Association between gut microbiota and psoriasis: a bidirectional two-sample Mendelian randomization study

doi:10.21203/rs.3.rs-3251626/v1

Background:

Research has found that the composition of gut microbiota is related to psoriasis and its subtypes. However, the causal effect of gut microbiota on psoriasis is still unclear.

Methods:

A two sample Mendelian randomization randomized study was conducted using the aggregated statistical data of intestinal microbiota in the meta-analysis of the largest available genome-wide association studies conducted by the MiBioGen Alliance. The summary statistical data for psoriasis, arthropathic psoriasis, and psoriasis vulgaris are from the FinnGen Alliance R7 release. Reverse variance weighting, maximum likelihood, MR Egger, weighted median, weighted model, MR-PRESSO, and cML MA were used to examine the causal relationship between gut microbiota and psoriasis, arthropathic psoriasis, and psoriasis vulgaris. In the forward Mendelian randomization randomization analysis, reverse Gregor Mendel randomization analysis was performed on bacteria found to have causal relationships with psoriasis, arthropathic psoriasis and psoriasis vulgaris. Cochran's Q statistics are used to quantify the heterogeneity of Instrumental variables estimation.

Results:

A higher genetically predicted abundance Odoribacter was associated with a reduced risk of psoriasis. While a higher genetically predicted abundance of Ruminiclostridium5 was associated with an increased risk of psoriasis. The genetically predicted relative abundance of Verrucomicrobiae, Verrucomicrobiaceae, Akkermansia, Verrucomicrobiales were positively associated with arthropathic psoriasis. A higher genetically predicted abundance of Rikenellaceae served as protective factors for arthropathic psoriasis. Specifically, a higher genetically predicted Atinomycetaceae, Eubacterium fissicatena group, Lactococcus, and Actinomycetales were associated with a higher risk of psoriasis vulgaris. In contrast, higher genetically predicted Odoribacter was a lower risk of psoriasis vulgaris. No significant heterogeneity or level pleiotropy of Instrumental variables estimation was found.

Conclusion:

This MR study offer novel perspectives regarding the prevention, advancement, and therapy of psoriasis by concentrating on specific bacterial groups. Additional research is required to specify the exact mechanism relating the association between gut microbiota and psoriasis along with its classifications.

psoriasis

arthropathic psoriasis

psoriasis vulgaris

gut microbiota

casual inference

Mendelian randomization study

genetics

Psoriasis is a common non-infectious chronic inflammatory disease with a complex etiology[1–3]. Risk factors for psoriasis include genetic factors, smoking, obesity, infection and medication, among others[1, 2, 4, 5]. According to data from the World Health Organization (WHO), psoriasis is relatively common in the general population, affecting approximately 2–4% of the global population, while the incidence varies by geographical location. Psoriasis is primarily characterized by dermatological lesions, with common clinical symptoms including sharply defined, erythematous and pruritic plaques. It can also trigger inflammation in other organ systems, such as the gastrointestinal, cardiovascular, and musculoskeletal systems[6]. Psoriatic arthritis can lead to severe disability and significantly exacerbate the severity of psoriasis-related complications and mortality[7, 8]. Despite increasing research into psoriasis and psoriatic arthritis, their etiology remains under investigation[8]. The current view emphasizes the critical role of genetic, immunological, and environmental factors in psoriasis and psoriatic arthritis. Currently, psoriasis cannot be cured, and various treatment options are only able to suppress the progression of the disease, severely affecting the physical and psychological quality of life of patients[9].

Studies have shown that the gut microbiome plays a crucial role in the gut-skin axis[10, 11]. The bacterial communities of the gut microbiome can affect the condition of the skin through their metabolism and immune effects[12, 13]. Growing evidence suggests an association between dysbiosis of gut microbiota and psoriasis[14–17]. Research has indicated that the mechanism of the gut-skin axis in psoriasis involves the function and differentiation of T cells, as well as the imbalance of Treg and Th17 cells[10, 13, 18]. It has been demonstrated that the gut microbiome of psoriasis patients has reduced bacterial diversity and altered relative abundance of certain bacterial taxa[13, 19]. Additionally, the microbiome characteristics of severe psoriasis patients have been shown to differ from those with mild psoriasis[11]. However, the gut microbiome status of psoriasis patients and the interactions between the microbiome and the immune system are not entirely understood at present. The results of these studies are inconsistent and may suffer from residual confounding and reverse causality issues, making it difficult to infer a causal relationship between the gut microbiota and psoriasis.

