Proper propulsion of food through the gut relies on peristaltic movements (Sanders et al., 2012). ICCs, enterochromaffin (EC) cells, the enteric nervous system (ENS), and GI smooth muscle cells are some of the most important factors regulating peristalsis of both longitudinal and circular smooth muscle (Grover et al., 2011; Mazzone et al., 2020; Spencer and Hu, 2020; Jin et al., 2021; Singh et al., 2021a; Singh et al., 2021b; Singh et al., 2021c; Wei et al., 2021a; Zheng et al., 2021). Further, functional defects of particular GI cells, for instance, ICCs, SMCs, EC cells, enteric neurons, and immune cells can hamper gut peristalsis (Figure 1). Gut dysmotility caused by impaired peristalsis is a key pathophysiological mechanism of these disorders (Shin et al., 2019; Spencer and Hu, 2020).

Gut microbial dysbiosis is highly overrepresented in FGIDs, particularly in IBS and FD. (Barbara et al., 2016b; Wei et al., 2021b; Singh et al., 2021d). Moreover, gut immune dysfunction, altered gut-brain axis, visceral hypersensitivity, impaired gut epithelial barrier function, altered gut motility, along with other pathophysiological mechanisms, have been demonstrated in gut microbial dysbiosis (Backhed et al., 2005; Barbara et al., 2016b; Cani, 2017; Shin et al., 2019; El-Salhy et al., 2021). Increased understanding of host-microbe interactions has shed light on the key pathophysiological role that microbes play in developing FGIDs (Schroeder and Backhed, 2016). Activation of the mucosal immune response via disruption of the gut microbial composition leads to gut barrier dysfunction, also known as the leaky gut. The development of a leaky gut also causes gut dysmotility and visceral hypersensitivity, which are pathophysiological characteristics of FGIDs (Barbara et al., 2016b; Singh et al., 2021d). While many studies have highlighted the possibility that altered gut microbial composition may trigger the development of FGIDs, it is not currently clear if this connection is more than merely a correlation (Malinen et al., 2005; Shukla et al., 2015; Ghoshal et al., 2018; Mars et al., 2020). It should be noted that disease progression can also be affected by the host diet, immune response, and host environment. Additionally, the interactions between the host and the gut microbiota or microbial-produced metabolites modulate the gut-brain physiology.

Metabolites generated by the gut microbiota continually signal to the hosts’ organs and regulate pathophysiological mechanisms during both health and disease (Sekirov et al., 2010; Schroeder and Backhed, 2016). Short-chain fatty acids (SCFAs) are key fermentation products produced by the microbiota in our gut. IBS-C patients have decreased SCFAs (propionate and butyrate), and patients with IBS-D have increased butyrate levels compared to healthy controls (HCs), emphasizing the significant role of SCFAs in regulating gut motility (Sun et al., 2019). Further, microbiota-produced SCFAs interact with EC cells and enhance the expression of tryptophan hydroxylase 1 (Tph1), which finally increases the production of serotonin in the gut of both mice and humans (Reigstad et al., 2015). Moreover, tryptamine (a monoamine, like serotonin, that is derived from tryptophan) has been shown to improve gut motility acting through 5-HT4 receptors located on colonic epithelial cells in mice (Williams et al., 2014; Bhattarai et al., 2018). Moreover, microbial dysbiosis-induced BA pool alternations might be a key pathological mechanism of FGIDs. Gut dysmotility and visceral pain are associated with elevated BA levels in IBS-D patients (Mars et al., 2020). Taken together, host physiology is greatly impacted by microbe-derived metabolites and may be targets of future therapeutic options for patients with FGIDs.

A subset of FGID patients have been shown to have dysfunction of their gut immune response (Muller et al., 2014; Grover et al., 2018; Black et al., 2020b; Gottfried-Blackmore et al., 2021; Ji et al., 2021). For example, an increase in the amount of immune cells in the gut (such as mast cells, T cells, macrophages, and eosinophils) of FGID patients has been reported in multiple studies (Barbara et al., 2011; Matricon et al., 2012; Barbara et al., 2016b; Singh et al., 2017). Activated mast cells release cytokines, histamines, prostaglandins, and tryptase, which are associated with intestinal barrier dysfunction and altered nociceptive pathways in FGIDs (Barbara et al., 2004; Barbara et al., 2007; Dothel et al., 2015; Aguilera-Lizarraga et al., 2021). Intestinal barrier dysfunction leads to the permeation of pathogens and food antigens, which causes a heightened immune response in the gut and greatly impacts the severity of symptoms experienced by patients with FGIDs (Camilleri et al., 2012; Wouters et al., 2016b).

