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Review

Gut–Brain–Microbiota Axis in Irritable Bowel Syndrome: A Narrative Review of Pathophysiology and Current Approaches

by
Mihaela Stoyanova
1,
Vera Gledacheva
2,* and
Stoyanka Nikolova
1
1
Department of Organic Chemistry, Faculty of Chemistry, University of Plovdiv, 4000 Plovdiv, Bulgaria
2
Department of Medical Physics and Biophysics, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(12), 6441; https://doi.org/10.3390/app15126441
Submission received: 28 April 2025 / Revised: 31 May 2025 / Accepted: 6 June 2025 / Published: 7 June 2025
(This article belongs to the Special Issue Drug Discovery and Delivery in Medicinal Chemistry)
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Abstract

Irritable bowel syndrome (IBS) is a widespread functional gastrointestinal disorder characterised by chronic abdominal discomfort and altered bowel habits. Despite its high impact on life quality and healthcare systems, the initial pathophysiology of IBS is not yet fully understood. The present narrative review aims to synthesise and integrate recent evidence regarding the multifactorial nature of IBS, focusing on the interplay between gut–brain interactions, microbiota, and immune responses, without proposing a novel model but rather reinforcing and updating existing conceptual frameworks. A comprehensive literature search of relevant studies published in English during the past two decades was conducted using Pub-Med, Scopus, and Google Scholar. The selected articles were thoroughly evaluated to provide a complete overview of IBS-related research. The review demonstrates that IBS is not only a multifactorial condition involving gut–brain axis dysregulation, altered gut motility, visceral hypersensitivity, and microbiome disturbances, but also a crucial psychosocial factor. Modern therapeutics targeting the microbiota and neurogastroenterology pathways show promising results but require further investigation. IBS represents a heterogeneous disorder with complex interrelated mechanisms. Improvements in understanding its multifaceted nature are of paramount importance in developing more effective diagnostic and therapeutic approaches. Continued research is essential to unravel the intricacies of IBS and improve patient outcomes.

1. Introduction

Today, likely because of the often additional mental and emotional burdens on individuals, visceral functional issues have become common [1,2]. Nonetheless, despite the efforts of physiologists and physicians working in this area, the medical understanding of these conditions remains inadequate [3]. Although IBS has been known for years, it still has unmet needs regarding its diagnosis and defining characteristics.

2. Materials and Methods

This paper reviews the current evidence supporting the characteristics and treatment of IBS. For this review, available literature was searched using PUBMED, MEDLINE, and EMBASE databases using the search terms ‘(IBS characteristics OR IBS treatment OR IBS microbiome)’ (through 20 March 2025). The results were limited to English-language publications. Duplicate records were removed (Figure 1). The specific publications included in this review were then manually selected from the search results for relevance to this topic.

3. Results

3.1. Characteristics of IBS

IBS is a functional digestive condition that significantly impacts quality of life and social functioning [4,5,6]. Only a small part of the pathophysiology of IBS is known [7]. Between 5% and 10% of the general population suffers from illness [8], which is characterised by frequent stomach pain associated with irregular stool frequency or form [9]. The majority of patients fall into one of three categories based on their predominant stool pattern: IBS with diarrhoea, IBS with constipation, or mixed-stool-pattern IBS, which includes both constipation and diarrhoea. Typical symptoms are used to make an IBS diagnosis in standard clinical practice [10]. This medical condition is frequently treated by focusing on the patient’s most troublesome or predominant symptom rather than the underlying pathophysiology [11]. Consequently, the majority of therapeutic measures do not change the disorder’s long-term natural history, and treatments have poor success rates [12]. IBS’s widespread prevalence and unsatisfactory response to tested treatments have caused a significant negative economic impact [13]. IBS has an important effect on quality of life and can cause severe impairment [14]. Therefore, enhancing the efficacy of upcoming treatments requires a deeper comprehension of the possible mechanisms involved in forming the symptoms.