Mendelian randomization (MR) is an effective method that can overcome biases due to confounding and reverse causation[20]. It uses genetic variation as an instrumental variable (IV) to assess potential causal relationships between specific risk factors and the outcome of interest, such as a disease or trait[21]. This approach has been widely applied to studying the causal relationships between gut microbiome and diseases[21]. In this study, a large-scale, non-overlapping genome-wide association study (GWAS) database was used to conduct bidirectional MR analysis to evaluate the potential causal relationship between the gut microbiome and psoriasis.

Data source

We obtained the latest GWAS dataset on the human gut microbiome from the MiBioGen consortium. This dataset represents the largest, multi-ethnic, genome-wide analysis of human autosomal genetic variation and the gut microbiome, specifically designed to investigate associations between host genetics and the microbiome. The study recruited 18,340 participants from a variety of countries and regions, with a predominance of European groups. This comprehensive study identified 211 bacterial taxa, comprising 9 phyla, 16 classes, 20 orders, 35 families (of which 3 were unknown), and 131 genera (of which 12 were unknown).

After excluding 15 microbial taxa with incomplete information on family and genus, we were left with a final dataset of 196 bacteria. Obtaining GWAS summary data for psoriasis, arthropathic psoriasis, and psoriasis vulgaris from the FinnGen Consortium's L12 data provided a starting point for our analysis. Specifically, the dataset for psoriasis consisted of 4,510 cases and 212,242 controls, with a total of 16,380,464 single nucleotide polymorphisms (SNPs), the dataset for arthropathic psoriasis consisted of 1,637 cases and 212,242 controls, with a total of 16,380,462 SNPs, and the dataset for psoriasis vulgaris consisted of 2,802 cases and 212,242 controls, with a total of 16,380,459 SNPs. It is worth noting that all populations included in these datasets were from European groups, as detailed on the GWAS website (https://gwas.mrcieu.ac.uk/datasets/).

The requirement for additional ethical approval was waived in this study because the publicly available data had already undergone appropriate ethical and institutional review board approval, which was not required for our research.

Assumption of Mendelian randomization

The success of MR studies depends on three key assumptions. Initially, we must verify that the genetic variants in question are independently and significantly related to exposure, which we have achieved by using P-values and F-statistics from correlation tests. Second, we must establish that there is no relationship between exposure-related genetic variants and outcomes. Finally, the third assumption assumes that these variants should not be correlated with any confounding variables[22, 23].

Selection of Instrumental Variables

As an initial step in MR analysis, we used SNPs with a threshold P-value of 1 x 10 − 5 as genetic instrumental variables[24]. This approach was adopted to optimize the proportion of genetic variation accounted for by genetic predictors and to increase the pool of eligible SNPs for subsequent sensitivity analyses. The F-statistic, which measures instrument validity, serves as a reliable benchmark for assessing robustness. The formula F = R2(n-k-1)/k(1-R2) is used, with R2 representing the variance accounted for by the instruments, n indicating the sample size, and k representing the number of IVs selected. To prevent the possibility of weak instrument bias, we established a conventional threshold value of F-statistic > 10. SNPs with F-statistic below 10 were removed from the dataset. To avoid the effect of LD on results, the included genetic variants were analyzed using a buffer approach, with r2 > 0.001 and a buffer window < 10,000 kb. We then removed SNPs that were significantly associated with psoriasis, arthropathic psoriasis, and psoriasis vulgaris based on the following criterion: P(outcome) < P(exposure). Ultimately, we eliminated SNPs with palindromic structures to ensure that screened SNPs were aligned with exposure and outcome alleles[25].

Statistical analysis of Mendelian randomization

In this study, various MR-related statistical methods were employed including inverse variance weighting (IVW), Simple Mode, MR-Egger regression, weighted median, weighted model and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) to determine whether there is a causal relationship between gut microbiota and hemorrhagic stroke. The IVW method is able to estimate the causal effect of exposure on outcome by integrating ratio estimates for each SNP. Essentially, it transforms MR estimates into a weighted regression of SNP-outcome effects on SNP-exposure effects[25]. The weighted median method is dependable when most individual instrument causal effect estimates are derived from valid instruments, even if some IVs are considered invalid. The weighted model approach is accurate when most individual instrumental variable causal effect estimates are derived from valid IVs, even if up to 50% of the data are derived from invalid instruments[25]. The MR-Egger method is useful for estimating causal effects through the Egger regression slope coefficient, which can help identify and address potential small study biases. The simple model represents an unweighted empirical density function for causal estimation. Among these methods, the IVW provides the most precise estimates, assuming that all SNPs are valid instruments. If the IVW method yields a significant result (P < 0.05), even when other methods do not, and there is no evidence of pleiotropy or heterogeneity, the result can be considered positive, as long as the beta values of the other methods point in the same direction.

