Causal relationship between gut microbiota, structural connectivity, and psoriasis: A Mendelian randomization

doi:10.21203/rs.3.rs-4991141/v1

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Research Article

Causal relationship between gut microbiota, structural connectivity, and psoriasis: A Mendelian randomization

https://doi.org/10.21203/rs.3.rs-4991141/v1

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Background

Previous studies have demonstrated a causal relationship between gut microbiota/structural connectivity and psoriasis. However, it is not clear whether structural connectivity act as mediator in the pathway from gut microbiota to psoriasis.

Methods

Based on genome-wide association studies (GWAS), we performed two-step MR-analysis in order to examine the role of structural connectivity (N = 26,333) as potential mediators between gut microbiota (N = 13,266) and psoriasis (N = 15,967). Summary statistics for gut microbiota were sourced from MiBioGen consortium, while the data of structural connectivity and psoriasis came from the GWAS catalog.

Results

Through MR analysis, we identified 2 gut microbiota and 15 inflammatory proteins related to psoriasis such as genus Coprococcus3 and LH Limbic to caudate (OR = 1.33, 95% CI: 1.00–1.76, P = 0.048; OR = 0.70, 95% CI: 0.56–0.86, P = 0.001). After MVMR analysis, LH Limbic to caudate remained significant in relation to a decreased risk of psoriasis (P = 0.0005) while the association was no longer significant between genus Coprococcus3 and psoriasis (P = 0.121). The mediating effect was calculated as 0.047 (OR = 1.049, 95% CI: 1.006–1.109) accounting for 16.6% of the total effect.

Conclusion

Our study provides genetic evidence that in the pathway from gut microbiota to psoriasis, structural connectivity act as mediators.

gut microbiota

structural connectivity

Mendelian randomization

psoriasis

GWAS

Psoriasis is a chronic, recurrent, inflammatory, and systemic disease mediated by the immune system, triggered by a combination of genetic and environmental factors. The common clinical features include scaly, erythematous patches or plaques, which can appear either localized or widely distributed. According to the World Health Organization, psoriasis prevalence ranges from 0.33–0.6% across different racial groups and impacts approximately 125 million people globally¹.

Gut-brain-skin axis, proposed in recent years, has highlighted the relationship between gut/brain and skin disorder and indicated that gut microbiota may play a role in skin diseases through influencing brain activity¹. It is reported that there is a decreased abundance of Bifidobacterium and Akkermansia muciniphila in patients with psoriasis compared with controls^2,3. However, due to selected sample or measuring method varied in different study, there is inconsistent finding in some study. Although underlying mechanism is not fully understood now, it is believed that gut microbiome plays an important role in the immune system development and regulation of immune homeostasis which indicates that imbalance of gut microbiota may result in the occurrence of psoriasis. Additionally, It is observed that intestinal dysbiosis is associated with different diseases of the nervous system which indicates that the immune system and the nervous system could crosstalk with each other and gut microbiota may regulate neuroinflammation and neurodegeneration in the central nervous system through immune system¹.

Previous studies have demonstrated the negative impact of psoriasis on quality of life and cognitive function, along with its correlation to an increased risk of cognitive impairment, potentially progressing to dementia. In a study by Najafi P et al, there is a significant difference in network interconnection by connectivity analysis compared with controls4. In addition, this network was activated during ongoing itch in patients with psoriasis. Individuals with psoriasis face a higher risk of developing other comorbidities, such as depression, anxiety, and suicidal ideation, suggesting a possible link between structural connectivity and psoriasis⁴.

GWAS has identified many human genetic variants associated with diseases by analyzing correlations between genetic variations and disease outcomes. Using these genetic variants as instrumental variables (IVs), MR infers causal relationships between exposures and outcomes. MR reduces confounding biases in epidemiological studies and determines directional causality between phenotypes using bidirectional MR⁵. We conducted MR and mediation analyses to explore whether structural connectivity mediates the relationship between gut microbiota and psoriasis.

2.1 Study design

Herein, a two-step MR analysis was conducted to determine whether brain structural connectivity mediated the pathway from gut microbiota to psoriasis. First, we conducted two-sample MR analysis to assess the causal effect of gut microbiota and brain structural connectivity on psoriasis. Next, we identified gut microbiome and brain connectome factors related to psoriasis risk. Finally, we performed mediation analysis to determine whether structural connectivity mediated the relationship between gut microbiota and psoriasis. Details are shown in Fig. 1. Our study followed the STROBE-MR guidelines and did not require ethical approval⁶.