3.2. The Role of Microbiomes

Numerous microorganisms, including bacteria, fungi, parasites, and viruses, can be found in the human gut. The microbiome, a collection of microorganisms including bacteria, fungi, viruses, and archaea, and their individual genomes, coexist harmoniously with the human body and continuously communicate with the human genome. The gastrointestinal system is home to around 100 million bacteria, which is 10–100 times the amount of eukaryotic cells in our body. The gut bacteria and the human body have developed into a mutually advantageous symbiotic relationship after years of common development [15,16,17]. Microbes have co-evolved with humans throughout our lengthy history [18,19,20,21,22,23], displaying recurring changes that correspond to the many phases of an individual’s existence.
The gut microbiome is a diverse ecosystem, whereas metabolic activity and collective effects on the host affect proper physiological function and disease predisposition [24]. The gut microbiota plays a crucial role in human health by fermenting dietary fibres, producing short-chain fatty acids, and regulating the immune system [25,26]. Studies indicate that people with IBS have a different gut microbiome than healthy controls [27].
Disruptions to the homeostasis of the enteric microbiome can compromise the intestinal mucosal barrier and reduce immunity [28]. Furthermore, alterations to the structure of complex commensal communities may result in the insufficient education of the host immune system, leading to immune-mediated diseases [29]. For example, the common fungus Candida albicans interacts with a range of bacteria, including Enterococcus faecalis and Clostridium difficile [30,31], altering their assembly and function through interactions with cell membranes, competition or cooperation for nutrients, and the production of secondary metabolites and antimicrobial peptides [32,33,34]. Maintaining intestinal homeostasis requires striking a careful balance between tolerance to commensal microorganisms and defence against enteric pathogens. A disturbance in this equilibrium has been connected to gastrointestinal tract inflammatory diseases [35].
An estimated 1.6 million people die each year from fungal diseases, which is more than three times the projected number of deaths from malaria and comparable to tuberculosis [36]. This is explained by the fact that individuals with weakened immune systems are more vulnerable to fungal infections than healthy individuals. Fungal infections have also become a major contributor to human morbidity and mortality worldwide, as a result of the HIV epidemic and medical advancements in recent decades (such as the discovery of antibiotics, improvements in cancer treatment, and surgical transplants), which have increased the number of immunocompromised people [37].
Invasive, cutaneous, and mucosal infections are among the many diseases caused by human pathogenic fungi [38]. Fungal infections are the cause of death and morbidity, especially in those with compromised immune systems. Compared to bacterial infections, invasive fungal infections currently have fewer accessible therapeutic medications [39]. The rising mortality and morbidity caused by fungal infections is also linked to antifungal resistance, the limited number of currently available antifungal medications, and the increased toxicity of these therapies [40,41,42]. IBS, specifically IBS with diarrhoea symptoms, or other functional gastrointestinal disorders, is often preceded by acute enteric infections [43]. The degree of inflammation is correlated with the probability of future visceral hypersensitivity, which may be one of the underlying causes for the beginning of symptoms [44,45]. In certain patients with IBS, intestinal inflammation may be driven by an immune response that is modified as a result of microbiota dysregulation [46]. Various environmental factors influence the production of neurons during the development process in the central nervous system. The intestinal microbiome plays a pivotal role in regulating and directing the neural development of the central nervous system [47]. Some IBS symptoms, such as visceral hypersensitivity, the influence of gut microbes on the host immune response and intestinal barrier integrity, and aspects of the brain–gut axis, could be accounted for by these changes. The preservation of the intestinal barrier is largely attributed to a well-established interaction among the gut microbiome, mucosal lining, host cells, immune defence system, and intestinal vascular barrier. This relationship involves a complex network of bidirectional interactions and regulation of inflammatory processes [48]. Bacterial overgrowth in the small intestine is characterised by an unusual increase in bacterial counts there; this phenomenon is seen as a significant positive indicator for patients with IBS [49].
For intestinal health and overall well-being, a healthy and diverse microbiome is essential. Healthy individuals typically possess a varied microbial composition, featuring beneficial bacteria like Lactobacillus spp. and Bifidobacterium spp. [50]. The gut microbiota mainly consists of four phyla: Actinobacteria, Bacteroidetes (Bacteroidota), Firmicutes (Bacillota), and Proteobacteria spp., which are all crucial for metabolic processes and immune function [51]. Patients with IBS usually exhibit changes in their gut microbiota, such as a reduction in Bifidobacterium spp. and an increase in Bacteroides spp. [52]. However, the reasons behind these changes and their stability are still under investigation [53].
