Causal Relationships between Gut Microbiota and Depression/Anxiety Disorders: A Two-Sample Mendelian Randomization Study

doi:10.21203/rs.3.rs-3913406/v1

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Causal Relationships between Gut Microbiota and Depression/Anxiety Disorders: A Two-Sample Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-3913406/v1

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Background

Evidence shows that the composition of the gut microbiota (GM) is associated with depression and anxiety disorders. However, the causal relationship between them remains controversial.

Methods

To investigate the potential causal relationship between the gut microbiota and depression/anxiety disorders and to identify specific bacterial taxa, we conducted a two-sample Mendelian randomization (MR) analysis on the gut microbiome implicated in depression and anxiety disorders. We incorporated summary data from a genome-wide association study (GWAS) of the microbiome derived from 7,738 individuals participating in the Dutch Microbiome Project (DMP) as our exposure variable. Concurrently, the GWAS of depression and anxiety disorders was employed as our outcome variable. The principal estimates were procured using the inverse-variance weighted (IVW) test complemented by four robust methods: MR Egger, weighted median, simple mode, and weighted mode. In addition, we performed comprehensive sensitivity and directionality analyses.

Results

The results showed that 5 bacterial taxa were positively correlated with depression, 6 were negatively correlated; 5 were positively correlated with anxiety disorders, and 11 were negatively correlated.

Conclusions

This study provides new insights into the connection between the gut microbiota and the pathogenesis of depression and anxiety disorders and offers new perspectives for the diagnosis and treatment of these disorders.

Gut Microbiota

Depression

Anxiety Disorder

Mendelian Randomization

Depression and anxiety disorders are two of the most common mental disorders. Depression refers to a significant and persistent low mood, loss of pleasure or interest in things experienced by the patient [1]. Approximately 3.8% of the world’s population suffers from depression, leading to more than 700,000 suicides each year [2]. Anxiety disorders refer to intense, excessive, and persistent fear and worry that occur in everyday situations and are often accompanied by autonomic nervous symptoms and motor restlessness, which interfere with the patient’s normal functioning [3]. Approximately 20%-30% of people between the ages of 15 and 25 have experienced anxiety disorders, and some of them continue to persist [4, 5]. In addition, the COVID-19 pandemic has significantly increased the global burden of depression and anxiety disorders [6]. The risk factors for depression and anxiety disorders include genetics, the environment, and epigenetics, with genetics playing a significant role in making depression and anxiety disorders highly heritable and revealing significant familial aggregation [1, 3]. Currently, effective treatments for these diseases include evidence-based psychotherapies and drug treatments (SSRIs/SNRIs, etc.) [1, 7, 8]. However, existing treatment plans cannot meet the large and increasing disease burden, and patients urgently need additional treatment options to provide opportunities for disease relief.

The gut microbiota refers to the total microbial community in the human gastrointestinal tract. Increasing evidence suggests that the gut microbiota is not an isolated unit but communicates and influences the body’s major systems through various mechanisms [9]. The gut-brain axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract [10]. Studies have shown that gut microbiota can affect the central nervous system and neurological and mental diseases (including anxiety disorders, depression, Parkinson’s disease, etc.) through interactions with the gut-brain axis, and the composition of the gut microbiota in these patients is significantly different from that in healthy people [11–14]. Specifically, the gut microbiota can interact with neurological, humoral and immunological components of the body in the gastrointestinal tract, thereby affecting the function and development of the central nervous system. The specific pathways involved include the production of various bioactive substances (neurotransmitters, short-chain fatty acids, acetates, and propionates), the induction of inflammatory cytokines, and even the triggering of the vagus nerve [10, 15]. Therefore, the gut microbiota is another important target for the diagnosis and treatment of such neuropsychiatric diseases [14]. Current research suggests that the gut microbiota is related to anxiety and depression, but the causal relationship between the two is still uncertain.