The gut luminal-mucosal interface contains food particles along with many other molecules that can induce immunogenic responses creating a constant challenge for the gut immune system (Ghoshal, 2020). As a core pathophysiological mechanism, dysfunction of the intestinal barrier activates the gut immune response, which can hamper gut function and increase the symptom severity in patients with FGIDs (Barbara et al., 2016b; Wouters et al., 2016b). The gut epithelium is an astounding barrier that allows for the selective absorption of essential nutrients, water, and electrolytes, while preventing harmful toxins, metabolites, and pathogens from penetrating the gut epithelium (Camilleri, 2019). Epithelial tight junction proteins help to maintain this selective barrier to prevent harmful molecules from penetrating the epithelium while allowing for the passage of essential nutrients (Camilleri, 2019; Motta et al., 2021). Decreased expression of these tight junction proteins, caused by genetic, pathogenic, or other factors, leads to intestinal barrier dysfunction (Bischoff et al., 2014; Desai et al., 2016; Martinez et al., 2017; Aguilera-Lizarraga et al., 2021). Several studies have shown the decreased expression of zonula occludens-1, occludin, and adhesion proteins, as well as decreased transepithelial resistance in duodenal biopsies from FGIDs patients compared to HCs, suggesting impaired intestinal barrier function in a subset of these disorders (Bertiaux-Vandaele et al., 2011; Turcotte et al., 2013; Fritscher-Ravens et al., 2014; Lee et al., 2020). Thus, healthy gut barrier integrity is critical for host defense, pathogen colonization resistance, and, more importantly, gut homeostasis.

Gut bacteria and their derived molecules, along with food particles are recognized and transduced through interaction with receptors on neuroimmune cells and enteroendocrine cells (Sternini et al., 2008). Visceral sensitivity is affected by the gut immune response in a manner relative to the proximity of neurons to immune cells as well as the propagation level of inflammatory reactions (Barbara et al., 2004; Aguilera-Lizarraga et al., 2021). More importantly, visceral hypersensitivity is a key pathophysiological mechanism leading to the development of FGIDs (Singh et al., 2016; Black et al., 2020b; Grover et al., 2021). Visceral hypersensitivity can be explained by an increased perception of gut mechano-chemical stimulation, which typically manifests in an aggravated feeling of pain and burning (Farzaei et al., 2016; Bellono et al., 2017). Activation of transient receptor potential vanilloid subtype 1 (TRPV1) is triggered by nerve growth factor (NGF), thermal stimulus, capsaicin, prostaglandins, acidic pH, and inflammatory mediators, which further release neuropeptides that aid in visceral pain sensation. (Farzaei et al., 2016). Furthermore, upregulation of TRPV1 has been associated with abdominal pain in IBS patients in a plethora of studies (Akbar et al., 2008; Grover et al., 2021).

Gut function is heavily influenced by the coordinated communication between the gut and brain (Quigley, 2017). This bi-directional interaction is essential for normal gut motility, visceral sensation, intestinal barrier integrity, gastric secretions, and immune response (Rhee et al., 2009). Just as the brain has a fundamental role in the maintenance of normal gut functions, the gut also has a vital role in modulating brain function. The gut-brain axis also aids in indirect signaling between the host and gut microbiota; for instance, gut microbial-induced epithelial barrier dysfunction alters this bi-directional interaction (Carabotti et al., 2015). The emotional motor system enables the perception of gut stimuli and modulates several gut functions (Needham et al., 2020). Consequently, alterations to the gut microbiota may regulate neurotransmitter synthesis or consumption, leading to emotional state and behavior alterations (Van Oudenhove et al., 2016). Many patients with FGIDs also experience psychological conditions such as stress, anxiety, and depression, indicating these conditions play a significant part in the development of FGIDs (Drossman et al., 2018). In addition, patients with FGIDs have been shown to have both abnormal structure and functional networks in parts of the brain that process information such as the visceral motor system and vagovagal reflux, as evidenced by functional brain MRI studies (Enck et al., 2017; Guleria et al., 2017; Ford et al., 2020). Taken together, it is clear that impaired brain function can lead to altered gut physiology, such as gut dysmotility and heightened visceral sensitivity, underpinning the symptoms of FGIDs. Further, dysregulated gut homeostasis can also lead to physiological changes in the brain, significantly hampering psychological health.