Antibiotic exposure, on the other hand, is a risk factor for IBS [54]. Nonetheless, there is a lack of direct evidence showing that exposure to antibiotics during motherhood can cause IBS to develop in adulthood. Infants’ gut microbiota is very sensitive to the impact of antibiotics. Human health can be significantly impacted by alterations in microbiota composition and microbial colonisation [55]. After antibiotic treatment, a notable alteration in the gut microbiota is the proliferation of three genera—Bacteroides spp., Peptostreptococcus spp., and Enterobacter spp.—while the abundance of the Bacteroidetes (Bacteroidota) phylum diminishes [56]. Research from a European infants study found that maternal antibiotic use during the perinatal and breastfeeding periods may reduce Bacteroides spp. counts, while antibiotic treatment in newborns can alter microbiota composition by raising Enterobacteriaceae spp. levels [57], which is associated with IBS patients. The aforementioned alterations in gut flora can elevate the risk of intestinal disorders, such as IBS, through the modulation of the intestinal microbiota. To examine the link between antibiotic exposure in early life and IBS incidence, it is still necessary to conduct long-term evaluations of the impact of antibiotics on gut flora as well as large-scale retrospective studies. Antibiotics have been connected with the development of IBS and alter the gut microbiota [58]. Although small intestine bacterial overgrowth has been associated [59], its significance is mostly because of the limits of the diagnostic procedures, such as the culture of jejunal aspirates and breath tests [60].
Live bacteria called probiotics can change the nature of the gut microbiota when they are ingested as part of a diet. There are more and more probiotics available on the market. Probiotics are generally thought to be harmless, although they can have negative effects on people with impaired immune systems. Daily doses of these bacteria range from 106 to 1010 CFU, and they are beneficial to health. It is crucial to remember that probiotics might differ in their composition and effects; they are not all the same [61]. The type of probiotics and the conditions for which they are used determine their effectiveness.
It is safe and useful for patients with IBS to take probiotics, especially if they are used for less than eight weeks. The side effects of probiotics have been found to be less harmful than those of many other contemporary treatment options. It has been demonstrated that using probiotics improves stool consistency, gastrointestinal transit time, and overall stool frequency [62]. Probiotic-rich foods include kefir, yoghurt, and a few other fermented foods. These microorganisms could all help to improve gut health. The most often used microorganisms from these sources are Lactobacillus bulgaricus, Streptococcus thermophilus, Bifidobacterium strains, Lactobacillus delbrueckii subsp., and Lactobacillus strains. According to studies, they contain anti-inflammatory properties and enhance gut health. In addition to the common Lactobacillus spp. and Bifidobacterium spp., probiotic supplements often include bacteria from Enterococcus spp. and Streptococcus spp.
Ten of the twelve most often found fungi are yeasts, according to Suhr and Hallen-Adams [63], and the most prevalent species are Candida albicans and Saccharomyces cerevisiae. Given that yeast can ferment food and that a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols has been demonstrated to reduce IBS symptoms both temporarily and over time, this may be pertinent [64]. Crucially, the widespread dietary presence of S. cerevisiae may account for at least some of its high detection frequency, while Candida albicans is thought to be a gut commensal [65]. The idea that intestinal fungi and yeasts may play a significant role in the pathophysiology of IBD is becoming more well recognised [66,67].
There are numerous probiotic product formulations available, providing a variety of practical choices [68]. The filamentous fungus Aspergillus oryzae is included in these formulations together with other microbes, including Bacillus spp. and yeasts like Saccharomyces cerevisiae and S boulardii. These probiotics offer versatility and a variety of delivery techniques because they can be easily delivered as capsules, pills, powders, sprays, or pastes. Compared to pharmacotherapeutic drugs, probiotic use is a more natural approach with fewer side effects [69].
Several clinical trials have examined the impact of probiotics on functional bowel disorders (FBDs), with varying degrees of success [70]. Although there is currently no conclusive proof that one probiotic is superior to another, the published data points to a generally beneficial effect of probiotics on IBS symptoms when compared to a placebo [71,72]. According to findings from animal research, probiotics may have an impact on gut motility, visceral hypersensitivity, inflammation and immunological activity, gut barrier integrity, gut microbiota composition, and gut–brain connection in people with IBS [73].
Prokinetic drugs can speed up the transit of intra-luminal contents by increasing the gut’s peristaltic movements by the amplification of muscle contractions [74]. Depending on where the receptor targets are located, prokinetic drugs can either operate broadly, impacting several gastrointestinal regions, or more specifically, affecting just a few of them [75].
Prokinetics have been suggested as a treatment for IBS-C, gastroparesis, and chronic constipation based on prior clinical trials and meta-analyses [76]. Notably, using specific probiotic products appears to reduce depressed symptoms and change brain activity in IBS [77] and control gut–brain function in humans [78]. This is relevant for IBS and other FBDs where gut–brain interactions are thought to be paramount [79,80].