We conducted an MR-Egger analysis to evaluate whether the genetic instruments exhibited pleiotropic effects on the outcome. Furthermore, we utilized MR-PRESSO to identify any horizontal pleiotropy and minimize its impact by eliminating outliers. In the event that horizontal pleiotropy was detected using both MR-Egger and MR-PRESSO in the chosen SNPs, we re-ran the analysis without these pleiotropic SNPs[25]. To ensure unbiased causal estimations, we conducted leave-one-out analyses by sequentially removing each instrumental SNP and re-running the IVW analysis to identify any influential SNPs. All statistical analyses were conducted in R (version 4.3.0) using the Two-sample-MR and MR-PRESSO R packages for MR analysis.

Selection of Instrumental Variable

In summary, we selected 2093 SNPs of interest for psoriasis, 2100 SNPs for psoriasis vulgaris, and 2100 SNPs for arthropathic psoriasis, respectively, using the gut microbiota as the exposure. According to the results of the MR analysis, 18 SNPs were causally associated with psoriasis, the number of SNPs was 35 for psoriasis vulgaris and 61 for arthropathic psoriasis (Fig. 1–3, Table 1–2). All F-statistics were greater than 10, indicating no weak bias.

Table 1

Instrumental variables for the causal relationship between gut microbiota and psoriasis
Psoriasis and subtypes	Taxa	Gut microbiota	SNP	Effect allele	Other allele	Gut micriobiota			outcome			R²	F
Psoriasis and subtypes	Taxa	Gut microbiota	SNP	Effect allele	Other allele	β	SE	P	β	SE	P	R²	F
Psoriasis	Genus	Odoribacter	rs10093869	A	G	-0.0577795	0.0125389	3.67443E-06	0.0021	0.0227	0.9248	0.001482062	21.23087834
			rs10423795	T	C	-0.0550695	0.0121164	6.5793E-06	0.0318	0.0231	0.1687	0.001441884	20.65448367
			rs28417404	A	G	-0.0726896	0.0161372	3.68036E-06	-0.023	0.0378	0.5434	0.001416297	20.28745061
			rs4793970	A	G	-0.0576329	0.0129154	6.02698E-06	0.0497	0.0234	0.0334303	0.001389962	19.90969031
			rs6856150	A	G	-0.0881922	0.0194146	6.05954E-06	0.0283	0.0342	0.4069	0.001440321	20.63206699
			rs74553962	T	G	0.121449	0.0264106	9.48681E-06	-0.0303	0.0428	0.4798	0.00147595	21.14319581
			rs77779484	G	A	-0.133489	0.0268526	6.56251E-07	0.0556	0.0469	0.235	0.00172445	24.70913572
	Genus	Ruminiclostridium5	rs10827477	A	G	-0.0547387	0.0115163	2.1918E-06	0.0077	0.0235	0.743599	0.001576738	22.58927536
			rs113753996	T	C	0.0820689	0.0174463	3.98896E-06	0.0672	0.0289	0.0201201	0.001544405	22.12533389
			rs1223978	C	T	-0.0484169	0.0108254	8.16188E-06	-0.0229	0.0225	0.3109	0.001396307	20.00070638
			rs1492620	T	C	-0.0830505	0.0180073	3.52574E-06	0.0081	0.0334	0.8078	0.001484649	21.26799667
			rs2482038	C	A	0.0518991	0.0108777	1.70314E-06	0.0055	0.0228	0.8099	0.001588681	22.76065626
			rs2791343	T	C	0.051717	0.0113369	5.53962E-06	0.018	0.0229	0.4302	0.001452541	20.80737517
