Changes in gut bacteria linked to anxiety and depression in inflammatory bowel disease

A comprehensive literature search was performed across six electronic databases—PubMed, Embase, the Cochrane Library, Web of Science, EBSCOhost, and Scopus—from database inception to October 17, 2025. Only studies published in English were considered. The primary search terms included “Inflammatory Bowel Diseases,” “Crohn Disease,” “Ulcerative Colitis,” “Gastrointestinal Microbiome,” “Microbiota,” “Depression,” “Anxiety,” “Mood Disorders,” and “Stress, Psychological.” These terms were combined using the Boolean operator “AND,” while related terms within each concept (IBD, gut microbiota, and anxiety/depression) were combined using “OR.” The full search strategy is provided in. Supplementary material

Studies are considered eligible if they meet the following criteria: (1) Study design: human study, cohort study, and randomized controlled trial; (2) Population: adults with IBD; (3) Exposure factors: to investigate the effects of anxiety or depression on the gut microbiota of IBD, or conversely, the effects of gut microbiota on anxiety or depressive symptoms; (4) Outcome measures include at least one of the following: incidence of anxiety and depression, progression, and gut-related biomarkers of anxiety and depression progression; (5) Publication type: peer-reviewed full-text article.

Studies were excluded if they fell under the following categories: (1) duplicate publications; (2) full texts were unavailable or contained high bias (e.g., poorly designed trials, lack of participant data, etc.); (3) reviews, observational studies, case reports, letters to editors, or conference abstracts.

Table 1 shows the specific screening criteria. Duplicate publications were removed after a comprehensive search of multiple databases. Next, titles and abstracts were screened, followed by full text screening based on inclusion/exclusion criteria. The screening and selection process was conducted independently by two reviewers (Tao Zhang and Lin Wang). Any discrepancies were resolved by consensus. A total of 10 studies were ultimately included in the full text review (Figure 1).

Two reviewers (Xiaozhen Cheng and Ling Wang) independently extracted data from 10 studies using Excel, including the following: (1) Study information: first author, publication year, country, study design, sample size; (2) Study subjects: participant characteristics, including age and IBD type; (3) Exposure factors: gut microbiota, gut microbiota assessment methods (and index scoring criteria/biomarkers); 4) Outcomes: baseline incidence and progression of anxiety and depression.

Two reviewers, Zhetan Ren and Ru Man, independently assessed the risk of bias using the Critical Appraisal Skills Programme (CASP) checklist. The CASP checklist was applied to both cohort studies and randomized controlled trials. For cohort studies, the assessment focused on the validity of the results, the nature of the results, and the local applicability of the findings. Local applicability referred to whether the results could be applied to the relevant clinical setting or population. For randomized controlled trials, the assessment focused on study design, methodological quality, results, and local applicability. Each checklist item was answered as “yes,” “no,” or “not sure.” A high number of “not sure” responses indicated that the reliability of the study findings should be interpreted with caution. The applicability score was calculated as the number of “yes” responses divided by the total number of checklist questions for each study. A higher score indicated better study quality. Disagreements between reviewers were resolved through discussion.

In this review, we initially planned to perform a quantitative meta-analysis. This analysis would have been conducted if at least two studies reported comparable exposures or interventions, microbiota-related outcomes, psychological outcomes, and extractable effect estimates. However, after full-text assessment and data extraction, quantitative synthesis was considered infeasible. This was due to substantial clinical, methodological, and statistical heterogeneity across the included studies.

First, the included studies differed markedly in study design, IBD subtype, disease activity status, exposure or intervention type, comparator definition, and follow-up duration. The interventional studies also used heterogeneous strategies. These included probiotics, fecal microbiota transplantation, cognitive behavioral interventions, mindfulness-based interventions, and usual care comparisons. Second, microbiota-related outcomes were assessed and reported using different approaches. These included alpha diversity, beta diversity, specific bacterial taxa, microbiome health indices, microbial dysbiosis indices, predicted or measured functional pathways, bile acid profiles, metabolomic signatures, and proteomic features.