3.3. Gut–Brain Communication

The pathogenesis of IBS is complex and includes factors like visceral hypersensitivity and changes in gut microbiota, with the gut–brain axis being essential to developing symptoms. A strong association between infection and the onset of neuropsychiatric disease has been investigated [81]. As a result of inflammation, neurons are activated in the affected area, leading to the secretion of neuropeptides. These substances are also significant for immunomodulation, as they encourage immune cells. Throughout the intestinal epithelium, the enteroendocrine cells of the intestinal epithelial layer are essential in regulating coordinated communication among agents functioning along the brain–gut–microbiome axis. Intestinal endocrine cells detect alterations in luminal microorganisms via microbial inclusions; simultaneously, the cells communicate with the host system via neuroendocrine molecules [82]. Gut immune cells directly control the regulation of neuroimmunity and the brain’s reaction to inflammation, as well as influence endocrine signalling of immune factors through the gut–brain axis [83,84]. The gut microbial community (primarily Gram-negative bacteria) can also be regulated by the central nervous system, which influences its composition and homeostasis via the stress system (including the autonomic nervous system locus and hypothalamic–pituitary–adrenal axis) (Figure 2) [85].
In clinical practice, the correlation between ecological dysregulation and functional gastrointestinal illnesses, as well as central neurological disorders provides evidence of interactions between the microbiota and the brain–gut axis [86,87].
The human body’s microbiota composition changes dynamically throughout the life cycle, establishing a close connection with organisms from the earliest life stages. Consequently, the formation of the gut microbiota runs alongside that of the central nervous system, featuring swift and significant developmental transformations in infancy, childhood, and adolescence. Gut microbiota disturbances during early life can impact neurodevelopment and may result in adverse morbidity in adulthood [88]. For example, challenges during the neonatal period heighten the chances of developing functional gastrointestinal disorders later in life [89].

