Irritable bowel syndrome remains a complex disorder of gut-brain interaction: Too many actors on stage

Abstract

The recent study published in the World Journal of Gastroenterology examines the interplay among the neuroendocrine axis, gut microbiota, inflammatory markers, and gastrointestinal symptoms in irritable bowel syndrome (IBS). By integrating all these factors into a single study, this approach reflects the modern concept of functional gastrointestinal disorders as disorders of the gut-brain interaction to be approached in a multiparametric manner, also incorporating non-gastroenterological elements and extending evaluations to parameters related to the neuroendocrine axis. This invited letter to the editor summarizes the main results of the aforementioned study and highlights its multiparametric approach, including variables not strictly gastroenterological, in the study of IBS, and discusses its strengths and limitations.

Key Words: Neuroendocrine axis; Gut microbiota; Inflammatory response; Irritable bowel syndrome; Functional gastrointestinal disorders; Biopsychosocial model; Mucosal inflammation; Cytokines; Serotonergic system; Melanocortin system

Core Tip: This letter highlights the complex interplay among the neuroendocrine axis, gut microbiota, and inflammatory response in irritable bowel syndrome (IBS). By adopting a multiparametric approach, the findings proposed by the commented article suggest that IBS involves both gastrointestinal and neuroendocrine factors, supporting the biopsychosocial model for understanding and managing functional gastrointestinal disorders.

TO THE EDITOR

We read with interest the recent study published in the World Journal of Gastroenterology by Zhang et al[1] entitled, “Correlation between the neuroendocrine axis, microbial species, inflammatory response, and gastrointestinal symptoms in irritable bowel syndrome”, in which the authors compared established elements of the postulated pathogenic hypotheses for irritable bowel syndrome (IBS), including factors related to the neuroendocrine axis, gut microbiota, and pro-inflammatory cytokines.

INSIGHTS OFFERED BY THIS NEW WORK

The authors recruited, over 1 year, 80 patients with IBS [most of whom had IBS with diarrhea (IBS-D)] and an equal number of healthy controls, ensuring sample homogeneity in terms of sex, age, body mass index, and educational level. They collected neuroendocrine variables [cortisol, adrenocorticotropic hormone (ACTH), serotonin (5-HT)], serum inflammatory markers [interleukin 6 (IL-6), IL-8, and IL-10], clinical data (gastrointestinal symptoms assessed using the Bristol stool form scale and the ROME III diagnostic criteria for functional gastrointestinal disorders), and gut microbiota characteristics (using the 16S rRNA technique). The results demonstrated higher levels of ACTH, cortisol, and serotonin (5-HT) in patients with IBS compared to controls, with no intragroup differences among IBS phenotypes [IBS-D, IBS with constipation (IBS-C), and a combination of IBS-D and IBS-C]. Regarding gut microbiota, Bacteroides were more prevalent in the IBS group than in controls, while Bifidobacteria, Lactobacillus, and Clostridium, showed opposite trends.

Pro-inflammatory cytokine levels (IL-6, IL-8) were higher, and one anti-inflammatory cytokine (IL-10) assessed was lower in the IBS group than in healthy controls. An intriguing finding was the greater increase in ACTH (and cortisol) levels among diarrhea-predominant patients compared to constipation-predominant patients at all measurement points (8:00 am, 4:00 pm, and 12:00 am).

IBS REMAINS A COMPLEX FUNCTIONAL GASTROINTESTINAL DISORDER WITH AN INTRICATE INTERPLAY OF MULTIPLE FACTORS

There is nothing new under the sun regarding each of these elements individually. Still, comparing all these factors within the same research setting was interesting. This multidimensional approach will likely become increasingly necessary in light of the well-known and historical shift that has legitimized IBS (C1 class according to ROME IV criteria) as an essential part of a highly diverse group of functional gastrointestinal disorders, with its specific diagnostic criteria[2]. This transition moves away from viewing IBS merely as a diagnosis of exclusion or a fallback for clinicians when organic gastrointestinal disorders have been ruled out[3]. As a result, IBS has emerged as a complex product of a biopsychosocial mechanism in which genetic, epigenetic, and environmental factors interact with psychosocial elements (e.g., stress, psychological traits, coping abilities) and intrinsic physiological dynamics of the gut (including motility, sensitivity, and gut microbiota), ultimately producing the clinical phenotype of functional gastrointestinal disorders[4].