Third, psychological outcomes were measured using different instruments. These included HADS, SAS, SDS, PHQ-9, GAD-7, DASS, PSS, and quality-of-life-related scales. These differences prevented direct harmonization of outcome metrics. In addition, statistical reporting varied substantially across studies. Many studies reported the direction of association, taxon-specific differences, correlations, or multi-omics signatures. However, they did not consistently report standardized effect sizes, standard errors, confidence intervals, or sufficient raw data for recalculation. As a result, no single exposure–outcome or intervention–outcome comparison included enough statistically comparable studies to generate a reliable pooled estimate.

Therefore, pooled effect sizes were not calculated. I² statistics, subgroup analyses, sensitivity analyses, and publication bias assessment were also not performed, because these analyses were not appropriate for the available evidence.

Accordingly, this study used a structured descriptive synthesis approach. We summarized the findings according to study design, microbiota domain, psychological outcome, intervention type, statistical reporting, and evidence direction. The consistency and limitations of the available evidence were presented in both tabular and textual formats.

A total of 10 studies were included in this systematic review. These included six prospective cohort studies (Chen et al., 2021; Feng et al., 2022; Humbel et al., 2020; Scaldaferri et al., 2023; Thomann et al., 2022; Yuan et al., 2021) and four randomized controlled trials (RCTs) (Ewais et al., 2021; K et al., 2024; Liu et al., 2025; Shang et al., 2023). Together, these studies involved 1,040 patients with IBD, including UC and CD. The cohort studies mainly examined the associations between gut microbiota characteristics and symptoms of anxiety and/or depression. The RCTs evaluated the effects of microbiota-related interventions on microbial composition and psychological outcomes. The detailed characteristics of the cohort studies and RCTs are summarized in Tables 2, 3, respectively. To facilitate comparison of the core evidence, we also summarized the main microbiota-related findings, psychological outcomes, statistical reporting, and evidence direction in a standardized evidence summary table (Table 4).

Four RCTs met the inclusion criteria, evaluating probiotics, FMT, and psychological interventions with concurrent microbiota assessment (Ewais et al., 2021; K et al., 2024; Liu et al., 2025; Shang et al., 2023). All studies reported both microbiota and psychological outcomes.

Risk of bias was assessed using the CASP checklists for cohort studies and randomized controlled trials. Overall, the included studies clearly defined their research questions. They were considered to have acceptable methodological quality. However, several domain-specific concerns were identified.

In cohort studies, the main limitations included incomplete adjustment for confounders, heterogeneous microbiota assessment methods, variable psychological outcome measurements, and limited external validity. In randomized controlled trials, the main concerns included incomplete reporting of allocation concealment or blinding, small sample sizes, short follow-up durations, attrition in biological sample collection, and limited precision of outcome estimates.

These issues may have introduced residual confounding, measurement bias, performance bias, detection bias, and reduced comparability across studies. Overall, the included studies were judged to be of moderate methodological quality. Therefore, the findings should be interpreted cautiously. Detailed domain-level CASP assessment results are provided in. Supplementary material

By integrating evidence from both prospective cohort studies and randomized controlled trials, this review identifies a consistent pattern suggesting that anxiety and depressive symptoms in patients with IBD are associated with gut microbiota dysbiosis.

At the observational level, cohort studies consistently identified a characteristic microbial pattern associated with psychological symptoms. This pattern included reduced α-diversity, enrichment of pro-inflammatory taxa, and depletion of SCFA-producing bacteria. It was observed across different IBD subtypes and study populations. This suggests that it may represent a shared microbial signature related to psychological comorbidities in IBD.

Notably, in several studies, these associations persisted after adjustment for inflammatory markers. They were also observed when analyses were restricted to patients in remission. These findings argue against a purely secondary effect of intestinal inflammation. Instead, they suggest that microbiota–psychological interactions may reflect a relatively independent dimension of gut–brain axis dysregulation.

At the interventional level, evidence from RCTs provides further support for a potential mechanistic link. Microbiota-targeted strategies, including probiotics and fecal microbiota transplantation, were associated with concurrent improvements in psychological symptoms and partial restoration of microbial composition or function. This parallel change suggests that gut microbiota may mediate mental health regulation in IBD.

However, the effects were not uniform across interventions. Microbiota-targeted therapies tended to produce concordant changes in microbial and psychological outcomes. In contrast, some psychological interventions significantly improved mental health without causing substantial microbiota alterations. This divergence suggests that multiple and partly independent pathways may contribute to psychological symptom modulation in IBD. Their relative contributions may vary according to intervention type.