3.4. The Role of the Enteric Nervous System in IBS

The enteric nervous system, which regulates gastrointestinal motor, sensory, mucosal barrier, and secretory responses, can be affected by adverse events in early life, psychological factors, or gastrointestinal infections, according to the biopsychosocial model developed to explain symptoms of abdominal pain and disordered bowel habit in IBS [4,90].
Clinical evidence suggests that mental disorders are important factors in the development and progression of IBS, a disease with multiple causative factors [91]. Early life stress is one of the most common factors in the deterioration of IBS patients [92]. This stress may come from family, work or other social environments, or it may be caused by individual personality factors (Figure 3).
Functional magnetic resonance imaging (MRI) studies have also found heightened visceral stimuli response among IBS patients, with the increased activation of the anterior cingulate cortex, prefrontal cortex, and thalamus in response to rectal distention in most instances [93]. These responses also appeared to be modulated by anxiety and depression [94].
Neurotransmitters are responsible for sending messages throughout the body from neurons to target cells, including muscles, glands, and other neurons [95]. Histamine, serotonin (5-hydroxytryptamine, 5-HT), glutamate, γ-aminobutyric acid (GABA), dopamine, acetylcholine, and catecholamines are among the neurotransmitters that the enteric microbiota regulates crucially [96,97]. Each of these biological substances affect the activity of the enteric nervous system either individually or collectively as part of the pathology of IBS [98].
5-HT is one of the most extensively studied neurotransmitters in IBS research [99]. Enteric 5-HT stimulates inflammation, activates the immune system, changes gut motility, increases mucosal permeability, and enhances visceral hypersensitivity, all of which work together to activate IBS symptoms [99]. In fact, pharmacological treatments targeting 5-HT receptors are commonly used in contemporary clinical practice to treat IBS [100]. Overall, 5-HT and enteric microbiota are a viable focus for IBS research and medical treatment.
Several investigations were conducted to support the idea that a deficiency in 5-HT production and release is linked to IBS. Among the most effective methods for examining this relation were gene knockdown and gene transformation. Researchers state that when intestinal 5-HT production decreases, the intestinal lining weakens, which eventually causes constipation or clogging and raises 5-HT levels in the gut [101]. One theory is that people with IBS have enterocytes that lack the 5-HT transporter (SERT). Another theory centres on the reduced quantity of enterochromaffin cells in the gastrointestinal tract of those who experience IBS [102].
5-HT, essential for gastrointestinal motility, has a positive effect on information transmission to the central nervous system, and once released, can activate both intrinsic and extrinsic primary afferent neurons. Via SERT, 5-HT is reabsorbed by enterocytes and converted to 5-hydroxy-indole acetic acid (5HIAA), which limits its effects. The idea that 5-HT plays a key role in the development of IBS symptoms is further supported by the successful testing of therapeutic approaches which focus on different 5-HT receptors in IBS [103].
Studies show chronic increases in enterochromaffin cells in people who developed post-infectious IBS compared to people exposed to an acute enteric infection but who recovered, providing some of the first information regarding the potential role of 5-HT metabolism in IBS. Following this, a study [104] that analysed 5-HT levels in platelet-depleted plasma revealed that patients with IBS who experienced constipation had a lower 5-HT release following a typical meal when compared to those with post-infectious IBS and healthy people. Additionally, post-infectious IBS patients had a higher peak in postprandial 5-HT than either patient with constipation IBS symptoms or healthy controls. Another team of researchers found comparable results in healthy individuals who were fed and stopped eating, as well as IBS patients who had either diarrhoea or constipation symptoms. Furthermore, patients with constipation symptoms had a 5-HIAA/5-HT ratio within a normal range, while those with IBS who also experienced diarrhoea had a lower 5-HIAA/5-HT ratio [105]. This suggests that patients with diarrhoea may have a decreased 5-HT reuptake, while those with IBS who experience constipation are likely to have a reduced 5-HT release.
Several studies have looked at the relationship between intestinal barrier function, mucosal inflammation, immunological activation, and 5-HT metabolism. According to Cremon [106], 5-HT-positive enterochromaffin cells are more frequent in colonic biopsies from IBS patients than in biopsies from healthy controls; actually, this proportion was higher in IBS patients who experienced diarrhoea symptoms than in those who suffered from constipation symptoms. In this study, mucosal 5-HT was likewise significantly higher in IBS patients, and it was correlated with both a degree of stomach pain and mast-cell numbers.