2.2 Data source

We obtained GWAS summary data for gut microbiota from the MiBioGen consortium, which included 18,340 participants from 24 cohorts in 11 countries, with the majority (N = 13,266) of European ancestry. The MiBioGen team performed 16S rRNA gene sequencing to classify gut microbiota into five taxonomic levels: phylum, class, order, family, and genus⁷. For structural connectivity, we obtained GWAS summary data from Wainberg M et al⁸, available in the GWAS Catalog under IDs GCST90302648 to GCST90302853. Using diffusion MRI tractography, Wainberg M et al. extended prior white matter GWAS by examining 206 tractography-based structural connectivity measures of the brain’s organizational framework. The study by Wainberg M et al. included 26,333 participants from the UK Biobank, a larger sample than previous structural connectivity GWAS. Additionally, genetic associations for psoriasis were derived from a GWAS analysis by the IEU Open GWAS project, which included 44,161 individuals, mostly of European ancestry (GWAS ID: ebi-a-GCST90019016, n = 15,967 cases, n = 28,194 controls; https://gwas.mrcieu.ac.uk/)⁹. Psoriasis cases were diagnosed by dermatologists based on established criteria.

2.3 Instrumental variables (IVs)

We applied particular criteria in our study to choose IVs for MR analysis with SNPs. (1) Correlation with exposure: SNPs were required to demonstrate a significant correlation with gut microbiota, having a p-value of less than 5×10^-8. Due to the scarcity of SNPs that met this criterion, a p-value threshold of 1×10^-5 was suggested for gut microbiota, whereas a p-value threshold of 5×10^-6 was used for structural connectivity^10,11. (2) Linkage disequilibrium (LD) removal: a clumping procedure was applied to eliminate linkage disequilibrium (LD), using an R^2 threshold of 0.001 and a window size of 10,000 kb. (3) Robustness assessment: the association between IVs and exposures was evaluated using the F statistic, calculated as

SNPs with an F value below 10 were excluded to minimize biases. (4) Association with outcome check: SNPs selected were examined in LDlink to identify any associations with the gut microbiota/structural connectivity. SNPs related to those were excluded to avoid potential pleiotropy. These criteria were implemented to ensure the reliability of our MR analysis.

2.4 Statistical analysis

2.4.1 Primary analysis

To determine the causal association between gut microbiota and structural connectivity in relation to psoriasis, we employed the inverse variance weighted (IVW) method as our primary approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode as complementary methods¹². The IVW method is the primary causal effect estimation in Mendelian randomization studies, exhibiting higher statistical power in hypothesis testing. It integrates the Wald estimates for each SNP through a meta-analytic approach to evaluate the impact of gut microbiota and inflammatory proteins on inflammatory diseases. During regression analysis, the intercept term is omitted, and the fitting procedure incorporates the inverse of the variance (se²) of the outcome as a weighting factor. The results will remain unbiased with horizontal heterogeneity absent. Based on the fundamental premise that the strength of the instrumental variable remains unaffected by direct effects, MR-Egger regression is employed to identify and adjust for causal relationships between IVs and outcomes. When the intercept approaches zero, indicating the absence of horizontal pleiotropy, the findings from MR-Egger align closely with those from IVW^13,14.. Additionally, we carried out reverse two-sample MR analysis to explore the causal relationship from psoriasis to gut microbiota and structural connectivity.

2.4.2 Sensitivity analysis

Cochran's Q test was used to assess heterogeneity among IVW IVs. When heterogeneity is identified by a p-value below 0.05, the random-effects IVW model is applied¹⁵. In addition, To detect pleiotropy among SNPs, we used the MR-Egger intercept, considering a p-value below 0.05 as indicative of significant pleiotropic effects¹⁴. By employing the MR pleiotropy residual sum and outlier (MR-PRESSO) methodology, we detected outliers and evaluated the robustness of our analysis to examine the existence of horizontal pleiotropy. Through the identification and removal of such outliers, we obtained refined estimates that accounted for their influence. Moreover, to ensure the reliability of our analysis, leave-one-out analysis was carried out¹⁶.

