of chloride and HCO₃-into the intestinal lumen. Moreover, cGMP reduces absorption of Na+ ions by Na+/H+ exchanger [11]. All these events lead to the accumulation of osmotically active molecules in the intestines what causes massive influx of water and increased excretion [12]. The pro-excretory properties of GC-C activators have been exploited in the development of synthetic GC-C agonists that are used in the treatment of functional GI disorders manifested by chronic constipation, such as IBS-C [8, 13, 14].

CFTR is a cyclic AMP (cAMP)-regulated ion channel that transfers chloride and thiocyanate ions through the membrane of various types of epithelial cells. It consists of two transmembrane domains linked by the R domain whose phosphorylation by the protein kinase A (PKA) leads to the opening of the gate for the ions [15]. The expression of CFTR alters throughout the GI tract. The lowest level is observed in the mucosal epithelium of the stomach. In the ileum the expression is relatively high and exhibits decreasing gradient along the crypt axis [16]. Furthermore, a small subpopulation of the cells of yet unrevealed function has been shown to express CFTR in the duodenum and jejunum [16]. In the colon the expression of CFTR is the highest in the base of the crypts and resembles the pattern occurring in the small intestine [16]. In the physiological conditions CFTR is responsible for the proper production of the mucus, secretion of fluids into the intestinal lumen and has a strong impact on GI motility and excretion. Knock out of Cftr gene impairs the intestinal transit and lowers the volume of fluids in the gut [17]. On the other hand, CFTR upregulates some of the genes associated with the GI inflammation and stimulates accumulation of mast cells in the intestinal smooth muscle tissue [18]. In line, cystic fibrosis patients (possessing mutation on the Cftr gene) reveal prolonged intestinal transit compared to healthy controls [18].

CFTR is one of the most important factors involved in the proper formation of the intestinal mucus, which constitutes a niche for the growth of intestinal microbiota. Thus, perhaps not surprisingly, loss of CFTR is associated with significant decreases in GI bacterial community richness, evenness and diversity as well as reduced abundance of protective species, including a multitude of Lactobacillales members [19].

The properties and functions of CFTR made it an attractive target for the treatment of disorders accompanied with deregulated motility and abdominal pain.

Endogenous opioid system (EOS) consists of three main types of opioid receptors, namely µ, κ and Δ (MOR, KOR and DOR respectively). Their respective endogenous ligands, endorphins, dynorphins and enkephalins as well as enzymatic machinery dedicated to their degradation, including various proteases [e.g. aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV)] [20]. Opioid receptors are widely distributed in the human body. All opioid receptor subtypes have been localized in the gastrointestinal tract of many mammalian organisms. In human body the highest concentration of MOR in the human body has been detected in the myenteric and submucosal plexuses, on immune cells in the lamina propria and ileal longitudinal muscle. DOR was detected in the enteric ganglia and fibers of esophagus, duodenum, ileum, cecum as well as in the proximal, and distal colon. KORs were localized on the myenteric and submucosal neurons, smooth muscle fibres as well as mucosa in rats [21]. Furthermore, opioid receptors were also found in high amounts on lymphocytes and macrophages, which suggest their involvement in the modulation of function of these cells [22]. EOS is crucially involved in numerous physiological processes, including pain signaling in the central and the peripheral nervous system, and respiration.

In the GI tract opioid receptors play a major role in the regulation of GI transit, secretion and immune responses. The major effects of opioid receptor agonists in the GI tract are reduction of intestinal contractility and impairment of peristalsis caused by blockade of neurotransmitter release [22]. Moreover opioids promote water and electrolyte absorption thus decreasing the volume of intestinal content and frequency of excretion. On the other hand, Moreover, both natural and synthetic opioid agonists exhibit potent analgesic effects and decrease abdominal pain in both physiological and pathophysiological conditions [23–25]. To date, several EOS-targeting compounds reached the market and found a place in the clinical treatment of GI-related conditions (e.g. loperamide, alvimopan, oxycodone, racecadotril; for comprehensive review please see Mosinska et al. [21]).