Serotonin is predominantly secreted in the gastrointestinal tract. Intestinal periodic pulsatile distension promotes its release from mucosal cells [107,108]. 5-HT activates the 5-HT3 and 5-HT4 receptors found in the intrinsic primary afferent neurons of the enteric nervous system, mediating secretory and motor responses in the gastrointestinal tract and innervating smooth muscles [109]. 5-HT influences the lipo-polysaccharide-triggered release of several pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8/CXCL8, IL-12, and tumour necrosis factor α (TNFα) [110].
Among them, IL-1β is a cytokine that promotes inflammation. It is expressed at high levels in response to various stimuli. Produced mainly by leukocytes, IL-1β modulates the function of both immune (dendritic cells, macrophages, and neutrophils) and non-immune cells (Figure 4) [111].
The pathophysiology of inflammatory bowel disease (IBD) consists of two primary components: the deterioration of intestinal epithelial integrity due to heightened pro-inflammatory mediators, and a dysfunction in the intestinal immune system that results in chronic inflammation from immune cell aggregation and microbiota imbalance [112]. Traditional treatments for IBD, guided by pathological and physiological symptoms, focus on diminishing inflammation and attenuating the immune response through medications like 5-aminosalicylic acid (5-ASA), corticosteroids, immunosuppressants, antibiotics, or anti-TNF biological agents [113,114,115].
The first-line treatment for IBD consists of aminosalicylates, then corticosteroids, and subsequently immunosuppressants. Additionally, antibiotics (such as ciprofloxacin and rifampicin) and probiotics (like bifidobacterium spp. and lactobacillus spp.) are employed to correct imbalances in the gut microbiota. Should these treatments not adequately manage inflammation, surgical options like colorectal resection might be required [116]. Concerning the treatment methods mentioned above, clinical studies have shown that the long-term use of medications like 5-ASA can lead to serious side effects, including cytotoxic effects on healthy cells [117]. During IBD, epithelial cells and activated macrophages exhibit the overexpression of specific antigens or receptors, including mannose receptors, interleukins like IL-1β, and chemokines [118]. Despite the development of sustained-release medications like capsules and tablets, their efficacy is restricted, and they have demonstrated advantages only in a subset of individuals with IBD [119,120,121]. As an example, Sandborn et al. discovered that while anti-TNF-α monoclonal antibody therapy was effective for many patients, it necessitated a higher dosage [122]. Moreover, as time progressed, up to 50% of patients experienced diminished effectiveness, accompanied by heightened risks of adverse reactions like lymphoma, infections (especially the recurrence of tuberculosis), and lupus-like syndrome [123]. Moreover, conventional medicines can often result in side effects such as allergic reactions, nausea, and pancreatitis [124].
Thus, assuring that medications used for colorectal inflammation treatment are effective and safe is of utmost importance. To tackle this problem, sophisticated targeted nanomaterial drug delivery systems (NDDSs) have been created. These systems facilitate the delivery of drugs to inflamed regions, reduce their absorption by healthy tissues, and enhance their effectiveness.
NDDSs employ nanotechnology to produce nanomaterials comparable in scale to biomolecules and viruses, making them perfect for cellular recognition and uptake. Since the 1930s, vaccines have incorporated nano-sized aluminium adjuvants, and lipid NPs have recently been investigated for messenger RNA (mRNA) delivery. By 2022, more than 90 nanomedicines had received global approval, with around 60 approved by the U.S. FDA and about 30 by the Pharmaceuticals and Medical Devices Agency. NDDSs have demonstrated the ability to improve IBD treatment by enhancing drug bioavailability, shielding drugs from gastrointestinal acidity, and targeting them at sites of inflammation. This increases their therapeutic effectiveness while reducing drug exposure to healthy tissues [125,126,127,128]. Moreover, targeted NDDSs can focus drugs at the sites of inflammation, which lowers the necessary dosage and improves effectiveness by utilising inflammatory tissue-specific ligands to aim at particular cells [129]. The results show that NDDSs aimed at specific targets can enhance IBD therapy by directing drugs to inflamed tissues, limiting contact with healthy tissues, and decreasing adverse effects [130,131,132].
In summary, inorganic, organic, and polymeric nanocarriers can serve as NDDSs for drug delivery in IBD treatment, with their biological effects affected by factors such as shape, size, and physicochemical properties [133]. Inorganic nanocarriers are promising due to their simple preparation, stability, and ability to load drugs effectively; however, they encounter clinical safety issues [134]. On the other hand, organic nanomaterials from animal and plant sources can also function as efficient drug carriers, offering advantages such as high biocompatibility, low toxicity, controlled release, and regulation of gut microbiota. However, despite their clinical potential, they face challenges such as unstable preservation and decomposition due to gastric acid.