Recent studies outside the IBD context have also linked gut microbiota dysbiosis to psychiatric disorders. These include depression, anxiety, and cognitive impairment. Such findings support the broader relevance of the microbiota–gut–brain axis (Huang et al., 2025; Wu et al., 2026a). Recent microbiome and neuroimaging evidence in first-episode major depressive disorder has further linked altered gut microbial profiles to changes in functional brain connectivity (Wu et al., 2026b). This suggests that microbial alterations may participate in psychological and neurobiological dysfunction beyond intestinal inflammation.

In parallel, depression and anxiety have often been associated with elevated peripheral inflammatory markers. This indicates that microbiota-related, inflammatory, and psychological pathways may overlap. However, they are not necessarily identical. Therefore, in IBD, microbiota–psychological associations should be interpreted as partially independent of inflammatory activity, rather than completely separate from it.

Taken together, current evidence suggests that gut microbiota alterations in IBD may be more than passive correlates of psychological comorbidities. However, most available evidence is observational or derived from small-scale interventional studies. Therefore, the directionality, causal relationships, and dominant pathways linking microbiota alterations to psychological symptoms remain unclear.

The gut–brain axis is a multi-layered communication network. It links the gut microbiota, immune system, and central nervous system (Morton et al., 2023). In IBD-related anxiety and depression, the available clinical evidence does not support a single linear mechanism. Instead, the findings of this review suggest that microbiota–psychological associations may involve overlapping immune–inflammatory, microbial metabolic, and neuroendocrine pathways. However, the strength of evidence differs across these mechanisms.

Based on the included studies, the most consistently supported mechanisms involve reduced microbial diversity, enrichment of pro-inflammatory or opportunistic taxa, depletion of SCFA-producing bacteria, and alterations in bile acid metabolism. In contrast, other mechanisms are mainly supported by indirect evidence in the IBD population. These include tryptophan metabolism, vagal signaling, HPA-axis activation, microglial responses, and neuroendocrine regulation. Therefore, the following discussion prioritizes mechanisms with direct support from the included clinical studies. More speculative pathways are presented as complementary hypotheses.

Within the immune–inflammatory axis, several included studies reported enrichment of pro-inflammatory or opportunistic taxa in IBD patients with psychological symptoms. These taxa included Enterobacteriaceae, Escherichia–Shigella, Streptococcus, Veillonella, and Ruminococcus gnavus. Such microbial patterns may promote inflammatory signaling through microbial components such as lipopolysaccharide. Lipopolysaccharide can activate TLR4-mediated NF-κB signaling and promote the release of pro-inflammatory cytokines. These cytokines include interleukin-6, tumor necrosis factor-α, and interleukin-1β (Ge et al., 2022).

These inflammatory mediators may influence central nervous system function through systemic circulation, immune–neural communication, or vagal pathways. In this way, they may contribute to anxiety- and depression-like symptoms (Fakhfouri et al., 2024; Sălcudean et al., 2025). Clinical observations that psychological symptoms may improve in parallel with anti-inflammatory treatment further support the relevance of this pathway (Chang et al., 2024). However, associations between inflammatory markers and psychological symptoms were not consistent across the included studies. This suggests that inflammation is an important contributor, but not the only pathway linking microbiota alterations to psychological symptoms in IBD.

The microbial metabolic axis appears to be one of the most directly supported mechanisms in this review. Across several cohort studies, psychological symptoms were associated with depletion of SCFA-producing or butyrate-associated bacteria. These included Roseburia, Faecalibacterium prausnitzii, Lachnospiraceae, and Ruminococcaceae.

SCFAs can regulate immune cell function, intestinal barrier integrity, blood–brain barrier homeostasis, and neuronal energy metabolism. These effects may involve histone deacetylase inhibition and G protein-coupled receptor signaling (Pi et al., 2024; Sun et al., 2024). Therefore, reduced SCFA-producing capacity may provide a plausible metabolic route linking gut dysbiosis to psychological symptoms.