Alosetron is a 5-HT3 receptor antagonist effective the treatment of IBS-D in women. It is a therapeutic agent with a limited use and is available only for severe and unresponsive to other agents IBS-D cases. It improves pain and discomfort as well as stool frequency and urgency [7, 26]. Alosetron was approved by the US Food and Drug Administration (FDA) in 2000, after a seven month review process. However, eight months later it was removed from the market following reports of serious complications, such as severe constipation and ischemic colitis that, in several cases, lead to a surgery. In 2002 FDA reconsidered the case of alosetron and reintroduced it to the market under a risk management plan with a lower recommended starting dose of 0.5 mg twice daily [7]. In 2005 and 2007 Chang et al. [27] and Krause et al. [28] respectively, have shown the effectiveness of alosetron in the treatment of IBS-D both in men (n = 662) and women (n = 705) reporting low incidence of serious adverse events. The recent 9-year evaluation of trends in alosetron postmarketing safety under the risk management program indicate that incidence of ischemic colitis and constipation remain rare and stable, at approximately 1 case/1000 patient-years [29]. The indications for alosetron in women with severe IBS-D include: (i) chronic IBS symptoms (generally lasting 6 months or longer), (ii) the absence of anatomic or biochemical abnormalities of the GI tract excluded, (iii) disability or restriction of daily activities due to IBS and (iv) no adequate response to conventional therapy.

Ramosetron is a potent and selective 5-HT3 receptor antagonist, which has been initially developed for the treatment of nausea and vomiting [30]. Clinical studies showed that ramosetron is effective against IBS-D. In a double-blind, placebo-controlled, parallel-group study of 418 male and female patients with IBS-D ramosetron increased the monthly responder rates of IBS symptoms compared to placebo [31]. In another 12-week randomized controlled trial of 539 patients, a positive response to treatment was reported by 47 % [32]. Furthermore, the drug was active after oral administration. A long-term efficacy for overall improvement of IBS symptoms was also demonstrated. Seven % of patients reported adverse events after ramosetron treatment; however, no serious adverse events (severe constipation, ischemic colitis), were reported for long-term treatment with ramosetron [33]. Ramosetron is only licensed for use in Japan and selected Southeast Asian countries (e.g. India).

Loperamide is a synthetic peripherally-restricted MOR agonist, which does not cross the blood-brain barrier. It decreases gastric emptying, slows peristalsis, delays intestinal transit and relaxes the segmental colonic smooth muscles. On the other hand it increases fluid absorption and inhibits intestinal secretion of electrolytes [34]. In IBS-D loperamide combats diarrhea and reduces stool frequency; however, it has only limited effect on abdominal pain. Clinical features of loperamide are well-established, the drug is safe and effective hence it is often recommended as a first-line therapy for functional GI disorders accompanied with diarrhea in adults. At high doses loperamide may induce constipation; therefore, the treatment starts with a relatively low dose (approx. 2 mg) and then it is titrated up or down based on the symptoms [7, 34]. Clinical studies demonstrated that loperamide is well tolerated in a 5-week therapy [35].

Trimebutine (used in the form of trimebutine maleate) is a weak agonist of peripheral MOR, KOR and DOR receptors, which also exhibit antimuscarinic properties [36]. Trimebutine accelerates gastric emptying, induces premature phase III of the migrating motor complex in the intestine and modulates the contractile activity of the colon [37]. Clinically, trimebutine has been shown to alleviate both acute and chronic abdominal pain in patients with IBS and it may also be used in children with abdominal pain. Recently, Karabulutu et al. [36] evaluated the effect of trimebutine versus non-medication in 345 children and adolescents demonstrating the effectiveness (94.9 % patients in trimebutine group experienced significant relief) [36]. The indications for trimebutine include: (i) IBS, (ii) abdominal pain and abdominal cramping and (iii) dyspepsia. It may be administered in multiple doses per day with the maximal total daily dose of 600 mg.

Eluxadoline is a peripherally-restricted mixed MOR agonist and DOR antagonist approved by FDA in May 2015 [34, 38]. In 2013 a phase II clinical trial (n = 807) demonstrated the effectiveness of eluxadoline versus placebo against global IBS-D symptoms [39]. Patients receiving a drug were significantly more likely to meet the US FDA response end point during the full 12 weeks of the study than those receiving placebo. Eluxadoline was well tolerated with a low incidence of constipation. Phase III trials (n = 2428 patients in total) confirmed these results and showed that treatment with eluxadoline (75 or 100 mg twice daily) lead to simultaneous improvement in abdominal pain and stool consistency on the same day for ≥50 % of days over weeks 1–12 and 1–26 of the study (for more details please see Nee et al. [34]). On the other hand a nonsignificant improvement in worst abdominal pain scores in those who received eluxadoline compared to placebo was observed. Common adverse effects in the two phase III clinical trials were nausea, headache, nasopharyngitis, abdominal pain and constipation but rates of discontinuation due to constipation were low (approx. 1.5 %) for both eluxadoline and placebo [40]. Known contraindications to the treatment with eluxadoline include: (i) biliary duct obstruction, or sphincter of Oddi disease or dysfunction, (ii) alcohol abuse or addiction, or patients who drink more than three alcoholic beverages per day, (iii) a history of pancreatitis or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction, (iv) a history of chronic or severe constipation or known or suspected mechanical gastrointestinal obstruction.

