IBS is one of the most prevalent disorders of the gut–brain interaction (DGBI), formerly known as functional GI diseases. These conditions are characterized by the presence of chronic GI symptoms in the absence of identifiable structural or biochemical abnormalities, in contrast to organic GI diseases, which display evident inflammatory features [13].

Since the publication of the first Rome Criteria in 1994, the Rome IV Criteria (the fourth and current iteration) are currently considered to be the gold-standard symptom-based criteria to diagnose DGBI [14]. The Rome IV Criteria define IBS as the presence of persistent or recurrent lower abdominal pain (occurring at least one day per week in the last 3 months), with two or more of the following: related with defecation, associated with a change in stool frequency or associated with a change in stool form. Symptoms must have been present for at least 6 months [15].

Since no universally recognized specific biomarkers exist, diagnosis of IBS is mainly based on the clinical symptoms suffered by the patient, using the Rome IV Criteria. A careful history and physical examination, including digital rectal examination to exclude a rectal mass or dyssynergic defecation are needed when IBS is suspected [16]. Pictograms enhance comprehension by the patient and may be used to more accurately assess symptoms [17]. The IBS symptom severity score (IBS-SSS) is commonly employed to evaluate the severity of the disease, scoring from 0 to 500, with scoring below 175, 175 to 300, and above 300 representing mild, moderate, and severe IBS, respectively [18,19].

Abdominal pain, a hallmark in IBS patients [8,17], is generally self-reported through questionnaires and confirmed by the clinician through detailed medical history and physical examination [17]. In addition to the duration and frequency of abdominal pain events, the visual analog scale (VAS) is often used to evaluate pain intensity, with scores ranging from 0 (no sensation) to 10 (strongest imaginable sensation) [19,20]. Visceral hypersensitivity, a key contributor to abdominal pain in IBS, is defined as the increased perception of visceral stimuli (chemical, mechanical) [21]. Patients with visceral hypersensitivity tend to have abdominal pain, mainly due to intraluminal retention of the gas or solid contents and mechanical stress to the gut wall [22]. As with somatic pain, visceral pain is transmitted to conscious perception in the brain through a 3-neuron pathway, involving peripheral vagal, thoracolumbar, and lumbosacral afferents, which transmit the nociceptive information to the spinal cord nuclei, from which it travels to the upper nuclei in the brain through ascending pathways, with inhibitory modulation exerted by descending pathways. Visceral hypersensitivity may be due to a reduced threshold to the perception of luminal stimuli, to the dysregulation of central processing or both. In IBS, colonic or rectal distension may be used to evaluate the presence of visceral hypersensitivity and could be useful to search for new treatments. Indeed, IBS patients display lowered pain thresholds in response to rectal distension induced by a barostat, as compared to healthy volunteers and patients with other GI diseases [23].

The Bristol scale is used to determine stool appearance, which varies from 1 (hard, lumpy stool) to 7 (watery stool), suggestive of severe constipation and severe diarrhea, respectively, whereas normal stool form is given 3–4 points on this scale [24]. Although IBS is commonly classified into two main subtypes based on stool form and frequency, namely constipation-predominant (IBS-C) and diarrhea-predominant (IBS-D), it is well recognized that many patients experience both constipation and diarrhea in varying proportions, either alternately or simultaneously, a presentation defined as mixed IBS (IBS-M) [14]. According to the Rome Foundation Global Epidemiology Study, IBS-C and IBS-M each account for approximately one-third of all IBS diagnoses, followed by IBS-D (28.7%) and unclassified IBS (6.5%) [4]. Interestingly, GI transit measurement (using radiopaque markers and scintigraphy as the gold standard, as well as other more research-oriented methods such as breath tests, ingestible capsules sensing endoluminal pH or gas content, 3D-GI transit test or magnetic resonance imaging capsule markers test, or even the blue dye muffin or sweetcorn for whole GI transit test) has been proved to be relevant to identify changes in bowel habits (stool frequency and form), although its relevance for other GI symptoms in IBS, such as abdominal pain, is not clear [25].

