Gut-brain axis: biological correlations between inflammatory bowel disease and anxiety or depressive disorders - a scoping review of reviews

Abstract

Objective

The bidirectional communication between the nervous system and the gastrointestinal tract plays a crucial role in maintaining homeostatic balance.The present study aims to understand the gut-brain axis and how this complex interaction relates to inflammatory bowel disease and the development of anxious and depressive symptoms.

Method

The search for articles was conducted in the MEDLINE, LILACS, and Cochrane databases. Reviews published between 2009 and 2025 that addressed the gut-brain interaction with a focus on the development of inflammatory bowel disease (IBD) and anxious and/or depressive signs were included. Incomplete studies and those that addressed only one aspect were not selected.

Results

The search resulted in 87 studies; after four selection stages, 15 articles remained according to the inclusion and exclusion criteria. The highest number of publications was from the period of 2021 to 2024. The level of evidence collected consistently reported that patients with IBD were more likely to develop depressive and/or anxiety symptoms. Studies further indicate that inflammatory markers, including C-reactive protein (CRP), explain a large part of the risk for psychiatric conditions.

Conclusion

The gut-brain axis should be understood as a potential factor in the development of mood disorders (anxiety and depression) in patients with IBD, due to the shared dysbiotic and immunological characteristics. By providing a comprehensive view of this complex bidirectional interconnection, the clinical significance of this association is reiterated, as well as the urgency to deepen the understanding of its pathophysiology.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12888-026-07889-2.

Introduction

Inflammatory Bowel Disease (IBD), which encompasses Crohn’s Disease (CD) and Ulcerative Colitis (UC), is a group of chronic inflammatory conditions affecting the gastrointestinal tract that impacts millions of individuals worldwide, significantly affecting their quality of life. Since the first observations in the 1970s, IBD patients have already shown a higher prevalence of anxious and neurotic symptoms as well as introversion compared to the general population [1]. Recent clinical data indicate a prevalence of anxiety and depression at 35% among patients with IBD [2].

These epidemiological observations, together with the correlation between genetic predisposition to mood disorders and the development of IBD, suggest a strong link between the pathology and the nervous system [1]. In this context, the gut-brain axis (GBA) describes a complex and bidirectional communication network that connects all components of the nervous system, especially the enteric nervous system (ENS). This interaction is fundamental in the pathophysiology of various disorders, including inflammatory bowel diseases and psychiatric comorbidities such as anxiety and depression [3].

In this sense, intestinal inflammation and ENS dysfunction, which are characteristic of IBD, can increase intestinal permeability. This phenomenon allows the translocation of pro-inflammatory cytokines and microbial products into the bloodstream, which, in turn, contribute to neuroinflammation and the development of psychological conditions associated with depression and anxiety [1]. Furthermore, constant exposure to psychological stress is responsible for altering the gut microbiota’s balance, increasing the number of pathogenic bacteria, and contributing to pathological changes in the gut-brain axis [4].

Given the growing number of literature reviews addressing different components of the gut brain axis in the context of inflammatory bowel disease, this scoping review of reviews aims to identify and synthesize the existing scientific literature on the correlations and mechanisms linking inflammatory bowel disease to anxiety and depression, focusing on the bidirectionality between the brain and the gut, with the intention of guiding future research and therapeutic strategies aimed at improving the overall quality of life of patients.

Methods

The following scoping protocol of reviews protocol was developed based on the PRISMA-ScR guideline (Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews) and registered in OSF Platform. The full review protocol was previously outlined and is available after embargo (as recommended by the OSF Platform in the case of articles that will be submitted for peer review) or upon request to the authors. The search was carried out on the MEDLINE, BVS/LILACS, and Cochrane databases and included studies published between 2009 and 2025, in the Portuguese, English, Japanese, and Spanish languages, available in full, that addressed the biochemical and physiological association between the intestine and the brain, focusing on the pathological development resulting from the brain-gut axis dysregulation.