Prokinetic medications can amplify muscular contractions in the gut to help enhance peristaltic movements of the gut; therefore, accelerating transit of intra-luminal contents (Acosta and Camilleri, 2015). Prokinetic medications can act in a generalized fashion, affecting multiple regions of the gut, or in a more specific manner, only affecting certain areas of the gut based on the location of the receptor targets (Camilleri and Atieh, 2021). 5-HT4R agonists, 5-HT3R antagonists, 5-HT1AR agonists, ghrelin receptor agonists, dopamine-2 receptor antagonists, and muscarinic receptor antagonists are all prokinetic agents that have been demonstrated to restore altered gut motility in patients with gut motility disorders and FGIDs (Simren and Tack, 2018; Grover et al., 2019; Ghoshal, 2020; Camilleri and Atieh, 2021).

Probiotics, antibiotics, and FMT are therapeutic approaches to modulate gut microbial dysbiosis. The effectiveness of probiotic treatment for symptom improvement for FGIDs has been well documented; however, there is a lack of consistency between the current studies. Several studies have indicated improved symptom severity in patients with IBS treated with specific probiotic strains, including Bifidobacterium lactis DN-173 and Bifidobacterium animalis DN-173010154 (Aragon et al., 2010). One study observed that Lactobacillus gasseri OLL2716 was capable of shifting the gut microbiota community in the stomach of FD patients to comparable levels as HCs (Koga et al., 2019). Another study showed restoration of altered gut transit with symptoms improvement in IBS-C patients following probiotic treatment composed of Bifidobacterium lactis (Aragon et al., 2010).

Antibiotic use has also been demonstrated to improve symptom severity in patients with microbial dysbiosis-associated gut motility disorders and FGIDs (Pimentel et al., 2006; Ghoshal et al., 2011b; Ghoshal et al., 2018). For example, interventional studies reported that IBS-C and functional constipation patients have decreased breath CH₄ following treatment with rifaximin alone or a combination of rifaximin and neomycin, which improved the constipation phenotype (Pimentel et al., 2006; Ghoshal et al., 2018). Further, FD patients treated with rifaximin demonstrated improved dyspeptic symptoms, including belching and abdominal bloating/fullness in randomized controlled trials (Iovino et al., 2014). Moreover, meta-analysis and systematic reviews have demonstrated the efficacy of rifaximin and other antibiotics in treating small intestinal bacterial overgrowth (SIBO) (Gatta and Scarpignato, 2017).

In patients with FD, there is frequently the presence of Helicobacter pylori (H. pylori) infection (40–70%) (Ghoshal et al., 2011a; Naz et al., 2013; Kim et al., 2017; Rahman et al., 2021). The exact role of H. pylori infection in the development of FD symptoms remains controversial and it is not clear if it is an association and/or causation (Masuy et al., 2019b). Randomized controlled trials reported substantial symptom improvement after H. pylori eradication therapy (McColl et al., 1998; Bruley Des Varannes et al., 2001; Malfertheiner et al., 2003; Mazzoleni et al., 2011; Kim et al., 2013; Du et al., 2016). In contrast, several studies failed to confirm convincing results for the superiority of H. pylori eradication therapy over placebo groups to improve FD symptoms (Talley et al., 1999a; Talley et al., 1999b; Miwa et al., 2000; Veldhuyzen van Zanten et al., 2003; Zhao et al., 2013). However, owing to the improvement of symptoms in a subset of patients with FD, eradication of H. pylori is recommended as a first-line therapy in H. pylori associated-FD patients (Camilleri and Stanghellini, 2013; Suzuki and Moayyedi, 2013; Talley and Ford, 2015; Enck et al., 2017; Suzuki, 2017).