Rifaximin is another drug for IBS-D approved by FDA in 2015. It is a nonabsorbable, semisynthetic antibiotic belonging to the rifamycin family. The use of antibiotics for the treatment of IBS emerged from the observation that gut microflora differs between IBS and general population. Furthermore epidemiological data reveal that up to 31 % of IBS cases are caused by an episode of gastroenteritis [34]. Rifaximin targets the β-subunit of bacterial RNA polymerase which is responsible for the transcription process [41]. It does not affect the overall composition of the microbiota but appear to influence mainly potentially detrimental species such as Clostridium sp. and increases the presence of some species, such as Faecalibacterium prausnitzii [42].

Clinical trials suggest that the drug can reduce global IBS symptoms, improve bloating, abdominal pain, and stool consistency in patients with non-constipated IBS [43]. While other anti-IBS therapies require daily administration to maintain their efficacy, 2-week rifaximin treatment can achieve symptom improvement that persists up to 12 weeks post-treatment [44]. However, in the clinical trial it has been shown that 64 % of patients who underwent a 2-week therapy with rifaximin (550 mg) develop a relapse in the 18 weeks follow up hence FDA recommends a 14-day therapy with rifaximin at the dose of 550 mg (orally), three times a day. In case of the recurrence of the symptoms therapy may be repeated for another 14 days. Rifaximin is well-tolerated both after single and repeated treatments with a side effect profile comparable to that of placebo. The most common adverse events caused by rifaximin are headache, upper respiratory infection, nausea, nasopharyngitis, diarrhea and abdominal pain.

Crofelemer is a plant-derived drug originating from Croton lechleri, which belongs to the proanthocyanidin family. It was approved by FDA for the treatment of diarrhea associated with anti-HIV drugs [45]. It simultaneously targets two distinct channels, CFTR and calcium-activated chloride channel, both responsible for chloride and fluid secretion in the GI tract. Although it has been shown that crofelemer did not produce significant improvement in stool consistency, stool frequency, urgency and adequate relief it increased the number of pain-free days in female IBS-D patients after 1 and 3 month therapy and was well tolerated [46]. Further studies evaluating the analgesic potential action of this drug are needed to draw a clear conclusion on its therapeutic potential.

Antidepressants are commonly used in IBS-D. There are many Plethora of evidences for point to the link between mood-related disorders and functional GI diseases. Emotional fluctuations that often occur in distressed patients correlate with IBS symptoms. Moreover, IBS patients are more likely to develop psychiatric disorders (depression, anxiety) and dementia [47, 48].

The bidirectional communication between the brain and the gut, so called brain-gut axis, may be exploited therapeutically in IBS patients. Some of the tricyclic antidepressants, selective serotonin re-uptake inhibitors and serotonin-norepinephrine reuptake inhibitors have already been employed in the treatment of IBS and proved effective in symptom relief via mood stabilization, modulation of pain perception and amelioration of GI motility and secretion. A recent meta-analysis confirmed the efficacy of antidepressants, including tricyclic antidepressants, in the treatment of IBS symptoms [49]. In a randomized, double-blind, placebo controlled study low dose amitriptyline (10 mg) successfully ameliorated IBS-D symptoms [50]. Fifty out of 54 patients completed an intention-to-treat study; 68 % of those receiving amitriptyline had a complete response defined as a loss of all symptoms over a 2 month trial period compared to only 28 % of the controls. Adverse effects were similar between the two groups.

The first-line therapy for patients suffering from IBS-C involves laxatives and dietary fibers. Although this approach may effectively and safely combat slowed intestinal transit and constipation, it does not alleviate pain symptoms [51]. The effect of PEG 3350 plus electrolytes (PEG+E) on IBS-C has been tested in a randomized, double-blind, placebo controlled study by Chapman et al. [52]. One hundred thirty four patients received the treatment or placebo for 28 days. PGE+E was superior than placebo as assessed by spontaneous bowel movements (the primary endpoint), responder rates, stool consistency, and straining. There was no difference between PGE+E versus placebo in the mean severity score for abdominal discomfort/pain. PEG+E constitutes a well tolerable and effective treatment that should be considered suitable for use as a first-line treatment in functional GI disorders manifested by chronic constipation.