2.4.3 Mediation analysis

We conducted a two-step MR analysis to determine whether structural connectivity mediated the relationship between gut microbiota and psoriasis. First, a two-sample MR analysis was used to evaluate the causal relationship between gut microbiota, structural connectivity, and psoriasis. Next, we identified microbiomes and structural connectivities strongly associated with psoriasis and conducted MR analysis to assess the causal effect of selected gut microbiota on selected structural connectivity. Finally, MVMR was applied to identify structural connectomes maintaining a causal relationship with psoriasis, independent of gut microbiota. Notably, in the two-sample MR analysis, the impact of gut microbiota on psoriasis was termed the "total effect" (β1), while in MVMR, it was termed the "direct effect" (β2). The effect of structural connectivity on psoriasis in MVMR analysis was defined as β3, while the influence of gut microbiota on structural connectivity in the two-sample MR analysis was labeled as β4. The mediating effect was calculated as β3β4, and the mediated ratio as (β3β4)/β1¹⁷. Confidence intervals (95% CI) and odds ratios were estimated using the delta method. The Sobel test was used to assess the significance of the mediator.

To ensure the rigor of our results, it was considered significant if the p-value remains below 0.05 after applying the Benjamini − Hochberg procedure (FDR) in MR analysis¹⁸. Additionally, associations were considered suggestive when the p-value is less than 0.05 but the FDR-corrected p-value exceeds 0.05. The MR analysis in this study is conducted using R software (version 4.2.3), with the two-sample package (version 0.6.2) and MR-PRESSO (version 1).

3.1 Causal effect of gut microbiota/structural connectivity on psoriasis

In our MR analysis (Fig. 2), we found that genus Coprococcus3 and genus Dialister were causally associated with a higher risk of psoriasis (OR = 1.33, 95% CI: 1.00–1.76, P = 0.048; OR = 1.27, 95% CI: 1.05–1.54, P = 0.013). In opposition to this, we found that there were 15 structural connectomes related to psoriasis. Except for LH DorsAttn to LH DorsAttn which related to a higher risk of risk of psoriasis (OR = 1.60, 95% CI: 1.06–2.40, P = 0.024), the other were all associated with a decreased risk of psoriasis. LH Vis to thalamus, LH Vis to hippocampus, LH SomMot to RH SomMot, LH SomMot to RH dorsAttn, LH SomMot to RH SalVent Attn, LH DorsAttn to RH DorsAttn, LH DorsAttn to caudate, LH SalVent Attn to LH SalVent Attn, LH Limbic to caudate, LH Default to LH Default, LH Default to RH Limbic, RH dorsAttn to RH DorsAttn, RH SalVent Attn to hippocampus and RH Limbic to thalamus had a potentially protective effect on psoriasis (OR = 0.71, 95% CI: 0.54–0.94, P = 0.016; OR = 0.74, 95% CI: 0.55–0.98, P = 0.037; OR = 0.79, 95% CI: 0.65–0.96, P = 0.020; OR = 0.72, 95% CI: 0.58–0.88, P = 0.002; OR = 0.78, 95% CI: 0.64–0.96, P = 0.020; OR = 0.73, 95% CI: 0.58–0.91, P = 0.004; OR = 0.69, 95% CI: 0.52–0.92, P = 0.011; OR = 0.71, 95% CI: 0.52–0.98, P = 0.037; OR = 0.70, 95% CI: 0.56–0.86, P = 0.0008; OR = 0.66, 95% CI: 0.48–0.90, P = 0.009; OR = 0.74, 95% CI: 0.56–0.97, P = 0.028; OR = 0.63, 95% CI: 0.48–0.83, P = 0.001; OR = 0.71, 95% CI: 0.53–0.96, P = 0.025; OR = 0.76, 95% CI: 0.62–0.94, P = 0.011).

However, after applying FDR correction, the association was no longer significant. In addition, according to Cochran's Q statistic, MR-Egger intercept test, and MR-PRESSO, it indicated no heterogeneity or horizontal pleiotropy in this MR analysis. Furthermore, no individual SNP notably influenced the overall effect of gut microbiota or structural connectivity on psoriasis, as demonstrated in the leave-one-out sensitivity analysis. In reverse MR analysis, we did not find bidirectional causal relationship between gut microbiota/structural connectivity and psoriasis.