Along with probiotics and antibiotics, FMT has been shown to restore a balanced microbiota and is a potential treatment option for gut microbial dysbiosis (Khoruts and Sadowsky, 2016). However, it is still unclear whether FMT treatment for patients with FGIDs actually helps them or merely causes a placebo effect (Pulipati et al., 2020; Shanahan et al., 2021). Further, IBS patients’ symptoms were not significantly improved following FMT treatment when compared to the placebo group in a recent meta-analysis (Ianiro et al., 2019). In contrast, IBS patients’ symptom severity was significantly improved following treatment with FMT when compared to placebo (El-Salhy et al., 2020). Therefore, larger, more meticulous, and multicentric studies are warranted to accurately assess the benefit of FMT.

Increased mast cell number, pro-inflammatory M1 macrophages, and lymphocytes are characteristics of gut immune dysfunction and might be involved in the pathophysiology of gut motility disorders and FGIDs (Matricon et al., 2012). Additionally, ketotifen [A clinical trial (registration number NTR39, ISRCTN22504486) in the Netherlands], a mast cell stabilizer, was shown to increase the discomfort thresholds to rectal distension, improving abdominal pain in a subset of IBS patients (Klooker et al., 2010). However, mesalazine [ClinicalTrials.gov: NCT00626288 (phase 3)], an anti-inflammatory drug, failed to show any benefit in controlled trials on IBS (Barbara et al., 2016a). In a gastroparesis animal model, one study demonstrated that oxidative stress and damage of the pacemaker cells or enteric nerves was caused by depletion of resident M2 anti-inflammatory macrophages that express heme oxygenase-1 (HO-1) (Choi et al., 2010; Bharucha et al., 2016). However, gastric emptying was not significantly improved in a randomized-controlled trial following treatment with hemin, a HO-1-inhibitor in humans (Bharucha et al., 2016). Furthermore, patients with FD showed reduced number of mast cells and duodenal eosinophils, as well as reduced intestinal permeability and symptom severity when treated with proton pump inhibitors (Wauters et al., 2021). Further, the reduction of eosinophils was associated with clinical efficacy in these patients.

A murine model of visceral hypersensitivity, along with a subset of IBS patients, demonstrated HRH1 activation, which leads to increased submucosal neuronal responses to the TRPV1-agonist, capsaicin (Wouters et al., 2016a). Ebastine [ClinicalTrials.gov: NCT01908465 (phase 4)], the HRH1-antagonist, was found to reduce abdominal pain in a state-of-the-art study on IBS patients (Wouters et al., 2016a). Visceral analgesics, such as biased μ-OR ligands and CB2R agonists have proven to improve symptoms in patients with IBS (Camilleri, 2021). G protein-mediated pathways and beta-arrestin recruitment are activated by μ-OR-agonists that induce analgesia while mediating receptor internalization and desensitization, triggering the activation of μ-ORs in endosomes, and inhibiting gut motility (Raehal et al., 2011). The μ-OR-agonist, oliceridine, has been shown to help manage moderate or severe acute pain in patients who have not seen symptom improvement while taking other treatments (excluding opioids) (Markham, 2020). Furthermore, an animal model of visceral hypersensitivity had reduced visceromotor response to colorectal distension when treated with olorinab [ClinicalTrials.gov: NCT04655599 (phase 1)], a CB2R agonist (Castro et al., 2021). More importantly, olorinab may have exceptional efficacy in IBS patients, likely due to its potential analgesic effects; however, to confirm these results, more robust studies are needed. Neuromodulators are also used for the treatment of visceral hypersensitivity in patients with FGIDs (Drossman et al., 2018; Simren and Tack, 2018). Studies have demonstrated that TCAs, particularly amitriptyline, reduce visceral hypersensitivity in patients with IBS (Poitras et al., 2002; Morgan et al., 2005; Thoua et al., 2009). Dysregulated gut-brain interaction is a major pathophysiological mechanism in patients with FGIDs. This further reinforces that central neuron degeneration might be involved in the development of abdominal pain (Tornblom and Drossman, 2015; Drossman et al., 2018).

Modulation of altered GI secretion in chronic constipation and IBS-C patients via pharmacological agents for GC-C receptors and chloride channels on intestinal epithelium cells has been well studied (Pannemans and Tack, 2018). The maintenance of bowel function through fluid and electrolyte regulation is modulated by the gut GC-C receptors expressed by intestinal epithelial cells. The activation of GC-C receptors leads to the development of an ion gradient between the gut lumen and intestinal epithelium, which stimulates water movement in the lumen through the concurrent inhibition of sodium/hydrogen exchanger isoform three channels and activation of cystic fibrosis transmembrane conductance regulator (CFTR) channels (Brancale et al., 2017). Treatment with Linaclotide (approved in most parts of the world for treating IBS-C and chronic constipation), a GC-C receptor agonist, accelerated colonic transit and softened stool in patients with IBS-C (Chey et al., 2012; Rao et al., 2012; Black et al., 2018; Islam et al., 2018).