Mendelian randomization is a statistical method in which Single Nucleotide Polymorphisms (SNPs) are used to detect the causal effects of exposure factors on outcomes [16]. This method uses genetic variations determined before birth as instrumental variables to evaluate causal effects, effectively reducing the bias caused by confounding factors or reverse causality and thereby facilitating causal inference.

In this study, to explore the potential causal relationship between the gut microbiota and depression/anxiety disorders and to determine specific bacterial taxa, we conducted an MR study based on GWAS data.

Data Sources

The depression data were obtained from the GWAS Catalog of EMBL-EBI [17]. This dataset includes 13,559 cases and 435,855 controls, with 24,184,163 SNPs. The anxiety disorder data were obtained from a dataset created by the Neale lab in 2018 as part of the UK Biobank project [18]. This dataset includes 1,092 cases and 360,102 controls, with 9,440,635 SNPs. The human gut microbiome data we used were obtained from the Dutch Microbiome Project (DMP), which includes GWASs of 7,738 individuals (207 taxa and 205 pathways) [19]. All the data are publicly available.

Instrumental Variable Selection

Our research analysed the exposure factors at six levels, phylum, class, order, family, genus, and species, and selected suitable instrumental variables through a series of quality control steps.

The three major assumptions of Mendelian randomization (Figure.1) are as follows: (1) There is a strong correlation between the instrumental variables (SNPs) and the exposure factors (gut microbiota). It is required that each candidate IV is included in P < 5×10^− 8 to ensure the reliability of the results. The linkage disequilibrium (LD) threshold was set to R² < 0.001 and clumping distance = 10,000 kb to reduce the bias caused by linkage disequilibrium. (2) Genetic variation is unrelated to confounding factors. (3) Genetic variation is unrelated to outcome variables.

PhenoScanner [20] was used to exclude confounding factors related to depression and anxiety disorders (such as smoking and drinking) and SNPs related to these two outcomes. SNPs with palindromic structures were automatically excluded to avoid distortion of strand orientation or allele coding.

Mendelian randomization analysis

We conducted MR analysis on the gut microbiota with two outcomes (depression and anxiety disorders) respectively. The inverse-variance weighted (IVW) test was used as the main method and was supplemented by four methods: MR Egger, weighted median, simple mode, and weighted mode.

Sensitivity analyses

The sensitivity analysis included a heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. The heterogeneity test used Cochran’s Q to determine the heterogeneity of SNPs. If the Cochran’s Q test is statistically significant (P ≤ 0.05), it indicates that the results have significant heterogeneity. The horizontal pleiotropy test used MR Egger for analysis. If there is a significant intercept (P > 0.05), it indicates that the study has horizontal pleiotropy. Leave-one-out analysis was used to determine whether the significant results were determined by a single SNP.

Additional analyses

We conducted a steiger test to verify the directionality of the exposure and outcome and excluded possible reverse-positive results [Additional file 1–2].

Statistical software and version

All the statistical analyses were performed using R version 4.3.2. MR analyses were performed using TwoSampleMR version 0.5.8.