Importantly, this pathway may also help explain why microbiota–psychological associations persist in some patients even when conventional inflammatory activity is not prominent. Nevertheless, not all studies have reported consistent associations between SCFAs and psychological outcomes. The magnitude and direction of these effects may depend on baseline microbiota composition, host metabolic context, and methodological variability (Scaldaferri et al., 2023).

Bile acid metabolism represents another relatively well-supported metabolic pathway. Feng et al. identified concurrent gut microbiota dysbiosis and bile acid metabolism alterations in CD patients with psychological disorders. These alterations included reduced secondary bile acids and increased serum 7-dehydrocholic acid.

These findings suggest that altered microbial metabolism may influence psychological symptoms through bile acid-related signaling, in addition to SCFAs. Bile acids can interact with immune, metabolic, and neural pathways. Therefore, this mechanism may be relevant for linking microbial functional changes with gut–brain communication (Pan et al., 2024; Xu and Lu, 2025). However, evidence for this pathway remains limited to a small number of studies. Larger cohorts are needed for validation.

Other microbial metabolic pathways may also contribute to microbiota–brain communication. These include tryptophan metabolism and indole derivative production. Under inflammatory conditions, tryptophan metabolism can shift toward the kynurenine pathway and generate neuroactive metabolites. Gut microbiota may also influence serotonin-related signaling (Chen et al., 2024; Zhang et al., 2025). In addition, indole derivatives may affect central nervous system function through immune, metabolic, or barrier-related pathways (Meng, 2026).

These mechanisms are biologically plausible and have been widely discussed in the broader gut–brain axis literature. However, direct clinical evidence linking tryptophan metabolism or indole derivatives to anxiety or depression in IBD remains limited in the studies included in this review. Therefore, these pathways should be interpreted as complementary hypotheses rather than established mechanisms.

Neuroendocrine and neural pathways may provide additional explanations for the possible bidirectionality of microbiota–psychological associations. Psychological stress can activate the HPA axis and the sympathetic nervous system. These responses may alter inflammatory activity, intestinal permeability, mucosal immune responses, antimicrobial peptide secretion, gut motility, luminal conditions, and microbial community structure (Duan et al., 2021; Madison and Bailey, 2024; Marwaha et al., 2025).

Stress-induced neuroimmune alterations may further reinforce central inflammatory signaling. These alterations include microglial metabolic reprogramming and changes in synaptic plasticity (Fang et al., 2025; Huang et al., 2024). The vagus nerve may also serve as a communication route between the gut and the brain. Preclinical studies suggest that some probiotic-related anxiolytic effects may depend on intact vagal signaling (Verma et al., 2024).

Central nervous system activity and chronic stress may also modulate gut motility, secretion, and immune responses through vagal and sympathetic pathways. These changes may reshape microbial ecology (Zou et al., 2024). However, direct clinical evidence for vagal or HPA-axis-mediated mechanisms in IBD-related anxiety and depression remains limited. Compared with microbial diversity, SCFA-producing bacteria, and bile acid metabolism, these pathways are less well established. Therefore, they should be viewed as biologically plausible routes rather than mechanisms directly confirmed by the included studies.

Stress-related changes may also influence microbial metabolic function. Under chronic stress, beneficial taxa may decrease, SCFA production may be reduced, and intestinal barrier integrity may be impaired. These changes may contribute to the persistence or worsening of psychological symptoms (Jia et al., 2025). In addition, stress-induced changes in luminal pH and redox conditions may selectively suppress butyrate-producing bacteria. This may weaken the protective effects of microbial metabolic pathways (Kalkan et al., 2025). These findings provide a plausible explanation for feedback between psychological stress, microbial ecology, and metabolic disruption. However, direct evidence in IBD-related anxiety and depression remains limited.

Taken together, the current evidence most strongly supports a framework centered on gut dysbiosis, enrichment of pro-inflammatory or opportunistic taxa, depletion of SCFA-producing bacteria, and microbial metabolic disruption, especially bile acid alteration. Neuroendocrine, vagal, tryptophan-related, indole-related, and microglial pathways remain biologically plausible mechanisms. However, their direct contribution to psychological symptoms in IBD requires further validation.

Although these pathways provide a coherent explanation for microbiota–psychological interactions, they should be interpreted as mechanistic hypotheses rather than established causal pathways. The current evidence base is still largely derived from observational studies and small-scale clinical trials. This limits causal inference.