			rs2833828	G	A	0.0489617	0.0108702	6.81648E-06	0.0196	0.0228	0.3886	0.001416134	20.28510165
			rs4955951	A	G	-0.0713749	0.0165826	9.9552E-06	-0.0078	0.0349	0.8232	0.001293319	18.52358559
			rs6121460	G	A	0.0932955	0.0199206	2.64107E-06	0.0094	0.0413	0.8206	0.001530851	21.93086915
			rs79968837	A	G	-0.0950311	0.0193507	1.14623E-06	0.0365	0.0509	0.4735	0.001683017	24.11445402
			rs8053158	G	A	0.0740543	0.0159151	5.89807E-06	0.0645	0.0346	0.0626801	0.001511147	21.6481655
Arthropathic psoriasis	Class	Verrucomicrobiae	rs111862613	T	C	0.090699	0.0196746	3.73844E-06	0.0484	0.048	0.3136	0.001483304	21.24870441
			rs117107102	A	G	0.204683	0.0431572	2.91823E-06	0.0803	0.0837	0.3375	0.001569844	22.49035484
			rs11729256	T	C	0.0749798	0.0150177	6.73085E-07	0.0965	0.0476	0.0423302	0.001739432	24.92418621
			rs12908520	G	A	0.0618926	0.0130946	2.17165E-06	0.0136	0.0362	0.706801	0.001559183	22.3373815
			rs2602429	T	C	-0.0746844	0.0156194	2.58297E-06	-0.0399	0.0409	0.3295	0.001595583	22.85969225
			rs4242783	A	G	-0.0689292	0.0147693	2.63615E-06	0.0181	0.04	0.650401	0.001520224	21.77839811
			rs4936098	G	A	-0.0648843	0.0135928	1.1222E-06	-0.0302	0.0375	0.4215	0.001590201	22.78246303
			rs61779207	G	A	-0.0758309	0.0167762	6.7228E-06	0.0052	0.0432	0.9044	0.001426157	20.42887785
			rs74542928	T	C	0.112164	0.0236422	1.63222E-06	-0.0367	0.0834	0.659699	0.001570834	22.50455783
			rs9349825	A	G	-0.0704036	0.0147128	2.53688E-06	-0.0844	0.0458	0.0652499	0.001598035	22.89487895
			rs941682	G	A	-0.0631436	0.0143767	9.60993E-06	-0.0891	0.0401	0.0262803	0.001346594	19.2876598
	Family	Rikenellaceae	rs10217435	C	T	-0.0883756	0.0197506	6.50759E-06	0.118	0.0515	0.0221101	0.001397586	20.01904908
			rs10832801	A	C	-0.0534763	0.0122666	7.50412E-06	0.0584	0.04	0.1446	0.001326721	19.00262401
			rs1939881	G	A	-0.105589	0.0206213	5.64378E-07	0.0885	0.0767	0.2485	0.001829329	26.21467957
			rs2447496	A	G	0.0549203	0.0121904	6.08611E-06	0.0418	0.0407	0.3044	0.001416759	20.29407075
			rs2833282	G	A	0.0711137	0.0156966	4.31102E-06	0.0173	0.05	0.728799	0.001432697	20.52270719
			rs35909684	A	C	-0.0850181	0.0191539	7.09823E-06	0.0244	0.0684	0.7218	0.001375284	19.69915691
			rs36021379	A	G	-0.0656005	0.0144903	7.19515E-06	0.0133	0.049	0.7863	0.001430604	20.49268318
			rs4264350	T	C	-0.0526393	0.0108555	1.34831E-06	0.0346	0.0359	0.3349	0.001640926	23.51038971
			rs59663348	G	A	0.0570915	0.0125048	6.12238E-06	0.0339	0.0415	0.4139	0.001454919	20.84148633
			rs62532512	A	C	0.0504257	0.0107399	2.76427E-06	-0.0025	0.0362	0.9454	0.001538567	22.04157768
			rs6744030	C	T	0.0696747	0.0157103	9.31515E-06	0.0187	0.0439	0.6708	0.001372987	19.66620396
			rs6837275	A	G	0.0570355	0.011887	0.000001447	0.0286	0.0393	0.4669	0.00160668	23.01893686
			rs74474130	T	G	0.137747	0.0295688	3.61377E-06	-0.092	0.0979	0.3475	0.001514678	21.69882311
			rs77885767	C	T	-0.156209	0.0336482	2.84695E-06	0.1784	0.0849	0.0356796	0.001504238	21.5490293