Major MR Results for the Gut Microbiota Associated with Depression

MR analysis was performed on 412 types of bacteria at six levels, phylum, class, order, family, genus, and species, and 11 bacterial taxa related to depression were ultimately screened out [Additional file 3]. All the selected SNPs had a F value > 10, which can be used to effectively avoid bias caused by weak instrumental variables. Among these taxa (Figure.2), the bacterial taxa positively correlated with depression include: species Coprobacter fastidiosus [OR = 1.114, 95%CI(1.019, 1.217), P = 0.018, β = 0.108], genus Prevotella9 [OR = 1.212, 95%CI(1.018, 1.444), P = 0.031, β = 0.193], family Alcaligenaceae [OR = 1.253, 95%CI(1.018, 1.541), P = 0.033, β = 0.225], genus Bilophila [OR = 1.332, 95%CI(1.020, 1.739), P = 0.036, β = 0.286], genus Coprobacter [OR = 1.107, 95%CI(1.006, 1.218), P = 0.037, β = 0.102]. The bacterial taxa negatively correlated with depression include: species Bacteroides faecis [OR = 0.935, 95%CI(0.896, 0.975), P = 0.002, β=-0.068], species Bacteroides fragilis [OR = 0.898, 95%CI(0.821, 0.983), P = 0.019, β=-0.107], phylum Firmicutes [OR = 0.747, 95%CI(0.582, 0.960), P = 0.022, β=-0.291], genus Escherichia Shigella [OR = 0.764, 95%CI(0.603, 0.967), P = 0.025, β=-0.270], genus Eisenbergiella [OR = 0.857, 95%CI(0.748, 0.983), P = 0.028, β=-0.154], genus Clostridium sensustricto1 [OR = 0.816, 95%CI(0.674, 0.987), P = 0.036, β=-0.204]. The MR-Egger intercept test did not reveal significant pleiotropy (P > 0.05), indicating that our instrumental variables met the exclusion restriction assumption. Heterogeneity tests also did not reveal significant heterogeneity (P > 0.05), indicating that our instrumental variables had a consistent effect direction. Leave-one-out sensitivity analysis also did not reveal any outliers, indicating that our results are robust.

Major MR Results for the Gut Microbiota Associated with Anxiety Disorders

We screened out 16 gut bacterial taxa related to anxiety disorders [Additional file 4]. All the selected SNPs had a F value > 10, which can be used to effectively avoid bias caused by weak instrumental variables. Among the remaining 16 taxa (Figure.3), the bacterial taxa positively correlated with anxiety disorders include: genus Clostridium innocuum group [OR = 1.002, 95%CI(1.000, 1.004), P = 0.014, β = 0.002], species Parabacteroides goldsteinii [OR = 1.001, 95%CI(1.000, 1.002), P = 0.015, β = 0.001], genus Parasutterella [OR = 1.001, 95%CI(1.000, 1.002), P = 0.017, β = 0.001], species Parasutterella excrementihominis [OR = 1.001, 95%CI(1.000, 1.002), P = 0.017, β = 0.001], unknown genus(id.2041) [OR = 1.001, 95%CI(1.000, 1.003), P = 0.026, β = 0.001]. the bacterial taxa negatively correlated with anxiety disorders include: species Pseudoflavonifractor capillosus [OR = 0.998, 95%CI(0.997, 0.999), P = 0.000, β=-0.002], genus Ruminococcus1 [OR = 0.997, 95%CI(0.995, 0.999), P = 0.002, β=-0.003], genus Dorea [OR = 0.998, 95%CI(0.996, 0.999), P = 0.009, β=-0.002], genus Pseudoflavonifractor [OR = 0.998, 95%CI(0.997, 1.000), P = 0.011, β=-0.002], genus Ruminococcaceae UCG002 [OR = 0.998, 95%CI(0.997, 1.000), P = 0.014, β=-0.002], order Verrucomicrobiales [OR = 0.999, 95%CI(0.997, 1.000), P = 0.039, β=-0.001], genus Akkermansia [OR = 0.999, 95%CI(0.997, 1.000), P = 0.039, β=-0.001], family Verrucomicrobiaceae [OR = 0.999, 95%CI(0.997, 1.000), P = 0.039, β=-0.001], class Verrucomicrobiae [OR = 0.999, 95%CI(0.997, 1.000), P = 0.039, β=-0.001], genus Phascolarctobacterium [OR = 0.999, 95%CI(0.998, 1.000), P = 0.044, β=-0.001], species Phascolarctobacterium succinatutens [OR = 0.999, 95%CI(0.998, 1.000), P = 0.044, β=-0.001]. Our MR-Egger intercept test did not reveal significant pleiotropy (P > 0.05), indicating that our instrumental variables met the exclusion restriction assumption. Moreover, our heterogeneity test did not reveal significant heterogeneity (P > 0.05), indicating that our instrumental variables had a consistent effect direction. Our leave-one-out sensitivity analysis also did not reveal any outliers, indicating that our results are robust.