Emerging evidence from humanized models suggests that restoration of SCFA production or modulation of tryptophan metabolism may ameliorate stress-related behaviors. These effects may be achieved through specific probiotics or fecal microbiota transplantation (Kalkan et al., 2025). Future studies should integrate longitudinal cohort designs, standardized microbiome profiling, metabolomics, immune phenotyping, formal mediation analyses, and neuroimaging techniques. Such studies are needed to clarify temporal relationships, identify dominant pathways, and determine whether specific microbiota-related changes contribute causally to psychological comorbidities in IBD.

Although current evidence shows a close association between gut microbiota alterations and anxiety and depressive symptoms in patients with IBD, this evidence has not yet translated into microbiota-based clinical decision-making. This association appears to be partly independent of inflammatory activity. However, its clinical application remains limited.

At present, IBD management is still mainly focused on controlling inflammation. Psychological comorbidities are usually managed symptomatically. Microbiota–immune–neurobiological interactions are rarely integrated into routine care. This inflammation-centered model may be insufficient for some patients. This is especially relevant for patients whose intestinal inflammation is well controlled but who continue to experience psychological symptoms. In these patients, non-inflammatory regulatory pathways may contribute to persistent psychological burden.

From a translational perspective, clinically actionable findings should be distinguished from investigational implications. Currently, the clinically actionable aspects mainly include routine recognition and assessment of anxiety and depressive symptoms in patients with IBD. Psychological comorbidities should also be considered when evaluating overall disease burden. In addition, psychological or behavioral support should be integrated into multidisciplinary care.

In contrast, microbiota-based clinical applications remain investigational. These include the use of microbiota profiles to stratify patients, predict psychological symptoms, or guide treatment selection. Similarly, microbiota-targeted interventions should not yet be considered routine treatments for anxiety or depression in IBD. These interventions include probiotics, prebiotics, SCFA supplementation, and fecal microbiota transplantation. Their efficacy, optimal target populations, dosing strategies, durability, and safety require further validation.

From both phenotypic and mechanistic perspectives, psychological comorbidities in IBD are unlikely to represent a uniform clinical entity. Rather, they may reflect different combinations of dominant pathways. In some patients, psychological symptoms may persist despite adequate inflammatory control. This may suggest a greater contribution of microbial metabolic and neuroregulatory mechanisms.

In other patients, especially those with poor response to anti-inflammatory therapy and pronounced dysbiosis, microbial composition and metabolite profiles may play a more central role. Patients with fluctuating symptoms and prominent stress-related features may show coupled dysregulation across neural, immune, and microbial pathways. However, these proposed subgroups remain hypothetical. They require prospective validation before being used in clinical decision-making.

Emerging interventional evidence provides preliminary support for microbiota- and neuroregulation-informed approaches. Microbiota-targeted strategies have been associated with improvements in psychological outcomes and changes in microbial composition or metabolic function. These strategies include probiotics, SCFA supplementation, and fecal microbiota transplantation. Their effects may occur through immune or metabolic pathways.

In contrast, psychological and behavioral interventions may act mainly through neuroregulatory mechanisms. They may also indirectly influence the gut environment. However, the comparative efficacy, optimal timing, dose–response relationships, and target populations of these interventions remain uncertain.

For example, fecal microbiota transplantation may warrant further study in patients with marked dysbiosis because it can induce large-scale microbial restructuring. Probiotics or prebiotics may be more suitable for evaluation in patients with mild-to-moderate symptoms or during maintenance phases. Interventions targeting neural regulation may be particularly relevant for individuals with stress-dominant or affective dysregulation profiles. However, these possibilities require validation in dedicated clinical studies.

From a clinical decision-making perspective, microbiota modulation should be considered a complementary strategy if future evidence supports its use. It should not be regarded as a replacement for anti-inflammatory therapy. Future studies should examine whether stratified assessment can support pathway-matched interventions. Such assessment may integrate inflammatory status, psychological symptom profiles, and microbiota characteristics. This approach may improve treatment precision in the future. However, its clinical utility requires prospective validation.

Future research should bridge the gap between associative evidence and clinical application. Large-scale longitudinal studies are needed to clarify the temporal and causal relationships between microbiota alterations and psychological symptoms. Standardized microbiome profiling techniques and psychological assessment tools are also essential. This would improve comparability across studies.