3.5. Signalling Pathway

Cells can interact and coordinate their activities through the intricate networks of chemicals and events known as signalling pathways. Cellular characteristics, such as growth, proliferation, and apoptosis, are ultimately influenced by the information they receive from internal or external stimuli. Errors in these pathways can result in diseases since they are essential for immunity, homeostasis, tissue repair, and development. Complex networks of molecular interactions known as signalling pathways transmit signals from cell surface receptors to intracellular effectors, which in turn influence cellular processes, such as differentiation, death, and proliferation. These signalling pathways are appealing candidates for therapeutic intervention because they are frequently dysregulated in a variety of illnesses, such as cancer [135], autoimmune diseases, and metabolic disorders [136].
Disruptions in the gut–brain axis, where the stomach and brain communicate via a variety of signalling pathways, are a component of IBS. These include the vagus nerve, the Toll-like receptor 4 (TLR4) pathway, the 5-HT signalling pathway, the MAPK pathway, mechanistic target of rapamycin (mTOR) signalling, and nuclear factor-kappa-B (NF-κB) signalling pathways (Figure 5). Symptoms like bloating, changed bowel habits, and stomach pain might result from the dysregulation of these circuits.
Multiple bidirectional routes involving immunological, endocrine, and neurological transmission connect the gut microbiota to the central nervous system. Neurotransmitters and digestive hormones that change the brain and behaviour can be produced by gastrointestinal tract cells under the influence of the microbiota [137,138]. In order to influence behaviour, they can also stimulate the vagus nerve, alter local immune populations that travel to the central nervous system, and release neuroactive compounds into the bloodstream [139,140]. Through adrenergic nerve transmission, which mainly affects intestinal motility, and the neurotransmitter effect on immunological mediators that influence microbiota composition and function, the central nervous system can regulate the gut microbiota [87].
Neuronal growth, brain function, cognitive regulation, and aging are all impacted by the “gut–brain axis,” a two-way communication system between the gut microbiota and the brain [141]. The central nervous, endocrine, and immunological systems are all part of the gut–brain axis, which is a network of information transmission between the gut and the brain [15,140].
The Toll-like receptor 4 is crucial for the development of IBS, according to a growing body of research in recent years [142,143]. As members of the transmembrane pattern recognition receptor family, Toll-like receptor 4 crosses the gap between innate and acquired immunity and is crucial for innate immune responses. Mucosal immune response, barrier function, cell adhesion, proliferation, migration, pathogen defence, epithelial cell injury healing, and other processes are all impacted by Toll-like receptor 4 [144]. Therefore, the formation and progression of various disorders, including autoimmune diseases, cancer, infections, and chronic inflammation, are facilitated by the deregulation of the Toll-like receptor 4 signalling pathway [145].
The development of IBD is significantly influenced by the production of proinflammatory cytokines, including as interleukin (IL)-1, IL-6, IL-17, IL-22, IL-23, TNF-α, and interferon-γ (IFN-γ) [146].
Certain amino acids (Table 1) may be potential biomarkers for the early diagnosis and treatment of ulcerative colitis patients, as evidenced by the different metabolic profiles of amino acids in ulcerative colitis [147]. Additionally, recent research indicates that amino acids play important roles in intestinal inflammation. The Trp of essential amino acids (EAAs) exerts beneficial regulatory function in mucosal growth or maintenance and the alleviation of intestinal inflammation by the 5-HT signalling pathway [148], in the recovery of colitis [149,150], and in the function of intestinal homeostasis and anti-inflammation in the intestine [151,152].
One of the nonessential amino acids, Gln, controls anti-inflammatory effects through the action of NF-κB signalling pathways, intestinal tight junctions, mTOR, and mitogen-activated protein kinase (MAPKs) [153,154,155].
Table 1. Functions of non-essential amino acids in intestinal inflammation on signalling pathways.
Table 1. Functions of non-essential amino acids in intestinal inflammation on signalling pathways.
Amino AcidsSignaling PathwaysFunctionsReferences
GlycineNF-κBStrengthen the intestinal mucosal barrier and reduce oxidative stress and TNF-a, IL-1, and IL6 levels[156,157,158,159]
AlanineUnclearEnhance intestinal defense and protection function[147,160]
GlutamineNF-κB, mTORMAPK/ERKEnhance the intestinal barrier, reduce proinflammatory cytokines, and have anti-inflammatory effect[161,162,163,164,165]
GlutamateUnclearStrengthen the intestinal mucosal barrier, alleviates heat stress-induced impairment of intestinal morphology, and reduce oxidative stress and TNF-a, and IL-1 levels[166,167,168,169]
CysteineNF-κB, Nrf2mTOREnhance intestinal barrier function, tight junctions, and homeostasis while lowering oxidative stress and decreasing TNF-α, IL-1β, IL-6, and IL-8[170,171,172,173,174,175,176]
ProlineUnclearIncrease levels of superoxide dismutase, tight junction proteins[177,178,179]
Aspartate and asparagineNF-κB and MAPKEnhance intestinal barrier function and lower the levels of proinflammatory cytokines[180,181,182,183,184,185,186]
TyrosineCalcium-sensing receptorsImprove intestinal health and immune response[147,187,188,189,190]
SerineUnclearIncrease colonic protection, mucosal healing and gut microbiota[191,192,193,194]
One of the possible pathophysiologies of IBS is a low-grade intestinal mucosal inflammatory response, and nuclear factor Kappa (NF-kB) is a crucial transcription factor in this response. As a transcription factor linked to the inflammatory response, NF-kB has the ability to control a number of inflammatory variables [195]. TNF-α, IL-1β, and IL-8 are all promoted by NF-κB activation, which results in a huge production of TNF-α and an inflammatory response [196,197].