Tegaserod is a partial 5-HT4 receptor agonist that reduces visceral sensitivity and stimulates the secretion of chloride from epithelial cells. It has been approved by FDA in 2002 and subsequently withdrawn from the market in 2007 due to possible adverse cardiovascular effects (heart attack and stroke) [26]. The putative adverse events caused by tegaserod most likely result from its non-selective binding to other serotonin receptors, such as 5-HT1, 5-HT2a and 5-HT2b [53]. FDA had been criticized for this decision and ultimately reconsidered it and allowed for reintroduction of tegaserod under an investigational new drug protocol for IBS-C and chronic idiopathic constipation in women younger than 55 who are not at risk for certain cardiovascular events [53, 54]. The effect of tegaserod on IBS-C in women has been evaluated in a large (n = 661) randomized, controlled trial [55]. It provided significant improvement and satisfactory relief of IBS symptoms over 4 weeks of treatment in 43.3 % of IBS-C patients. The most frequent adverse events leading to study discontinuation in tegaserod-treated patients were diarrhea (1.5 %) and abdominal pain (0.9 %). Although long-term safety of tegaserod was investigated in a prospective study suggesting that treatment was safe over a 12-month period tegaserod was not approved for use in the EU due to the opinion that its benefits does not outweigh its risks [56].

Prucalopride, which belongs to benzofurans, is a selective agonist of 5-HT4 receptor that exhibits prokinetic effect in the GI tract. It stimulates colonic peristalsis, which provides the main propulsive force for defecation. On the contrary to other 5-HT4, it does not induce cardiovascular adverse events, which may be attributed to its high selectivity over other types of 5-HT receptors and ion channels. Clinical trials with prucalopride (1974 patients in total; both men and women) demonstrated a significant increase in the proportion of patients achieving at least three spontaneous complete bowel movements (SCBMs) per week compared with placebo [57–59]. Response rates ranged from 24 to 28 % with 4 mg prucalopride, and 9.6–12 % with placebo. Clinically relevant improvement was also demonstrated in other measures, including satisfaction with bowel function, perception of the severity of constipation as well as quality of life. It should be also underlined that prucalopride is not effective in children with functional constipation, as showed by Mugie et al. [60]. Regardless of the patient’s age, prucalopride is well tolerated with no impact on the cardiovascular system [26]. The most frequently reported adverse events include headache, abdominal pain, nausea and diarrhea. Prucalopride has been approved in Europe for both men and women; however, it has not been allowed for sale in the USA.

Linaclotide is a 14 amino acid peptide agonist of GC-C which has been approved by FDA for the treatment of IBS-C in 2012 and to date is considered as a first-in-class drug by majority of gastroenterologists. It is characterized by low bioavailability (approx. 0.1 %), what enables local action in the intestines. Linaclotide activates GC-C and causes an increase in the level of intracellular cGMP with concomitant upregulation of HCO₃-and chloride ions what results in an increased secretion and acceleration of intestinal transit [8]. Clinical data demonstrated that linaclotide improves severity of abdominal pain as well as bowel movements in IBS-C patients (for more details please see Jarmuz et al. [8]). Phase I trial showed that linaclotide provides relief and is well tolerated in 42 patients [61]. Rao et al. [62] reported the effects of 12-week treatment with linaclotide in IBS-C patients (n = 800). One-third of patients receiving linaclotide reached the FDA-recommended primary endpoint (improvement of ≥30 % from baseline in the average of the daily worst abdominal pain score on a standardized scale and an increase of at least 1 CSBM from baseline in the same week for at least 6 of first 12 weeks of treatment). During the withdrawal period patients receiving linaclotide experienced sustained decrease of abdominal pain while placebo-treated patients had a gradual increase of the pain score. In another clinical study linaclotide administered orally improved global IBS-C symptoms during 26-week therapy [63]. In line with the previous studies linaclotide induced significant relief in approx. one-third of the patients. Abdominal discomfort, fullness, cramping and bloating were also significantly improved. The most common adverse effect, which leads to discontinuation of the medication with linaclotide is diarrhea, occurring in approximately 5 % of patients [64].