In addition, randomized controlled trials should systematically evaluate different interventions. Key issues include comparative efficacy, optimal timing, dose–response relationships, long-term durability, and safety. Integrative multi-omics approaches may help identify patient subgroups most likely to benefit from microbiota-targeted therapies. These approaches may include metagenomics, metabolomics, and immune phenotyping. They may also support the development of precision medicine in this field.

Overall, current clinical practice should focus on early identification of psychological comorbidities, integrated psychosocial care, and optimized IBD disease control. Microbiota-based stratification and microbiota-targeted therapies for psychological symptoms should remain within the research setting. Larger and more standardized trials are needed before routine clinical use can be recommended. Given that current evidence is mainly derived from associative analyses and small-scale interventional studies, clinical implementation of microbiota-based therapies remains premature. Their true efficacy, safety, durability, and appropriate clinical indications require further validation in high-quality studies.

This review has several notable strengths. First, it integrates evidence from both prospective cohort studies and randomized controlled trials, allowing for a comprehensive evaluation of the role of the gut microbiota in psychological comorbidities in IBD from both associative and interventional perspectives. Compared with previous reviews that primarily focused on a single study design, this approach enables a more coherent interpretation of potential causal pathways by linking temporal associations with intervention effects.

Second, this study highlights that microbiota–psychological associations may be at least partially independent of inflammatory activity. This observation provides an important conceptual advance. It suggests that microbial metabolic and neuroregulatory mechanisms may contribute to psychological comorbidities in IBD beyond inflammatory pathways. These mechanisms may not be fully captured by conventional inflammatory markers. This perspective supports the development of mechanism-based stratification and more targeted therapeutic strategies.

Several limitations should also be acknowledged. First, substantial heterogeneity existed across the included studies. The studies differed in patient characteristics, IBD subtype, disease activity status, microbiome profiling methods, psychological assessment tools, intervention types, comparator definitions, and follow-up durations. Microbiota outcomes were generated using different sequencing, profiling, and analytical approaches. Psychological symptoms were assessed using heterogeneous instruments with different constructs, thresholds, and scoring systems. The study populations also varied in IBD subtype, disease activity, age range, treatment background, and geographic setting.

Second, a meta-analysis was not performed because microbiota-related outcomes and statistical reporting formats varied substantially. The included studies reported heterogeneous microbiota outcomes. These included alpha diversity, beta diversity, specific taxa, microbiome health indices, microbial dysbiosis indices, bile acid profiles, functional pathways, metabolomic signatures, and proteomic features. Moreover, many studies did not provide standardized effect sizes, standard errors, confidence intervals, or sufficient raw data for recalculation. Therefore, reliable pooled estimates could not be generated. I² statistics, subgroup analyses, sensitivity analyses, and publication bias assessment were also not performed. As a result, the conclusions of this review should be interpreted as a structured synthesis of current evidence rather than quantitatively pooled estimates.

Third, the evidence base remains limited. Only 10 studies were included, and several had relatively small sample sizes. This limited number of studies reduces the statistical robustness and generalizability of the findings. This is especially relevant for subgroup interpretation according to IBD subtype, disease activity status, intervention type, and psychological outcome. Therefore, the conclusions should be interpreted cautiously. They should not be generalized beyond the populations and settings represented in the included studies.

Fourth, several included studies did not adequately or consistently control for key potential confounders. These included diet and medication use, such as antibiotics, biologics, corticosteroids, and probiotic exposure. They also included lifestyle factors, such as physical activity, sleep quality, and stress. These variables may influence both gut microbiota composition and psychological outcomes, thereby introducing residual confounding. Therefore, the observed microbiota–psychological associations should be interpreted cautiously. Future studies should more systematically collect and adjust for these factors.

Furthermore, publication bias was not formally assessed. This was because the number and comparability of studies were insufficient for funnel plot-based or statistical evaluation. In addition, no standardized framework, such as GRADE, was applied to evaluate the overall certainty of evidence. This may affect the strength of the conclusions. Finally, only English-language studies were included, which may have introduced language and regional bias.

The original contributions presented in this study are included in the article/, further inquiries can be directed to the corresponding authors. Supplementary material