			rs9389714	C	T	-0.0636841	0.0143416	8.79063E-06	0.0396	0.0629	0.529	0.001376418	19.71542307
			rs9578457	G	A	-0.141478	0.0315848	3.99448E-06	0.0323	0.0833	0.698101	0.001400537	20.06138173
			rs9603208	G	T	0.0821173	0.0159596	1.91801E-07	-0.0535	0.0594	0.3673	0.001847158	26.47064959
	Family	Verrucomicrobiaceae	rs111862613	T	C	0.0907065	0.0196746	3.7313E-06	0.0484	0.048	0.3136	0.001483549	21.25221872
			rs117107102	A	G	0.204683	0.0431572	2.91823E-06	0.0803	0.0837	0.3375	0.001569844	22.49035484
			rs11729256	T	C	0.0749798	0.0150177	6.73085E-07	0.0965	0.0476	0.0423302	0.001739432	24.92418621
			rs12908520	G	A	0.0619104	0.0130946	2.15139E-06	0.0136	0.0362	0.706801	0.001560079	22.35023159
			rs2602429	T	C	-0.0745516	0.0156195	2.69942E-06	-0.0399	0.0409	0.3295	0.001589902	22.77817698
			rs4242783	A	G	-0.0687992	0.0147694	2.75442E-06	0.0181	0.04	0.650401	0.001514484	21.69603396
			rs4936098	G	A	-0.0648691	0.0135928	1.1293E-06	-0.0302	0.0375	0.4215	0.001589457	22.7717901
			rs61779207	G	A	-0.0758811	0.0167762	6.63025E-06	0.0052	0.0432	0.9044	0.001428043	20.45593461
			rs74542928	T	C	0.112124	0.0236422	1.64611E-06	-0.0367	0.0834	0.659699	0.001569715	22.48850952
			rs9349825	A	G	-0.0704354	0.0147128	2.51287E-06	-0.0844	0.0458	0.0652499	0.001599477	22.915566
			rs941682	G	A	-0.0631526	0.0143767	9.5812E-06	-0.0891	0.0401	0.0262803	0.001346978	19.29315842
	Genus	Akkermansia	rs111862613	T	C	0.0911199	0.0196748	3.39234E-06	0.0484	0.048	0.3136	0.001497052	21.44594051
			rs117107102	A	G	0.204406	0.0431629	3.01141E-06	0.0803	0.0837	0.3375	0.001565192	22.42359949
			rs11729256	T	C	0.0750473	0.0150184	6.58385E-07	0.0965	0.0476	0.0423302	0.001742397	24.96675449
			rs12908520	G	A	0.061772	0.0130954	2.2648E-06	0.0136	0.0362	0.706801	0.001552933	22.24769742
			rs2602429	T	C	-0.0745352	0.0156201	2.71569E-06	-0.0399	0.0409	0.3295	0.001589082	22.7664074
			rs4242783	A	G	-0.0685454	0.0147701	2.99799E-06	0.0181	0.04	0.650401	0.001503205	21.53421474
			rs4936098	G	A	-0.0649225	0.0135934	1.1036E-06	-0.0302	0.0375	0.4215	0.001591931	22.80728332
			rs61779207	G	A	-0.0760539	0.0167769	6.32121E-06	0.0052	0.0432	0.9044	0.001434425	20.54749236
			rs74542928	T	C	0.112623	0.0236434	1.4802E-06	-0.0367	0.0834	0.659699	0.001583536	22.68681893
			rs9349825	A	G	-0.0703407	0.0147133	2.59884E-06	-0.0844	0.0458	0.0652499	0.001595077	22.85243446
			rs941682	G	A	-0.0632957	0.0143777	9.17128E-06	-0.0891	0.0401	0.0262803	0.001352893	19.37799592
	Order	Verrucomicrobiales	rs111862613	T	C	0.090699	0.0196746	3.73844E-06	0.0484	0.048	0.3136	0.001483304	21.24870441
			rs117107102	A	G	0.204683	0.0431572	2.91823E-06	0.0803	0.0837	0.3375	0.001569844	22.49035484
			rs11729256	T	C	0.0749798	0.0150177	6.73085E-07	0.0965	0.0476	0.0423302	0.001739432	24.92418621
			rs12908520	G	A	0.0618926	0.0130946	2.17165E-06	0.0136	0.0362	0.706801	0.001559183	22.3373815