The search strategy was elaborated using controlled descriptors (MeSH and DeCS) as well as free terms related to the central theme axis: anxiety, depression, inflammatory bowel diseases, and the brain-gut axis, to increase sensitivity in the search for relevant studies. Search strategies were tailored to each database to accommodate differences in indexing systems, controlled vocabularies, and search functionalities, while preserving a consistent conceptual framework across all searches. Below, the search strategy used in each database is presented (Supplementary Table 1):

To ensure consistency among the reviewers, a pilot phase was conducted in which the same 87 publications were examined, resulting in the removal of 10 duplicated articles. Furthermore, two reviewers worked independently, according to the PRISMA-ScR guidelines, in the selection of sources of evidence, screening of titles and abstracts, with subsequent reading of the entire text of these publications, to identify relevant research. The inclusion criteria for the study were a review study design, with a focus on pathophysiology related to the IDB interaction, depressive symptoms, and the brain-gut axis. The exclusion criteria considered were: absence of aetiological discussion or approach limited to epidemiology and treatment, considered not aligned with the study question; studies focused on populations with specific psychiatric disorders (e.g., PTSD), considered wrong population; only one of the two conditions that comprise IBD (colitis or Crohn’s disease), considered wrong outcome. Amongst all the pre-selected studies, 15 were selected. Furthermore, the disagreements in the study selection were resolved through a third reviewer to ensure a final determination of the study situation, thereby minimizing bias. The flowchart below illustrates the process of searching and selecting sources (Fig. 1).

Fig. 1.

Flow diagram of article search and selection

For the data charting, an extraction table was developed based on the objectives of this review and the PRISMA-ScR guidelines. Data extraction was performed independently, and the spreadsheet was subsequently reviewed by a second reviewer, allowing for iterative configurations. This way, the data was organized according to the variables of interest, such as study characteristics, gut-brain axis dysregulation, and observed psychological impacts. This process allowed the organization of evidence, the identification of gaps in the Medical literature, and the analysis of relevant findings.

In this scoping review of reviews, data extraction included article characteristics (country of origin, year of publication), biochemical and physiological correlations in the gut-brain axis dysregulation, focused on the emergence of psychopathologies in patients with inflammatory bowel disease (biochemical markers). Data was also extracted on the effects of these imbalances on the psychological health of individuals affected by this condition.

The extraction of data was performed using an Excel spreadsheet, a tool provided by the Microsoft Office software, which was standardized and previously developed. Data was extracted by one reviewer and checked by another.

Results

Database searches identified 87 studies. Of these, 10 were removed before screening, which were identified as duplicates. Subsequently, 75 articles underwent title and abstract screening, as well as a rapid scan of their general content. Two reviewers independently conducted this step, adhering to the predefined inclusion and exclusion criteria. From this total, 15 were removed because they were unrelated to the review’s theme. The remaining 60 articles were submitted for full-text evaluation by two other independent reviewers. Occasional discrepancies were resolved with the assistance of a third reviewer. In this phase, 47 articles were excluded for failing to meet the review’s criteria. Consequently, 15 articles were deemed eligible and included in this scoping review (Fig. 1).

Methodologically, all of these were literature reviews of articles that met the criteria established during the screening process. Most studies were conducted in China (5), while the remainder were carried out in the United Kingdom, Italy, Canada, Romania and Poland, with one study from each country; two from Australia, two from Germany and one multinational (France/Canada). Populations comprising adults with inflammatory bowel disease (IBD) (like Crohn’s disease or ulcerative colitis) in active or remission phases, drawn from clinical cohorts, epidemiological data, and animal models were noted. This geographical distribution allows the data to present the clinical profiles related to IBD and its connection with anxiety and depression across diverse locations (Table 1).

Table 1.

Presents the results from the analysis of the selected studies, including their identification, study type, objective, and outcomes