3.2 Mediation analysis

After screening out gut microbiota and structural connectome that were associated with psoriasis, we conducted two-sample MR analysis to figure out the causal effect of selected gut microbiota on filtered structural connectivity. It was found that genus Coprococcus3 was associated with a higher risk of LH Limbic to caudate (OR = 0.90, 95% CI: 0.82–0.98, P = 0.019). Additionally, we carried out MVMR analysis using genus Coprococcus3 and LH Limbic to caudate as the exposures, and psoriasis as the outcome. After MVMR analysis, LH Limbic to caudate remained significant in relation to a decreased risk of psoriasis (P = 0.0005) while the association was no longer significant between genus Coprococcus3 and psoriasis (P = 0.121). The mediating effect was calculated as 0.047 (OR = 1.049, 95% CI: 1.006–1.109; Table 1) accounting for 16.6% of the total effect.

Table 1

Mediating analysis from gut microbiota to psoriasis
Mediator	Pathway	β1	Mediating effect	Mediating proportion	Confidence intervals
LH Limbic to caudate	genus Coprococcus3 to psoriasis	0.283	0.047	16.6%	(1.006,1.109)
β1: impact of gut microbiota on psoriasis in two-sample MR analysis

To the best of our knowledge, this was the first study to use two-step MR analysis and explored whether structural connectivity acted as mediator in the pathway from gut microbiota to psoriasis. Based on GWAS data, we identified suggestive associations between gut microbiota/structural connectivity and psoriasis. Furthermore, through MVMR analysis, LH Limbic to caudate were found to act as mediator from genus Coprococcus3 to psoriasis. It is worth noting that this study pioneers the investigation of both the causal relationships between gut microbes/structural connectivity and psoriasis and the mediation role of structural connectivity from gut microbiota to psoriasis at the genetic prediction level.

In observational studies, there was a increasing abundance of genus Dialister in patients with psoriasis compared with controls according to studies by Wang X et al and Schade L et al^19,20. Our study found that the genus Dialister, a Gram-negative, anaerobic bacterium of Firmicutes (Bacillota), significantly increases the risk of psoriasis, aligning with results from prior research. Additionally, it is found that there is negative relationship between Dialister and inflammatory cytokines such as IL-2R which is involved in the pathogenesis of psoriasis and can be used as the predictor of disease severity and the marker of response to therapy²¹. As for genus Coprococcus3, based on our study, it was found to a risk factor for psoriasis. Furthermore, a study indicated that Coprococcus in patients with psoriasis has a significant association with multiple clinical indices, and it exhibits a positive correlation with fasting blood glucose (FBS) and IgA²¹.

Thalamus, serving as a nexus in the regulation of stress and immunity, has played a role in immune disorders such as multiple sclerosis^22,23. Additionally, the thalamus can mediate the conduction of itch, the main chief complaint in patients suffering from dermatological disorders such as psoriasis and atopic dermatitis²⁴. Functional networks of the brain, such as the visual network in the left hemisphere, are connected to the thalamus, which is involved in the processing and integration of sensory information²⁵. Given these mentioned above, there may be a association between LH Vis to thalamus and psoriasis while in our study, we found that LH Vis to thalamus and RH Limbic to thalamus had protective effect on psoriasis.

Limbic network as a complex network of brain structures includes hippocampus, amygdala, hypothalamus and others. It is reported that the limbic system network in the right hemisphere plays an important role in emotional processing and stress response. The stress response will activate the limbic system, and then regulate the hypothalamic-pituitary-adrenal axis (HPA axis) through the thalamus, affecting the release of stress hormones such as cortisol^26,27. Previous studies have shown that stress can be a triggering factor for psoriasis²⁸. Therefore, we hypothesized that there may be an association between the RH Limbic to thalamus pathway and psoriasis.

The Default Mode Network (DMN) is a network of brain regions that exhibits heightened activity during states of rest, characterized by the absence of focused engagement with external stimuli²⁹. Yi X et al reported that patients with psoriasis had altered brain activity and connectivity in the key brain areas within the DMN while LH Default to LH Default and LH Default to RH Limbic were found as protective factors for psoriasis in our study³⁰. Additionally, the precuneus, a key region within the DMN, is involved in resting-state self-referential processing and the retrieval of episodic memories. The right precunneus was found to be thinner than controls³¹. At the same time, the precuneus plays a key role in the processing of itch while in a study found there was a activation of precunneus in patients with atopic dermatitis³². Based on MR analysis, we also found other structural connectivity related to psoriasis such as LH SalVent Attn to LH SalVent Attn, LH DorsAttn to LH DorsAttn. However, related research is limited which requires more exploration.