4. Conclusions

To summarise, IBS comprises a range of immunological, microbiota-related, and gut–brain axis signalling changes. Various experimental results provide strong evidence supporting this notion. The current review brings together existing evidence within a well-established immune–brain–gut–microbial framework, reinforcing its importance in understanding the multifactorial pathogenesis of IBS. Current clinical treatment options are thought to be addressed in the future.

Author Contributions

Conceptualisation, S.N.; investigation, M.S.; resources, M.S. and V.G.; writing—original draft preparation, S.N. and M.S.; writing—review and editing, S.N. and V.G.; visualisation, V.G.; supervision, S.N.; project administration, S.N. All authors have read and agreed to the published version of the manuscript.

Funding

This study is funded by the Bulgarian Ministry of Education under the National Program “Young Scientists and Postdoctoral Students–2”, Project № MUPD-HF-016. Mihaela Stoyanova gratefully acknowledges this support.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AbbreviationMeaning
5-ASA5-aminosalicylic acid
5-HTSerotonin, 5-hydroxytryptamine
FBDFunctional bowel disorders
HPAHypothalamic–pituitary–adrenal
IBDInflammatory bowel disease
IBSIrritable bowel syndrome
ILInterleukin
mTORMechanistic target of rapamycin
MRIMagnetic resonance imaging
mRNAMessenger RNA
NDDSsNanomaterial drug delivery systems
NF-κBNuclear factor-kappa-B
TNFTumour necrosis factor

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Figure 1. PRISMA flowchart outlining the identification, screening, eligibility, and inclusion of studies in this narrative review. We created this image with Canva.
Figure 1. PRISMA flowchart outlining the identification, screening, eligibility, and inclusion of studies in this narrative review. We created this image with Canva.
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Figure 2. Multifactorial contributors to IBS: From stress to gut dysbiosis and altered GI function. We created this image with Canva.
Figure 2. Multifactorial contributors to IBS: From stress to gut dysbiosis and altered GI function. We created this image with Canva.
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Figure 3. The role of intestinal immune activation in IBS. We created this image with Canva.
Figure 3. The role of intestinal immune activation in IBS. We created this image with Canva.
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Figure 4. 5-HT as a key modulator of gut–immune crosstalk and inflammation in IBS. We created this image with Canva.
Figure 4. 5-HT as a key modulator of gut–immune crosstalk and inflammation in IBS. We created this image with Canva.
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Figure 5. Signalling pathways affecting IBS. We created this image with Canva.
Figure 5. Signalling pathways affecting IBS. We created this image with Canva.
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MDPI and ACS Style

Stoyanova, M.; Gledacheva, V.; Nikolova, S. Gut–Brain–Microbiota Axis in Irritable Bowel Syndrome: A Narrative Review of Pathophysiology and Current Approaches. Appl. Sci. 2025, 15, 6441. https://doi.org/10.3390/app15126441

AMA Style

Stoyanova M, Gledacheva V, Nikolova S. Gut–Brain–Microbiota Axis in Irritable Bowel Syndrome: A Narrative Review of Pathophysiology and Current Approaches. Applied Sciences. 2025; 15(12):6441. https://doi.org/10.3390/app15126441

Chicago/Turabian Style

Stoyanova, Mihaela, Vera Gledacheva, and Stoyanka Nikolova. 2025. "Gut–Brain–Microbiota Axis in Irritable Bowel Syndrome: A Narrative Review of Pathophysiology and Current Approaches" Applied Sciences 15, no. 12: 6441. https://doi.org/10.3390/app15126441

APA Style

Stoyanova, M., Gledacheva, V., & Nikolova, S. (2025). Gut–Brain–Microbiota Axis in Irritable Bowel Syndrome: A Narrative Review of Pathophysiology and Current Approaches. Applied Sciences, 15(12), 6441. https://doi.org/10.3390/app15126441

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