Identification	Study Type	Objectives	Population	Outcomes
Gracie et al., 2019 United Kingdom	Literature Review	To discuss the complex relationship between symptom reporting, inflammatory activity, and psychological well-being in IBD.	Adult patients with IBD and data from observational studies	The article highlights the complex relationship between symptom reporting, inflammatory activity, and psychological well-being in IBD. Psychological comorbidities, including anxiety and depression, are common in patients with IBD, with observational studies reporting a prevalence of up to 30%. The study emphasizes the limitations in the current understanding of the role of pharmacological and psychological therapies targeting gut-brain dysfunction in IBD; in other words, there is a lack of research addressing this bidirectional (gut-brain) axis.
Bonaz and Bernstein, 2013 France/Canada	Literature Review	The article suggests that depression and stress can lead to active IBD and can also play a role in triggering or amplifying symptoms (e.g., pain, fatigue, discomfort) in patients with IBD	Animal models and patients with active IBD	According to the article’s findings, animal models suggest that the cholinergic anti-inflammatory pathway may be a therapeutic target in IBD. Furthermore, the study concluded that rigorous studies on antidepressant pharmacotherapies, as well as on behavioral therapies, are needed.
Vollmer-Conn et al., 2021 Australia	Literature Review	To assess the extent and nature of the interrelationship between psychological factors and the disease course.	Patients with IBD and possible genetic/environmental/microbial factors	Recent findings suggest that while many of the factors contributing to IBD are known (such as genetics, environment, gut bacteria, physical and mental aspects, and the immune response in the gut), satisfactory explanations are still lacking as to how these factors interact with one another over time and how this interaction affects disease activity.
Chen et al., 2021 China	Literature Review	The study analyzes the tryptophan-kynurenine metabolic pathway and its relationship with depression and anxiety in IBD.	Patients with IBD and anxiety-depressive comorbidities	Psychological factors, particularly anxiety and depression, are a focal point of research on treatment adherence in patients with Inflammatory Bowel Disease (IBD), and the majority of studies have concluded that a correlation exists between them.
Ge et al., 2022 China	Literature Review	This article aims to elucidate the importance of further high-quality research that combines large clinical sample sizes, multiple diagnostic methods, and psychotherapy.	Large clinical samples with IBD	Current findings suggest that Inflammatory Bowel Disease (IBD) can hurt structural brain networks, manifesting as widespread neuroanatomical changes associated with stress. However, it remains unknown how frequently psychological disorders co-occur with IBD.
Yuan et al., 2023 China	Literature Review	The objective of this review is to provide new insights into how the microbiota-gut-brain axis and the innate immune system regulate inflammatory and infectious diseases.	Patients with depression and microbiota infections	Levels of Enterobacteriaceae and Alisma were found to be elevated in the fecal samples of patients with depression, whereas levels of Faecalibacterium were reduced (Jang et al., 2022). It can be inferred that alterations in the gut microbiota may promote harmful bacterial infections, induce systemic inflammation, and ultimately lead to depression.
Fracas et al., 2023 Italy	Literature Review	This manuscript provides a critical overview of gender differences in the frequency and clinical course of mood and anxiety disorders in patients with IBD.	Women with IBD and mood/anxiety disorders	The majority of studies confirm that women with IBD are more likely to develop mood disorders, with depression and anxiety rates reaching up to 65% in this population. Women with IBD require rigorous mental health monitoring and, ideally, a multidisciplinary approach involving mental health professionals. More data are needed to ensure individualized treatment for patients with IBD in the context of precision medicine.
Nowakowski et al., 2016 Poland	Literature Review	This review aims to present the current knowledge on the epidemiology of psychiatric disorders in patients with Inflammatory Bowel Disease (IBD) and the underlying biological mechanisms.	Epidemiological cohorts of IBD	Epidemiological studies confirm that the most common psychiatric disorders in patients with IBD are depression and anxiety. According to the Manitoba IBD Cohort Study, the lifetime prevalence of depression in patients with IBD is 27% (12% in the control group). Panara et al. estimated a prevalence of 20%. Estimates from European studies are lower, but in general, the prevalence of depression in IBD tends to range between 15% and 30%.
Atanasova et al., 2025 Germany	Literature Review	The objective of this article is to highlight contemporary empirical findings that support the pivotal role of the gut microbiome in the pathophysiology associated with inflammatory bowel disease and how these interactions affect patient mental health.	Patients with IBD and neuropsychiatry symptoms	Future studies should specifically address patients with IBD and neuropsychiatric symptoms, including approaches targeting the gut microbiome through dietary interventions or the administration of pre-, pro-, and synbiotics.
Wang et al., 2024 China	Literature Review	This article reviews the mechanism by which psychological disorders affect inflammatory bowel disease and how the brain-gut-microbiota axis is modified.	Patients with IBD	The review demonstrated the prevalence of depression and anxiety in patients with IBD to be 15% and 20%, respectively (9). It further indicates a high prevalence of symptoms, with approximately one-third of patients affected by anxiety and one-quarter by depression.
Colin et al., 2022 Australia	Literature Review	This review aims to reveal the pathophysiological alterations in the gut and brain in patients with IBD and in animal models of colitis.	Patients with IBD and colitis models	Depression reaches rates of 21% to 27% in patients with IBD, compared to 12% to 13% in healthy controls, with the depression rate rising to 35% during the active phase of IBD. A postulated etiological trigger for depressive symptoms in IBD patients is low-grade systemic neuroinflammation. Neuroinflammation has been reported to induce one or more of the following: (1) dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, (2) depletion of serotonin levels, and (3) altered hippocampal neurogenesis, all of which are implicated in major depressive disorder (MDD).
Gîlcă-Blanariu et al., 2023 Romania	Literature Review	This article provides an overview of current knowledge connecting stress, anxiety, depression, and sleep disturbances to IBD.	Swiss cohort 10 years with IBD	The study identified an increased prevalence of anxiety and depression among patients with IBD, affecting up to one-third of patients. Meanwhile, a Swiss cohort study with a 10-year follow-up period identified a significant correlation between the presence of depression and IBD symptom recurrence, for both patients with Crohn’s Disease (p = 0.0007) and those with ulcerative colitis (p = 0.0050), as well as between anxiety and IBD symptom recurrence (p = 0.031).
Fakhfouri et al., 2024 Canada	Literature Review	This article aims to analyze the crucial role of microglia in psychiatric disorders associated with Inflammatory Bowel Disease (IBD) and how different cerebral phenomena may be affected by IBD.	Patients with IBD and microglial neuroinflammation	The prevalence of depressive disorders in patients with IBD ranges from 21% to 25%, while anxiety disorders are present in 19.1% to 35% of these patients. Furthermore, modulating microglial phenotypes by modifying inflammatory pathways may have important translational implications for alleviating IBD-associated neuroinflammation.
Feng et al., 2024 China	Literature Review	This review aims to synthesize current advancements in this field and seeks to explore the effective management and treatment of IBD from the perspective of psychological comorbidities.	Patients with IBD and psychological comorbidities	These findings underscore the need for a comprehensive approach to IBD management, one that includes regular mental health assessments and the integration of biopsychosocial models to tailor personalized treatment plans and improve patient outcomes and Quality of Life (QoL). Furthermore, among those with IBD and concomitant anxiety or mood disorders, 79% experienced the onset of their anxiety disorder more than 2 years before their IBD diagnosis, and approximately half of those with coexisting mood disorders had their initial depressive episode more than 2 years prior.
Masanetz et al., 2022 Germany	Literature Review	Summarizing the pathogenesis of depression/anxiety in IBD via the gut-immune-brain axis.	Patients with IBD	The study found that, compared to patients with ulcerative colitis (UC) without depression or anxiety, patients with UC and comorbid depression/anxiety exhibited lower richness and diversity within their fecal microbial community. The axis knowledge supports targeted therapies like anti-TNF agents or fecal microbiota transplants to mitigate brain inflammation, improving outcomes for IBD comorbidities