In recent years, increasing attention has been given to the concept of the enterocerebral skin axis while our study identified the LH limbic to caudate pathway as a mediator from gut microbiota to psoriasis. In a mice model, the development of nerves and activation of microglia have been confirmed to depend on the gut microbiota³³. The occurrence of inflammatory diseases such as psoriasis involved in the activation of the immune system, nervous system, and gut microbiota. The homeostasis of gut microbiota plays an important role in regulating inflammatory and infective diseases. When microbial populations are imbalanced, unhealthy signals can reach the brain, resulting in mild systemic inflammation^34,35. Coprococcus, a butyrate producer, metabolizes carbohydrates through the butyryl-CoA CoA-transferase pathway and butyrate kinase enzymes to generate the majority of butyrate. Butyrate, one of the SCFAs, modulates the activity of innate immune cells, enhancing their immune response role which may result in the change in brain structure connectivity³⁶. The LH limbic to caudate pathway has been linked to depression, which increases pro-inflammatory cytokine levels and worsens psoriasis^37,38. Therefore, we supposed that LH limbic to caudate maybe a mediator from gut microbiota to psoriasis.

Strengths and Limitations

Our research offers several key advantages. First, this is the first study to investigate the causal relationship by MR analysis, between gut microbiota/structural connectivity and psoriasis. We also figured out that, through two-step MR, LH limbic to caudate served as mediator from genus Coprococcus3 to psoriasis, which provides genetic evidence for further treatment targeting gut microbiota or cytokines. In addition, our investigation was conducted based on robust methodology by leveraging GWAS and MR, which minimizes confounding biases relative to traditional studies. Furthermore, our research employs a comprehensive methodology to ensure result reliability. Sensitivity analyses were performed, utilizing Cochran’s Q test to assess heterogeneity, and MR-Egger intercept and MR-PRESSO to detect horizontal pleiotropy.

Despite its strengths, our research also has some limitations. First, since the GWAS data primarily originates from European populations, the findings may not be generalizable to other ethnicities. Secondly, although MR analysis helps infer causal relationships, it cannot completely eliminate all confounding variables. Additionally, while MR analysis serves as a hypothesis-driven approach, it necessitates experimental and clinical studies to confirm the causal relationship between gut microbiota/structural connectivity and psoriasis. Moreover, although we identified LH limbic to caudate as mediators, the mediating proportion was somewhat limited, suggesting that the mediating effect was not pronounced.

As far as we know, this is the first study to examine whether structural connectivity mediate the pathway from gut microbiota to psoriasis using a two-step MR analysis. Drawing from GWAS data, we identified a suggestive association between gut microbiota/structural connectivity and psoriasis. This study provides new insights into the interaction between gut microbiota and psoriasis, potentially encouraging further research on treatments targeting gut microbiota or structural connectivity.

Data Availability

The genome-wide association study (GWAS) data for structural connectivity/psoriasis is accessible through the GWAS catalog, while gut microbiota data is available from the MiBioGen consortium. Code used in the analysis are available at https://github.com/.

Author Contributions

ZH: contributed to shaping the research plan, analyzing the data, and drafting the manuscript's initial version.

JL,TL, QD, XL, LL: reviewed the manuscript and provided invaluable feedback for its revision.

Acknowledgements

We sincerely thank all the researchers who have generously shared their GWAS data.

Funding

This study did not receive specific funding.

Competing interests:

the authors have no conflicts of interest to declare.

Ethical approval:

not applicable.

Consent for publication:

not required.

Consent to participate:

not required.

Supplementary materials:

presented in additional files.

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Causal relationship between gut microbiota, structural connectivity, and psoriasis: A Mendelian randomization

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Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Method

2.1 Study design

2.2 Data source

2.3 Instrumental variables (IVs)

2.4 Statistical analysis

2.4.1 Primary analysis

2.4.2 Sensitivity analysis

2.4.3 Mediation analysis

3. Result

3.1 Causal effect of gut microbiota/structural connectivity on psoriasis

3.2 Mediation analysis

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1