Although it is beyond the scope of this letter to review the pathophysiological evidence of IBS, some preliminary summary considerations can be made to approach the topic. Several factors are, therefore, involved in the pathophysiology of IBS.

Genetics

It is well known from genome-wide studies that patients with IBS are associated with specific variants on chromosome 9 at the 9q31.2 Locus (single nucleotide polymorphism rs10512344), which has been primarily linked to the regulation of cellular ion transport membrane, mutations in the sucrase-isomaltase gene, as well as autonomic dysfunction[5-7]. Staying within the realm of ion channel regulation, additional genetic variants associated with IBS involve the sodium voltage-gated channel alpha subunit 5A gene, which encodes sodium ion channels explicitly expressed in the gastrointestinal tract, affecting both smooth muscle cells and interstitial cells of Cajal[8]. In addition to these findings, other genes related to neurotransmission have been implicated in IBS, such as polymorphisms in genes involved in 5-HT biosynthesis [such as tryptophan hydroxylase (TPH), TPH in isoforms 1 and 2] and genes associated with its reuptake (5-HT reuptake transporter)[9].

Epigenetics

It also plays a role, as epigenetic modifications that contribute to dysregulation of the gut-brain axis have been described in IBS. These modifications primarily involve microRNAs that regulate mediators of visceral pain sensitivity (such as 5-HT3) and modulate histone acetylation activity on target genes, both positively and negatively[10]. In particular, it has been observed that in patients with IBS, there are modifications in DNA methylation in key genes primarily involved in oxidative stress (such as glutathione-S-transferases Mu 5) and also implicated in the regulation of the adrenal axis, particularly the corticotropin-releasing factor gene[9].

Gut microbiota and intestinal barrier

Gut microbiota bidirectionally contributes to pathogenesis and can also be influenced by IBS. It remains challenging, even today, to define an utterly healthy microbiota for comparison with that of patients with IBS. However, it is known that IBS patients can benefit from the elimination of gut microbiota fermentable food components, such as fermentable oligosaccharides, diosaccharides, and monosaccharides and polyols (FODMAPs)[11,12]. Numerous bacterial species have been described as altered in IBS patients and differing levels of short-chain fatty acids[11]. It is also known that structural and functional alterations in the gut epithelial barrier in IBS promote low-grade inflammatory activity at this level[13]. This leads to increased intestinal permeability, allowing greater passage of both microbiota elements and their metabolites outside the intestinal lumen, further stimulating the low-grade inflammatory burden[13]. These changes are also associated with variations in the expression of pro-inflammatory cytokines and intestinal toll-like receptors[13].

Environmental factors

Environmental risk factors linked to IBS are indeed numerous. In addition to the already mentioned diet relationship between IBS and FODMAPs, it has also been reported that a diet rich in sugars and fats (of the Western type) increases the risk of IBS[14]. It is also well established that IBS can be post-infectious following infection by various pathogens, including but not limited to Campylobacter jejuni, Escherichia coli, Salmonella enterica serovar Typhimurium, Clostridioides difficile, Vibrio cholerae, and Giardia lamblia[15]. Other behaviors, including cigarette smoking and alcohol consumption, have been associated with IBS[16-18].

However, all these aspects and the neuropsychological factors contribute to the pathophysiological model of the microbiota-gut-brain axis (Figure 1)[19]. Psychological comorbidities in patients with IBS are highly prevalent, including stress and anxiety-depressive syndromes (which reach a prevalence of over 30% in these patients), in a bidirectional relationship of reciprocal influence[15]. A bidirectional interaction thus occurs between the central nervous system and the enteric nervous system, where the central nervous system modulates visceral sensitivity and motility, influencing the symptoms in IBS patients[20]. Conversely, the intestinal microenvironment, both in its neuroimmunological components and microbiome and microbiota, sends signals to the central nervous system[20].