The 15 analyzed studies evidenced the relationships between psychological well-being and IBD (11 articles); the influence of the gut microbiota on the development of anxiety and depression in patients with IBD (2 articles); the prevalence of these comorbidities in women (1 article); and therapeutic interventions (1 article).

The prevalence of psychological disorders, including anxiety and depression, in patients with IBD was assessed through self-report measures. The results indicated that over 30% of these individuals are affected by these mental health conditions [2]. A Romanian cohort study, “The Intertwining Roads between Psychological Distress and Gut Microbiota in Inflammatory Bowel Disease,” identified that anxiety and depression affect at least one-third of individuals with IBD. Within this study, a referenced Swiss study using the same methodology, with a 10-year follow-up period, demonstrated a higher prevalence of anxiety than depression, alongside significant correlations between these symptoms and IBD recurrence (p < 0.05 for both Crohn’s disease and ulcerative colitis). Separately, women with inflammatory bowel diseases exhibit increased susceptibility to developing anxiety and depression, with rates reaching up to 65% in this population [5].

Other studies have presented data that suggest that inflammatory bowel disease, when associated with stress, can negatively impact brain structures, promoting neuroanatomical changes and thereby triggering psychiatric comorbidities. Furthermore, research has demonstrated that inflammatory biomarkers, such as C-reactive protein (CRP), interleukins, and the systemic immune-inflammation index (SII), mediate a substantial portion of the risk for developing psychiatric disorders [1, 6]. This risk is exacerbated by the proliferation of pathogenic strains in the gut microbiota, which alters the production of essential metabolites, such as short-chain fatty acids (SCFAs). SCFAs possess anti-inflammatory and blood-brain barrier-modulating properties and also affect the synthesis of neurotransmitters such as serotonin (5-HT), dopamine, and GABA [7–9]. Additionally, the tryptophan-kynurenine pathway is highly activated in inflammatory environments, degrading tryptophan into neuroactive metabolites, such as quinolinic acid and kynurenic acid. These metabolites exhibit neurotoxic properties and have been associated with the pathophysiology of depression [10].