Sensitivity analyses

The heterogeneity of SNPs was determined using Cochran’s Q, and the Q_pval of both MR Egger and IVW were > 0.05, indicating no heterogeneity [Additional file 5–6]. The horizontal pleiotropy between the instrumental variables and the outcomes was analysed using MR Egger, and all P values were > 0.05, providing no evidence of horizontal pleiotropy [Additional file 7–8]. Leave-one-out analysis revealed that no single SNP dominated the overall effect.

This study used data from a large cohort study in Europe, separately analyzed the 16S rRNA gene sequencing of the gut microbiota and depression/anxiety disorders, and provided evidence for the causal relationship between the gut microbiota and depression and anxiety disorders. The results showed that there was a significant causal relationship between the gut microbiota and depression, and some bacterial taxa were positively correlated with depression, while others were negatively correlated. These bacterial taxa may be potential biomarkers or therapeutic targets for depression. The five bacterial taxa that have the most significant impact on depression are as follows: (i) The genus Bilophila comprises anaerobic bacteria that are mainly distributed in the human colon and appendix and can use bile acids as energy to produce hydrogen sulfide and propionic acid. The Bilophila genus of bacteria has been found to be enriched in the intestines of patients with major depressive disorder (MDD) [21]. (ii) The phylum Firmicutes comprises gram-positive bacteria that are widely present in the human gut and are involved in many important metabolic processes, such as the synthesis of short-chain fatty acids, protein degradation, and vitamin synthesis. The Firmicutes phylum of bacteria is closely related to gut health and immune system balance. Research has shown that, unlike patients with bipolar depression, healthy patients have greater enrichment of the phylum Firmicutes [22]. (iii) The genus Escherichia Shigella comprises gram-negative bacteria that are present mainly in the human large intestine. The Escherichia Shigella genus of bacteria is related to intestinal inflammation, diarrhea, and food poisoning, but a higher abundance of Escherichia Shigella has been found to be associated with a lower risk of depressive symptoms [23]. (iv) The family Alcaligenaceae is a bacterial family of the order Pseudomonadales that is composed mainly of aerobic or facultative anaerobic gram-negative bacilli. Alcaligenaceae are related to gut microbiota imbalance and metabolic disorders and may induce depression by affecting the gut-liver-brain axis [24]. (v) The genus Prevotella9 is a bacterial genus of the Pseudomonadales order and is composed mainly of anaerobic gram-negative bacilli. According to our results, bacteria of the Prevotella9 genus are positively correlated with depression. However, current research shows that the abundance of the family Prevotellaceae is low in MDD patients and helps to improve patients’ depressive symptoms [25]. This may be due to heterogeneity between genera or other unknown reasons.

In addition, we also found a causal relationship between several gut bacterial taxa and anxiety disorders in our study, but the relationship was not significant. These bacteria can serve as potential biomarkers or therapeutic targets for anxiety disorders. The three bacterial taxa that have the most significant impact on anxiety disorders are as follows: (i) The genus Clostridium innocuum is a group of anaerobic bacteria from the phylum Firmicutes that is positively correlated with anxiety disorders. These bacteria can produce neuroactive substances, such as gamma-aminobutyric acid (GABA) and acetylcholine (ACh) in the gut [26]. These substances may increase anxiety by affecting the balance of neurotransmitters in the brain. (ii) The species Pseudoflavonifractor capillosus is an anaerobic bacterium of the order Clostridiales that is negatively correlated with anxiety disorders. (iii) The genus Ruminococcus1 is a group of anaerobic bacteria from the order Clostridiales that is negatively correlated with anxiety disorders. It can ferment various carbohydrates in the gut to produce short-chain fatty acids. These substances may improve mood and cognitive function by regulating neurotransmitters in the brain, thereby reducing the risk of anxiety [27].