Fluid secretion and gut motility are regulated by intestinal epithelial cells’ chloride channels (Jiang et al., 2015). Chloride ions are released into the lumen of the intestine via activation of type-2 chloride channels. This results in an ion gradient, which promotes the release of water and sodium into the gut lumen and therefore increases stool volume and accelerates gut motility. The locally acting selective type-2 chloride channel agonist Lubiprostone [United States Food and Drug Administration (U.S. FDA) approved medicine for treating patients with IBS-C and chronic constipation and is also approved for the treatment of IBS-C and chronic constipation in many other countries)] has been shown to improve the frequency and consistency of stool, which leads to reduced constipation, bloating, and straining in patients with IBS-C and functional constipation (Johanson et al., 2008; Drossman et al., 2009; Black et al., 2018).

IBAT inhibitor and FXR agonists have been proposed to modulate altered BA secretion in chronic constipation, IBS-C, and IBS-D patients (Vijayvargiya et al., 2018; Vijayvargiya and Camilleri, 2019; Khanna and Camilleri, 2021). Elobixibat [ClinicalTrials.gov: NCT01007123 (phase 2)] is an IBAT inhibitor that hinders the reabsorption of BA in the gut (Khanna and Camilleri, 2021). This results in increased concentrations of BA in the colon, promotes fluid secretion, and rescues colonic dysmotility. Treatment with Elobixibat leads to improved symptoms associated with constipation, including straining, constipation severity, stool consistency, stool frequency, and abdominal bloating in patients with IBS-C and functional constipation (Khanna and Camilleri, 2021). In contrast, since FXR agonists, obeticholic acid (US. FDA approved medicine) and tropifexor [ClinicalTrails.gov: NCT02713243 (phase 2)], inhibit hepatocyte BA synthesis, that further leads to a reduction in BA concentration in the colon’s lumen, which rescues diarrhea symptoms (Walters et al., 2015; Camilleri et al., 2020b).

Neuromodulators TCA, TeCA, SNRIs, and SSRIs are frequently used as a second-line treatment options for patients with FGIDs, particularly IBS (Drossman et al., 2018). TCAs inhibit the reuptake of noradrenaline (NA) and 5-HT and have demonstrated potential for their anti-depressant and analgesic effects (Tornblom and Drossman, 2015). In contrast, TeCAs block presynaptic α2-noradrenergic receptors on NA and 5-HT neurons resulting in increased NA and 5-HT neurotransmission (Tornblom and Drossman, 2015). SSRIs boost the neurotransmission of 5-HT by blocking the presynaptic 5-HT transporter. However, the effect of these drugs is more beneficial in the treatment of psychological disorders than chronic pain syndromes. Finally, SNRIs block the reuptake of both the 5-HT and NA, boosting their neurotransmission and modulating pain sensation (Tornblom and Drossman, 2015).

These findings suggest that pathophysiology-directed therapeutic modalities could provide precise clinical outcomes in FGIDs as there is significant clinical overlap among FGIDs.

In Table 2, we have summarized the candidate drugs for gastroparesis and FD.

Prucalopride [ClinicalTrials.gov: NCT02031081 (phase 2), NCT02510976 (phase 4)], a 5-HT4R agonist, exerts both gastro- and enterokinetic effects, which improves GI symptoms when assessed by the gastroparesis cardinal symptom index (GCSI) (Carbone et al., 2019). Felcisetrag [ClinicalTrials.gov: NCT03281577 (phase 2)] and Velusetrag [ClinicalTrials.gov: NCT01718938 (phase 2)] are additional selective 5-HT4R agonists that have gut prokinetic effects (Chedid et al., 2021; Kuo et al., 2021). They were shown to induce symptom relief and accelerate GI transit in idiopathic or diabetic gastroparesis patients (Chedid et al., 2021; Kuo et al., 2021). Defects in gut motility, including impaired fundus accommodation and delayed gastric emptying, have been shown in a subset of patients with FD (Asano et al., 2017; Enck et al., 2017). Further, treatment with prokinetic agents typically restores impaired gastric-duodenal motility in patients with FD-PDS (Masuy et al., 2019b).