Importantly, in contrast with organic diseases affecting the bowel such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), imaging and other diagnostic investigations are typically normal in most patients with IBS. Accordingly, as already mentioned, IBS is considered a “functional” disorder, and patients often require reassurance that their symptoms do not indicate a serious underlying disease. Thus, diagnostic investigations such as endoscopy (colonoscopy or flexible sigmoidoscopy, with biopsy), imaging analysis (computed tomography colonography, magnetic resonance enterography, wireless capsule endoscopy) and other diagnostic tools (including routine blood tests, C-reactive protein, celiac serology, fecal calprotectin, fecal elastase, 23-seleno-25-homo-tauor-cholic acid) are sometimes required to exclude conditions that can mimic IBS, such as coeliac disease, IBD, microscopic colitis, CRC or bile acid diarrhea (BAD). Indeed, BAD should be considered as a possible alternative diagnosis in patients with IBS-D [26]. The clinical history needs to also consider the possibility that the recent introduction of a new drug (NSAIDs, PPIs, statins, or selective serotonin reuptake inhibitors, SSRIs) may be causing the symptoms (i.e., diarrhea) [27]. Innovative medical technology, such as confocal endomicroscopy, capsule-based microbiota sampling, and even artificial intelligence approaches, applied to metabolomic profiling and dysbiosis detection, or to the endoscopic detection of subtle disease-associated mucosal changes, is increasingly being used, although still mainly for research, not for daily practice [28].

In addition to the presence of cardinal symptoms, e.g., abdominal pain and changes in bowel habits, and the absence of alarm symptoms and signs of organic disease when these need to be evaluated, IBS diagnosis may be supported by the following features, as determined during clinical history taking: onset post-infection or following recurrent antibiotic use, onset after acute or chronic stress, onset after previous psychological trauma, presence of extraintestinal symptoms, e.g., back pain, tiredness, gynecological issues, presence of other functional non-GI disorders, e.g., fibromyalgia, tension headache, chronic fatigue syndrome, presence of psychological comorbidities, e.g., anxiety or depression [16]. These features are related to the risk factors contributing to IBS development, as described in depth below, and its common comorbidities.

Despite performing better in terms of specificity, Rome IV criteria are somehow restrictive and less sensitive than Rome III (the previous iteration of the Rome criteria), although, interestingly, this can be improved by relaxing the number of days with abdominal pain to 3 per month instead of 1 per week [26], and this has been suggested as a possible improvement of future Rome Criteria iterations [26,29]. Whatever the case may be, using symptom-based criteria properly is key to avoid over-investigation, which, in addition to being generally unnecessary, as well as costly and time-consuming for the health system, may cause anxiety in patients with IBS [16]. This allows making a positive diagnosis of IBS and establishing treatment measures to manage it. For this, it is important first to explain the etiology and natural history of the condition in the context of the gut–brain axis to the patients, to manage their expectations (explaining that there is no cure for IBS and that long-term treatment is likely to be necessary), to provide lifestyle and dietary advice, including the use of probiotics or a low FODMAP diet in some cases, and, if no improvement of symptoms is achieved, to discuss treatment options targeted at the predominant symptom [16], as follows:

• -Abdominal pain: antispasmodics (hyoscine, peppermint oil) and gut–brain neuromodulators (e.g., a tricyclic antidepressant) as first- and second-line treatments, respectively,
• -Constipation: laxatives and secretagogues (lubiprostone, linaclotide), as first- and second-line treatments, respectively,
• -Diarrhea: loperamide and 5-HT3 receptor antagonists, eluxadoline or rifaximine, as first- and second-line treatments, respectively.

For refractory symptoms, brain–gut behavioral treatments, such as IBS-specific cognitive behavioral therapy or gut-directed hypnotherapy are suggested [16]. These approaches are primarily designed to treat GI symptoms, rather than to address psychological health needs per se, although mental health is recognized to be an important factor contributing to maintaining GI symptoms in IBS. Indeed, anxiety or depression symptoms affect 20–40% IBS patients [30] and somatization scores are elevated in them [31].