As these are self-reported data, the findings provide only an indication of these states and should not be confounded with a formal clinical diagnosis.

Discussion

The present scoping review of reviews highlighted relevant biochemical and physiological correlations between inflammatory bowel disease (IBD) and anxious and/or depressive psychiatric disorders. Rather than merely confirming prevalence rates, the findings collectively point to a complex interaction of neurobiological, immunological, microbial, and psychosocial mechanisms that help explain why patients with IBD are particularly vulnerable to mood disorders.

The included studies support the concept of the GBA as an integrative system in which immune, neural, microbial, and psychosocial factors converge to shape psychiatric vulnerability in IBD.

Integration between the gut-brain axis and the pathophysiology of inflammatory bowel disease

The findings suggest that the gut-brain axis is closely related to the pathophysiology of IBD, both in its intestinal expression and in the associated neuropsychiatric outcomes. Chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis in IBD promotes the release of cortisol and catecholamines, which negatively modulate the immune response, alter the integrity of the intestinal mucosa, and contribute to behavioral and emotional changes, key features seen in the manifestation of the disease [2, 11]. These neuroendocrine disturbances are known to influence mood regulation circuits, particularly those involving the hippocampus, amygdala, and prefrontal cortex, thereby increasing susceptibility to anxiety and depression [2, 11].

Thus, the presence of depressive and anxious symptoms in IBD should not be interpreted solely as a psychological reaction to chronic illness, but rather as a manifestation of shared biological pathways involving neuroimmune and neuroendocrine dysregulation [2, 11]. This interpretation aligns with integrative psychosomatic frameworks that conceptualize psychiatric symptoms as intrinsic components of systemic inflammatory diseases rather than secondary consequences [12]. This perspective supports the importance of clinical approaches that consider both intestinal inflammation and mental health simultaneously. 4.2 Shared inflammatory mechanisms.

Shared inflammatory mechanisms

Inflammatory bowel disease is characterized by a chronic inflammatory state, mediated by the dysregulated activation of helper T cells, mainly Th1 and Th17, by the excessive production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, and by the impairment of regulatory anti-inflammatory pathways, such as the action of IL-10 and TGF-β [11, 13]. These inflammatory mediators are increasingly recognized as central players in the pathophysiology of mood disorders.

One study found that this systemic inflammatory environment directly affects the central nervous system (CNS) through shared routes, such as: the breakdown of the blood-brain barrier (BBB), facilitating the entry of cytokines and endotoxins derived from the intestinal microbiota, promoting neuroinflammation; microglial activation, observed in experimental models and neuroimaging exams, releasing neurotoxic mediators that impair synaptic plasticity, alter neurotransmitter metabolism, and disrupt limbic circuits involved in emotional regulation; and modulation of the hypothalamic-pituitary axis, leading to chronic hyperactivation and dysfunction of negative feedback, exacerbating anxious and depressive effects [14].

Emerging evidence also indicates that microglia represent a central mechanistic link between intestinal inflammation and neuropsychiatric manifestation in patients with IBD. According to Fakhfouri et al. (2024), gut dysbiosis and systemic pro-inflammatory cytokine (mainly IL-6, IL-1β and TNF-α) release promote microglial activation and phenotypic changes in key brain areas, such as the hippocampus, involved in mood regulation and cognition. These alterations are associated with sustained neuroinflammation, disrupted synaptic plasticity and impaired neurogenesis, which contribute to anxiety and/or depression related outcomes in patients with IBD. In this context, modulating microglial phenotypes by targeting inflammatory pathways and subsequently reducing the release of pro-inflammatory cytokines may have important implications for alleviating IBD associated neuroinflammation and its psychiatric comorbidities [4].

Furthermore, inflammatory biomarkers, such as C-reactive protein (CRP), interleukins, and the systemic immune-inflammation index (SII), mediate a substantial portion of the risk for the development of psychiatric disorders in patients with inflammatory bowel disease, reinforcing the view that systemic inflammation is not merely a marker but a potential pathophysiological mediator to mental disorders in this population [1, 3].