Figure 1 The microbiota-gut-brain axis. The microbiota-gut-brain axis denotes the bidirectional communications between the central nervous system, the enteric nervous system, the gastrointestinal system, and the gut microbiota. This intricate interplay, when disrupted, underpins many of the pathophysiological elements underlying irritable bowel syndrome (IBS). 5-HT: Serotonin; SCFAs: Short-chain fatty acids.

HENCE, THERE IS A NEED FOR A MULTIPARAMETRIC RESEARCH PERSPECTIVE ON IBS: THE NECESSITY OF ADDRESSING THE COMPLEXITY OF THE WHOLE RATHER THAN ITS COMPONENTS

In light of all these considerations, studies focusing on IBS should likely adopt this perspective, considering not only parameters related to specific gastrointestinal categorization (such as symptoms and endoscopic findings) but also examining non-gut-specific variables of psychological and neuroendocrine origin.

For this reason, ROME IV has laid the groundwork for a revolution, likely to continue with ROME V, wherein functional gastrointestinal disorders are defined as "disorders of gut-brain interaction"[21]. This approach integrates most functional disorders with a psychological perspective, particularly cognitive-behavioral approaches, which run parallel to gastroenterological strategies to manage functional symptoms directly[21].

IBS is, to date, an epidemiologically significant condition, as large-scale population studies estimate that over 40% of the sample population experience a functional gastrointestinal disorder[22].

It is not surprising that ROME IV has incorporated functional gastrointestinal disorders, such as those in category D (i.e. centrally mediated disorders of gastrointestinal pain), whose diagnostic criteria include minimal gastroenterological aspects but a significant focus on central nervous system involvement[23]. Their therapeutic algorithms predominantly involve psychological and psychiatric interventions, with no gut-specific treatments[23]. This underscores the need to move beyond solely gastroenterological parameters, such as bowel movement frequency, abdominal pain, and stool consistency, as the sole determinants of the patient's clinical picture.

It is easy, however, to speak of a functional disorder while overlooking any consideration of potential "organic" factors in IBS, and the authors reopen this chapter with some of their findings. Their data show that patients with IBS, compared to controls, exhibited a higher pro-inflammatory burden (evident in increased serum levels of IL-6 and IL-8) and a reduced anti-inflammatory response (reflected in lower serum levels of IL-10).

This finding also highlights and echoes the concept of mucosal inflammation, which can coexist even in a functional disorder like IBS. This phenomenon has already been reported and extensively debated[24-26].

Notably, one of the most established markers of intestinal inflammation, fecal calprotectin, is a reliable indicator for distinguishing suspected inflammatory bowel disease from IBS[27]. However, patients with IBS may still present with elevated levels of this marker[28]. Conversely, in patients with inflammatory bowel disease, an IBS overlap can commonly occur[29-31], suggesting a bidirectional relationship. On the one hand, IBS may find more fertile ground in a condition that is highly debilitating and disrupts psychosocial balance[32,33]; on the other hand, IBS may develop within an already altered inflammatory environment, contributing to its microinflammatory pathogenic component[26].

It is, therefore, not surprising that mucosal inflammation (i.e. low-grade inflammation), although not reaching the characteristic and paradigmatic levels seen in its "organic disease" counterpart, inflammatory bowel disease, can also exist in a functional disorder like IBS as a potential pathogenic factor. However, it may not be sufficiently pronounced to warrant being a primary therapeutic target, as current international guidelines do not recommend robust immunomodulatory therapies as a treatment strategy for IBS[34-38].

In the authors' data, the pro-inflammatory markers also correlated with the variables they employed for analyzing the neuroendocrine axis (i.e. ACTH, cortisol, and 5-HT levels).

Indeed, the melanocortin system, once a neglected area of gastrointestinal research[39], is now emerging as a promising avenue due to its potential influence on pro-inflammatory and anti-inflammatory processes. Recently, we published our data in the World Journal of Gastroenterology, demonstrating an increased expression of melanocortin receptors 3 and 5, which have an affinity for ACTH, in the colons of patients with ulcerative colitis and Crohn's disease[40]. Moreover, one of our literature reviews revealed melanocortins have an inextricable role in regulating inflammatory processes throughout the body[41].