Thus, being a DGBI, accurate diagnosis of IBS should consider not only the GI symptoms but also its psychological impact, and recent studies suggest that IBS may be subclassified in at least seven clusters [32], as shown in Table 1.

These clusters are important because they predict healthcare-seeking, prior abdominal surgery, symptom severity, and impairment in quality of life in people with IBS [32]. Moreover, treatment can be adjusted according to the cluster to which the patient belongs. Thus, patients with low levels of GI and psychological symptoms (i.e., cluster 3) could be managed with simple dietary advice, first-line drugs, or reassurance. Individuals with predominantly GI symptoms (i.e., clusters 1 and 7) could be treated just with peripherally acting drugs (antidiarrheals, laxatives) targeting those specific symptoms. Patients with mainly abdominal pain and psychological symptoms (i.e., cluster 2) may benefit from a brain–gut behavioral therapy. Moreover, in patients with a combination of GI and psychological symptoms (i.e., clusters 4 and 5), combination therapies with a peripherally acting drug and either a gut–brain neuromodulator or brain–gut behavioral therapy may be the best therapeutic option. In patients with a high prevalence of other chronic medical conditions and previous abdominal surgery (i.e., cluster 6), a multidisciplinary approach including psychological input would be required. These findings may also be useful for the formulation of the coming Rome V Criteria.

It is important to highlight that the current concept of IBS, through Rome IV evolving to Rome V diagnostic criteria (to be released in 2026, [29]) recognizes the complex interplay between the neuroendocrine axis, gut microbiota, inflammatory markers, and GI symptoms, leading for the first time to the application of multiparametric approaches to study IBS, in accordance with the biopsychosocial model [33,34]. Thus, in a recent study conducted in IBS patients (irrespective of their subtype) in comparison with controls, the levels of adrenocorticotropic hormone (ACTH), cortisol, and serotonin were higher, Bacteroides were more prevalent and Bifidobacteria, Lactobacillus, and Clostridium were less prevalent, and pro-inflammatory IL-6 and IL-8 were higher, whereas the anti-inflammatory cytokine IL-10 was lower. Interestingly, ACTH and cortisol increases were greater in IBS-D than in IBS-C, irrespective of the measurement point (8 a.m., 4 p.m., 12 a.m.) [33]. Importantly, other researchers have recently used functional magnetic resonance imaging (fMRI) and the functional connectivity strength (FCS) method together with machine-learning algorithms to differentiate between IBS patients and healthy controls, revealing a unique pattern of FCS alterations in brain areas involved in pain regulation and emotional processing. These findings suggest that the identified abnormal FCS features might serve as effective biomarkers for IBS classification [19].

Various risk factors, such as mental stress, mainly in childhood, a previous transient infection or chronic low-grade inflammation of the GI tract, abnormal intestinal microbiota (dysbiosis), and dysfunction of colon motility have all been related to the development of IBS symptoms [35,36]. In these regards, Sulaimi and collaborators recently performed a study on the risk factors for developing IBS and found eight main categories (with some overlaps): dietary, genetic, environmental, psychological, gut microbiome, socio-economic, physiological, and pathological [37]. Among the different risk factors identified, the authors showed that the most frequently reported ones were female gender, gastroenteritis, anxiety disorders, and depression [37]. By identifying the risk factors underlying the onset of IBS, preventative measures can be established.

The gender-dependent differences in IBS incidence, prevalence, severity, and somatic comorbidities, such as joint and muscle pain, are related with the modulatory effect of progesterone on the serotonin system controlling peristalsis; furthermore, estrogen and progesterone inhibit smooth muscle contraction, contributing to explaining the reason for the higher incidence of the IBS-C type in women compared to men [38,39]. In a recent study, female patients showed extensive microstructural alterations in sensorimotor, corticothalamic, and basal ganglia circuits involved in pain processing and the integration of sensorimotor information, suggesting that the etiology and maintenance of symptoms for females with IBS is driven by greater central sensitivity for multiple sensory stimuli [40]. Interestingly, the proportions of female individuals were greatest in clusters with the highest psychological burden (Table 1) in the previously mentioned study [32].