Buspirone [ClinicalTrials.gov: NCT03587142 (phase 2)], a 5-HT1AR agonist, improves gastric accommodation and postprandial symptoms in patients with FD (Tack et al., 2012). Another 5-HT1AR agonist, Tandospirone, has shown significant resolution in FD symptoms compared to the placebo-treated group in a multicenter study (Miwa et al., 2009). Mirtazapine [ClinicalTrials.gov: NCT01240096 (phase 4)]), a TeCA with 5-HT1AR agonist activity on central and peripheral 5-HT1AR, leads to gastric fundus relaxation with improved nutrient volume tolerance, global dyspeptic symptoms, and early satiation nausea in patients with FD (Tack et al., 2016). Further, recent reports noted that mirtazapine improves nausea, vomiting, and loss of appetite in patients with gastroparesis (Malamood et al., 2017; Marella et al., 2019).

Relamorelin (US. FDA approved medicine), a ghrelin receptor agonist, stimulates nodose afferents and dorsal motor nucleus of the vagus neurons, while accelerating gastric emptying and improving pain, nausea, bloating, and fullness in diabetic gastroparesis patients (Chedid and Camilleri, 2017; Camilleri et al., 2020a).

Metoclopramide (US. FDA approved medicine), domperidone (not approved in United States , but can be used through an FDA IND, due to concerns over its cardiac side effects. In Europe, domperidone has long been available over the counter; however, based on recent concerns over risk for prolongation of the QT-interval and increased risk of ventricular arrhythmia, it has only limited availability in Europe on a prescription basis, and only short-term use is recommended), and itopride [ClinicalTrials.gov: NCT00110968 (phase 3)], available mainly in Asia and to some extent in Eastern Europe are D2-receptor antagonists that exert both prokinetic and antiemetic effects in patients with gastroparesis and FD (Patterson et al., 1999; Dumitrascu and Weinbeck, 2000; Masuy et al., 2019b). Treatment with metoclopramide may result in adverse reactions, including a very serious condition called tardive dyskinesia. Additionally, there is an FDA black box warning for long-term use of metoclopramide (Rao and Camilleri, 2010).

Acotiamide [ClinicalTrials.gov: NCT03402984 (phase 2)], a muscarinic receptor antagonist (acetylcholinesterase inhibitor), antagonizes the presynaptic muscarinic receptors and has a prokinetic effect throughout the gut (Altan et al., 2012; Masuy et al., 2019a) and has been developed and approved in Japan and India for the treatment of FD. Studies have shown its efficacy in improving impaired gastric accommodation in patients with FD (Altan et al., 2012; Matsueda et al., 2012).

In Table 3, we have summarized the candidate drugs for IBS, functional constipation, and functional diarrhea.

5-HT4R agonists accelerate gut transit (Simren and Tack, 2018; Ghoshal, 2020). Gut motility was substantially improved in IBS-C patients treated with Tegaserod when compared to the placebo-treated patients (Black et al., 2020a) (Johanson et al., 2004). This drug led to a slight increase in cardiovascular and cerebrovascular ischaemic events, and therefore use was discontinued. The US. FDA approved reintroduction of tegaserod in 2019 for female patients with IBS that had no history of cardiovascular disease and were younger than 65 years old (Shah et al., 2021). Further, there were no significant cardiovascular events related to tegaserod observed in patients with ≤1 cardiac risk factor in this study. Prucalopride (approved for chronic constipation in most parts of the world) is another 5-HT4R agonist that demonstrated significantly improved chronic-constipation symptoms when compared to the placebo-treated group; however, IBS-C studies lack randomized controlled trials (Camilleri et al., 2008).

Alosetron (FDA approved medicine), ramosetron [ClinicalTrials.gov: NCT01225237 (phase 4)], and ondansetron [ClinicalTrails.gov: NCT03555188 (phase 3)], 5-HT3R antagonists, have been demonstrated to effectively treat IBS-D patients (Simren and Tack, 2018). Among 18 randomized controlled trials 5-HT3R antagonists were the best at improving stool consistency and symptoms of IBS-D, such as abdominal pain (Rokkas et al., 2021).