In the authors' data, ACTH, cortisol, and 5-HT levels were significantly higher in patients with IBS than the controls. These findings had previously been reported[42,43] to highlight that patients with IBS, due to an altered response to corticotropin-releasing hormone, exhibit a reduced capacity for resilience and stress response, which aligns well with the biopsychosocial model already mentioned.

A more detailed study of the hypothalamic-pituitary-adrenal axis in the context of IBS could help elucidate why patients exhibit both the genesis of stress and a diminished ability to manage stress—an essential aspect of the physiological functioning of this axis[44]. Park et al[45], in a comparative study between IBS patients and healthy controls, demonstrated that IBS patients show reduced resilience, a finding that correlates with more severe gastrointestinal symptoms. Furthermore, stress-related psychiatric disorders, such as post-traumatic stress disorder, represent a significant risk factor for IBS, with an estimated odds ratio as high as 2.80 in recent meta-analyses[46]. Our research group has recently identified that academic stress can also be associated with a higher prevalence of IBS (according to ROME IV criteria) in a sample of medical and nurse students, alongside elevated levels of anxiety[47].

The serotonergic system is another major pathogenic factor studied in patients with IBS[48,49], and therapeutic interventions have been developed targeting this system, specifically through 5-HT3 receptor antagonism[50] and 5-HT4 receptor[51] agonism.

In support of the notion that these elements are not merely speculative, the authors provided data showing that circadian levels of ACTH and cortisol were more pronounced in patients with active diarrheal symptoms.

As is well known, the "higher" neuroendocrine and brain components can influence the gut microbiota and intestinal permeability[52]. Thus, it is unsurprising that the authors' data revealed more severe diarrheal symptoms in cases where these components are more compromised.

However, this study has the limitation of reduced generalizability, as it not only focuses on a specific population (i.e. Chinese) but also relies on patient inclusion based on national diagnostic criteria, which may not necessarily align with international standards. ROME IV has produced a comprehensive questionnaire rich in questions designed to provide diagnostic insights based on the available criteria for functional gastrointestinal disorders[53]. This tool helps navigate the numerous functional clinical entities with which IBS can easily be confused.

We believe standardizing diagnostic criteria for IBS is essential, considering that even within the criteria developed by the same source (ROME), there is significant variation between ROME III and ROME IV. The latter tends to "underestimate" IBS compared to the former due to its more stringent requirements[54].

Nonetheless, the authors excluded patients taking neuromodulators, strengthening the findings concerning IBS overall. However, given the study's small sample size, including an additional group of IBS patients treated with neuromodulators would have been interesting. This could have provided insights into whether these medications might have influenced the parameters observed, either positively or negatively. This is particularly relevant given that ROME IV has positioned neuromodulators as a critical element in managing functional gastrointestinal disorders, establishing a dedicated consensus[55] for their use in this context. Additionally, it could have been helpful to assess IBS-related symptoms using questionnaires such as the IBS symptom severity scale[56]. This would have provided a more standardized evaluation of symptom severity and enhanced the clinical relevance of the findings[57].

This all points to the need to pursue what, in our view, should be the future priorities of IBS research. It is essential to clarify better and dissect the brain-gut-microbiota interactions to identify modifiable and pharmacologically targetable elements and biomarkers. This can be achieved by understanding the neuroimmunological and neuroendocrine mechanisms underlying these interaction phenomena. In light of the existing data, it is essential to clarify further which genetic (and ideally epigenetic) variations and polymorphisms are most strongly associated with IBS, mainly those that determine the phenotypic variations among the different forms of IBS.

CONCLUSION

In conclusion, this study by Zhang et al[1] confirms that IBS is a complex puzzle of interrelated factors that shape and influence each other to produce gastrointestinal symptoms. It provides an impetus for conducting similar multiparametric studies to elucidate these intricate interactions further.

The need for this greater understanding reflects the necessity to identify effective therapeutic agents capable of fully engaging with the pathogenesis of the disease. It is true that in the non-functional counterpart of IBS, namely inflammatory bowel disease, there has been repeated recognition of the need to break through the therapeutic ceiling[58]. Despite increasing available therapies, many patients fail to achieve remission[58]. This is equally true for IBS, where[59,60], despite the proposed treatments, we still do not have a therapeutic agent/procedure[61-65] capable of dramatically controlling the pathophysiology of IBS in all patients.