Regarding gastroenteritis, different pathogens have been identified to cause post-infectious IBS (PI-IBS), such as Norovirus, Rotavirus, E. coli, Salmonella spp., Campylobacter spp., Giardia duodenalis and, more recently, SARS-CoV-2 [37,41]. PI-IBS is probably due to prolonged imbalances in the host immune cells and mediators affecting inflammatory homeostasis, as well as disruption of the intestinal mucosal barrier and intestinal dysbiosis, favoring the hypersensitization of nerve afferents [42,43]. The changes in microbiota composition caused by gastroenteritis, antibiotic use, food selections, and stress underlying the development of IBS, justify the recent interest in evaluating the therapeutic potential of probiotics in clinical trials. Additionally, prebiotics may also be useful to preserve a healthy microbiota balance [11,28].

The impact of stress on the development of IBS and the exacerbation of its symptoms is associated with the presence of anxiety and/or depression in these patients through the hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system, leading to altered gut motility and increased visceral sensitivity [44]. Microbiota dysbiosis is also induced by stress, facilitating gut barrier dysfunction (“leaky gut”) and immune system activation, a low-grade chronic inflammation contributing to dysmotility [45]. Failure in IBS symptom resolution in patients with undiagnosed anxiety and depression may facilitate seeking alternative therapies, whereas correct pharmacotherapies and psychotherapies may suffice [16].

All these studies highlight the complexity of IBS and the difficulties in realizing an accurate diagnosis and finding fully satisfactory treatments, which must address the different symptoms and signs of IBS in a personalized manner, ideally based on the pathogenetic mechanisms [16,46].

Indeed, IBS is a multifactorial disease involving multiple pathogenetic mechanisms intricately interconnected, operating in a complex synergistic manner (Figure 1). Gut microbiota dysbiosis can alter intestinal permeability by producing metabolites that affect tight junction proteins, which may trigger low-grade inflammation as bacterial products that may interact with immune cells in the lamina propria [47]. This persistent low-grade inflammatory state, in which mast cells seem to exert a key role [48], may trigger visceral afferent neurons, contributing to visceral hypersensitivity [49]. The modulation of transient receptor potential (TRP) channels, particularly TRPM8, TRPA1, and TRPV1, plays a key role in this process, influencing both pain perception and gut motility [50,51]. Meanwhile, stress-induced changes in the gut–brain axis, mediated via the HPA axis and autonomic nervous system, can alter neurotransmitter release and smooth muscle function, which is able to modulate gut microbiota, thus creating a feedback loop [49]. The activation of nuclear factor kappa B (NF-κB) pathways induced by leaky gut further fuels inflammation by regulating cytokine production and cellular stress responses [52,53]. Genetic factors may predispose individuals to these disturbances, affecting serotonin signaling, immune responses, and overall gut homeostasis. Additionally, the endocannabinoid system, particularly through the activation of CB1, CB2, and TRPV1 receptors, modulates inflammation, pain perception, and motility [54,55]. Oxidative stress, resulting from low-grade inflammation and metabolic changes, can damage the intestinal epithelium, exacerbate permeability issues, and impair smooth muscle function [56].

The complexity of IBS pathogenesis requires a multi-targeted therapeutic approach, which may simultaneously modulate several molecular targets to address multiple aspects of this disorder [46]. Developing new drugs for IBS is also difficult because of the lack of biomarkers and endpoints, which implies high placebo response rates, which do not facilitate pharmaceutical companies’ investment in this field [57,58,59]. The few new drug classes that have been developed recently have not led to any incremental increase in the likelihood of therapy success [60].

In recent years, there has been an increased acceptance of medicinal plants, driven by the belief that natural products have fewer side effects and are more effective and more affordable than their synthetic counterparts [11,12]. Given the complex and multifactorial nature of IBS, these herbal-based therapies have emerged as promising therapeutic and complementary approaches to conventional treatments, e.g., peppermint oil has already been mentioned as conventional antispasmodic first-line treatment of abdominal pain. The following section will explore in detail the mechanisms of action, clinical evidence, and potential benefits of various herbal remedies in IBS management.