Neurochemical alterations in the intestinal microbiota

Another relevant finding concerns the dysregulation of the intestinal microbiota, which has been identified as a key factor in gut-brain axis dysfunction. Several studies indicate that dysbiosis, defined as the loss of microbial diversity and the overgrowth of pathogenic strains, alters the production of essential metabolites such as short-chain fatty acids (SCFAs), intestinal serotonin (5-HT), dopamine, and GABA, compromising the intestinal barrier through the activation of neuroimmune responses that contribute to the genesis of depressive and anxious symptoms [7, 8, 10, 15].

SCFAs, such as butyrate, have anti-inflammatory and blood-brain barrier modulatory actions, in addition to inducing the expression of brain-derived neurotrophic factor, which is reduced in depressive states [7, 8].

Current evidence also indicates that IBD-associated dysbiosis, characterized by reduced SCFA’s producing bacteria and increased intestinal permeability promotes neuroinflammatory signaling via cytokines, microbial metabolites and HPA dysregulation. These processes contribute to neurotransmitter imbalance and stress-related behavioural symptoms, which in turn contribute to the development of anxiety and/or depressive symptoms. Collectively, these findings highlight the microbiota as a central factor between IBD-related gut dysbiosis and neuropsychological manifestations [15, 16].

The tryptophan-kynurenine pathway, in turn, is intensely activated in inflammatory environments, degrading tryptophan into neuroactive and neurotoxic metabolites such as quinolinic acid and kynurenic acid. This pathway, discussed by Chen et al. (2021), represents a direct biochemical link between intestinal inflammation and neuropsychiatric dysfunction [10]. Additionally, gut bacteria regulate the expression of neuroactive genes and directly influence neurogenesis and the stress response. Interventions with prebiotics, probiotics, psychobiotics, and fecal microbiota transplantation (FMT) have shown promising results in modulating the gut-brain axis in experimental models and in populations with inflammatory bowel disease [8, 9].

Psychosocial dimensions and bidirectional impacts: inflammatory bowel disease as a modulator of mental disorders and vice versa

Beyond biological mechanisms, psychosocial factors significantly modulate the relationship between IBD and mental health [1, 5]. Pain, functional disability, uncertainty about the course of the disease, and chronic disease-related stress all contribute to long-term psychological distress, which may further dysregulate immune and neuroendocrine pathways. A self-sustaining feedback loop between intestinal inflammation and psychological burden is produced by changes in gut motility, permeability, and immune activation brought on by stress. Recent integrative reviews on the gut–brain axis further suggest that psychosocial stressors can reshape gut microbiota composition and function, thereby amplifying neuroinflammatory signaling and vulnerability to mood disorders through sustained microbiota–immune–brain interactions [17].

Conversely, pre-existing anxiety and depressive disorders have been shown to worsen IBD outcomes, suggesting causal mechanisms and shared genetic predispositions. Chronic activation of the hypothalamic-pituitary-adrenal axis, associated with psychological stress, compromises immune function and alters microbiota composition, creating a negative feedback loop between gut and brain [1]. That is, chronic stress, when not adequately addressed, can intensify the intestinal inflammatory process and compromise the response to conventional treatment.

Multidisciplinary interventions for psychological disorders in patients with IBD

In recent years, increasing attention has been directed toward the psychological burden associated with IBD [18]. Compared with the general population, individuals with IBD exhibit higher prevalence rates of depression, anxiety, and stress, which are closely linked to poorer quality of life, persistent symptoms such as fatigue and pain, even during endoscopic or histological remission, reduced treatment adherence, and increased healthcare utilization [18]. The interplay between psychological comorbidities and their therapeutic interventions significantly influences disease prevention, management outcomes, and long-term prognosis [1]. Depression, in particular, is frequently associated with suboptimal treatment adherence among patients with IBD, representing an additional pathway through which psychological distress may exacerbate disease activity and worsen clinical outcomes.

In this context, psychological interventions have demonstrated not only clinical benefits but also economic advantages, as they are associated with reduced healthcare costs and more efficient use of medical resources [1, 18]. Longitudinal follow-up studies have reported meaningful improvements in mental health and quality of life, alongside a reduction in hospital admissions and overall healthcare utilization [18].