Depression and anxiety often present as comorbidities but are still different entities. The commonality between anxiety and depression includes negative affect (general psychological distress or negative emotions), while the unique feature of anxiety is physiological hyperarousal (tension, trembling), and the unique aspect of depression is low positive affect/lack of joy (loss of interest, despair) [28]. These unique symptoms of anxiety and depression persist across all age groups [29]. This study discussed the relationship between the gut microbiota and these two mental disorders separately. Future research can increase the analysis of the gut microbiota in comorbid patients to avoid interference between outcome variables. In addition, whether the microbiota that appears simultaneously in patients with depression or anxiety disorders plays a more important role in the onset of comorbid patients is worth exploring.

This study has several advantages. We used the latest GWAS data of 412 bacterial taxa for Mendelian randomization research, while the data used in previous studies may be insufficient and outdated. In addition, there is no reliable experimental or observational research support for the causal relationship between some microbiota and outcomes; therefore, this study can provide reliable evidence and ideas for further research in the future.

This study has certain limitations. First, we did not refine the types of depression/anxiety disorders but analysed a category of diseases as a whole. This approach may overlook the heterogeneity between different subtypes. Future research should consider a more detailed classification of the outcome to explore a more precise causal relationship. In addition, this study did not conduct reverse MR; that is, depression/anxiety disorders were used as exposure factors to assess their potential impact on the gut microbiota. Recent research has shown that mental stress can indeed affect the abundance of specific gut bacterial taxa by triggering the sympathetic nervous system, which may lead to uncertainty in the directionality of the causal relationship [30]. Although we tested whether the exposure was upstream of the outcome, this test cannot completely rule out the existence of reverse causality. In-depth research should use bidirectional MR methods to verify the directionality of causal relationships.

In conclusion, we comprehensively evaluated the potential causal relationship between the gut microbiota and depression/anxiety disorders. The microbiota related to depression included 5 positively correlated and 6 negatively correlated bacterial taxa. The microbiota related to anxiety disorders included 5 positively correlated and 11 negatively correlated bacterial taxa. This study may provide new insights into the connection between the gut microbiota and the pathogenesis of depression/anxiety disorders and offer new perspectives for the clinical diagnosis and treatment of patients. Comprehensive intervention in the gut microbiota of patients may improve patient symptoms and provide a good prognosis.

Ethics approval and consent to participate

This study does not contain any studies with human participants or animals.

Consent for publication

Not applicable.

Availability of data and materials

The original contributions presented in the study are included in this article and its Supplementary Material. More research data are reasonably available from the authors.

Competing interests

The authors declare that they have no competing interests.

Funding

Authors received no specific funding for this work.

Authors' contributions

TF is responsible for data analysis and manuscript writing. LL is responsible for data acquisition and collation. YC is responsible for management, supervision and modification. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

Additionalfile1.xlsx
Additional file 1: Steiger test results of depression
Additionalfile2.xlsx
Additional file 2: Steiger test results of anxiety disorder
Additionalfile3.xlsx
Additional file 3: MR results of depression
Additionalfile4.xlsx
Additional file 4: MR results of anxiety disorder
Additionalfile5.xlsx
Additional file 5: heterogeneity test (Cochran’s Q) of depression
Additionalfile6.xlsx
Additional file 6: heterogeneity test (Cochran’s Q) of anxiety disorder
Additionalfile7.xlsx
Additional file 7: horizontal pleiotropy test (MR Egger) of depression
Additionalfile8.xlsx
Additional file 8: horizontal pleiotropy test (MR Egger) of anxiety disorder

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Causal Relationships between Gut Microbiota and Depression/Anxiety Disorders: A Two-Sample Mendelian Randomization Study

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Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Materials and Methods

Data Sources

Instrumental Variable Selection

Mendelian randomization analysis

Sensitivity analyses

Additional analyses

Statistical software and version

Results

Major MR Results for the Gut Microbiota Associated with Depression

Major MR Results for the Gut Microbiota Associated with Anxiety Disorders

Sensitivity analyses

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1