Additionally, data suggest that many signs commonly labeled as depressive symptoms in patients with IBD (mainly fatigue and sleep disturbances) frequently reflect a somatic response directly correlated to dysfunction of the gut-brain axis and systemic inflammation, rather than merely a psychological reaction by living with a chronic disease. The studies included in this review describe a notable prevalence of anxiety and/or depressive symptoms in IBD patients with specific inflammatory biomarkers (e.g. CRP, interleukins), accounting for the majority of psychiatric manifestations; similarly, Moulton et al. [19] described that fatigue (affecting 44–86% of patients with active disease and 22–41% in remission) and poor sleep quality (up to 77% on patients with active disease) are commonly observed in IBD and are associated with the previously mentioned biomarkers, corroborating with the extra-intestinal manifestation hypothesis. The proposed mechanisms (increased intestinal permeability, microbial products translocation, microglial activation, intense activation of the tryptophan-kynurenine pathway) provide a plausible biological link between intestinal inflammation and somatic depressive symptoms.

Study limitations

This study presents some limitations. Firstly, as the present article included only revith-type studies, the findings reflect synthetized interpretations rather than primary data and also may limit the strength of evidence regarding causality. Additionally, the methodological heterogeneity of the included articles makes direct comparison between results difficult. Randomized clinical trials are still scarce in the field of the gut-brain axis applied to inflammatory bowel disease, and most data on microbiota and neurochemistry derive from animal models, thus requiring caution when extrapolating to humans. Finally, the exclusion of publications in languages other than Portuguese, English, Spanish, and Japanese, as well as the removal of articles published before 2009, may have restricted the scope of evidence.

Conclusion

This scoping review of reviews provides a brief overview of the scientific publications on the correlations and underlying mechanisms of action related to the comorbidity between Inflammatory Bowel Disease (IBD), anxiety, and depression, with a particular emphasis on modulation by the gut-brain axis.

The results of this article reinforce the association between anxiety and/or depression in patients with IBD and, as such, in this context, multidisciplinary interventions, involving gastroenterologists, psychiatrists, and nutritionists, may promote improvements in quality of life and reduce relapse rates. Furthermore, modulation of the intestinal microbiota emerges as a potential therapeutic strategy, which requires validation in controlled clinical trials.

Future studies should prioritize the investigation of plasma inflammatory biomarkers, such as C-Reactive Protein, IL-6, IL-8, TNF-α and the systemic immune-inflammation index, alterations in tryptophan-kynurenine pathway (e.g. kynurenine/quinolinic acid ratios), fecal metabolomics (such as SCFAs) and intestinal microbial composition (mainly SCFAs-producing bacteria like Faecalibacterium). The correlations between the brain and immune-microbiota interactions may be clarified by integrating differences pertained to those biomarkers and neuroimaging techniques (such as PET imaging of neuroinflammation).

Finally, the development of multimodal longitudinal cohorts and randomized trials is recommended to explore the effectiveness of microbial target interventions (including well characterized psychobiotics, dietary changes to enhance SCFAs production and fecal microbiota transplantation in controlled settings), as well as psychotherapeutic approaches, like cognitive behavioural therapy or mindfulness-based cognitive therapy, to assess efficacy of multidisciplinary, personalized intervention strategies.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

IBD

Inflammatory Bowel Disease

CD

Crohn’s disease

UC

Ulcerative Colitis

GBA

Gut-Brain Axis

ENS

Enteric Nervous System

PRISMA-ScR

Preferred Reporting Items for Systematic Reviews And Meta-Analysis Extension For Scoping Reviews

CRP

C-Reactive Protein

SII

Systematic Immune-Inflammatory Index

SCFAs

Short-Chain Fatty Acids

5-HT

Serotonin

HPA

Hypothalamic-Pituitary-Adrenal

CNS

Central Nervous System

BBB

Blood-Brain Barrier

FMT

Fecal Microbiota Transplantation

Author contributions

All authors contributed substantially to the conception and design of the study, data collection, analysis, and interpretation. MC, GS and LS were responsible for developing the research strategy. AC and HC conducted the literature search quality assessment. BN performed data extraction. PG participated in drafting and critically revising. All authors approved the final version for submission, and agreed to be accountable for all aspects of the work.

Funding

None.

Data availability

All data generated or analysed in this study are included in this article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.