			rs2602429	T	C	-0.0746844	0.0156194	2.58297E-06	-0.0399	0.0409	0.3295	0.001595583	22.85969225
			rs4242783	A	G	-0.0689292	0.0147693	2.63615E-06	0.0181	0.04	0.650401	0.001520224	21.77839811
			rs4936098	G	A	-0.0648843	0.0135928	1.1222E-06	-0.0302	0.0375	0.4215	0.001590201	22.78246303
			rs61779207	G	A	-0.0758309	0.0167762	6.7228E-06	0.0052	0.0432	0.9044	0.001426157	20.42887785
			rs74542928	T	C	0.112164	0.0236422	1.63222E-06	-0.0367	0.0834	0.659699	0.001570834	22.50455783
			rs9349825	A	G	-0.0704036	0.0147128	2.53688E-06	-0.0844	0.0458	0.0652499	0.001598035	22.89487895
			rs941682	G	A	-0.0631436	0.0143767	9.60993E-06	-0.0891	0.0401	0.0262803	0.001346594	19.2876598
Psoriasis vulgaris	Family	Actinomycetaceae	rs2889192	T	G	-0.0887537	0.0195009	3.64418E-06	0.0056	0.0392	0.8863	0.001445829	20.71108755
			rs34583783	G	T	0.123756	0.026427	5.47974E-06	-0.0293	0.0583	0.6152	0.001530571	21.92684158
			rs35011108	A	G	0.241826	0.0503796	1.82671E-06	0.1365	0.0558	0.0144301	0.001607976	23.03752584
			rs4073240	G	A	0.0747546	0.0164684	6.05327E-06	0.0487	0.0287	0.0893203	0.001438235	20.60213889
			rs58484246	T	C	0.0761407	0.0169007	6.12421E-06	0.0383	0.0291	0.1893	0.001416741	20.29381166
	Genus	Eubacterium fissicatena group	rs10147907	T	G	0.172263	0.039601	8.27237E-06	0.0585	0.0527	0.2669	0.001320929	18.91955807
			rs11818408	G	A	0.10585	0.0237114	8.20012E-06	0.0494	0.0286	0.0834008	0.001391056	19.92537995
			rs11876297	T	C	0.131469	0.0281712	2.66557E-06	-0.0046	0.0316	0.883	0.001520047	21.77585952
			rs151257695	A	G	0.20951	0.0454847	3.09678E-06	0.0792	0.0543	0.1448	0.00148087	21.21378315
			rs1768152	C	T	-0.139489	0.0316186	8.70062E-06	-0.029	0.0456	0.5254	0.001358582	19.45960092
			rs2733072	G	A	0.109644	0.0228306	1.49091E-06	0.0393	0.028	0.1603	0.001609597	23.06080017
			rs3771393	T	C	-0.130842	0.0266671	7.37904E-07	-0.0842	0.0351	0.0164399	0.001679942	24.07033029
			rs6934739	A	G	0.111463	0.0252788	9.75326E-06	0.059	0.0295	0.0455795	0.00135719	19.43962257
			rs7104872	G	A	0.138612	0.0291906	2.73149E-06	0.0602	0.0445	0.1759	0.001573669	22.54524177
	Genus	Lactococcus	rs10417872	G	T	-0.118306	0.024522	1.28677E-06	-0.0422	0.0308	0.1706	0.001624342	23.27239322
			rs123059	C	T	0.13671	0.0274694	1.26561E-06	0.0291	0.0338	0.3897	0.001728354	24.76518066
			rs12621813	G	A	0.108423	0.0239978	6.6083E-06	-0.008	0.0315	0.7991	0.001424828	20.40982407
			rs17168302	G	A	0.191857	0.0424761	6.28608E-06	0.0451	0.0454	0.3199	0.001424062	20.39883242
			rs2293361	C	T	-0.199221	0.0430969	1.39592E-06	-0.0417	0.0616	0.498901	0.00149146	21.36571584
			rs4766997	C	T	0.114599	0.023839	2.06144E-06	0.0536	0.0282	0.0571597	0.001612748	23.10600534
			rs55910161	C	T	0.146426	0.0307367	2.36211E-06	0.0199	0.0445	0.6548	0.001583855	22.6913953
			rs6674304	C	T	0.200758	0.0442121	6.1776E-06	0.1214	0.0736	0.0988189	0.001439195	20.61591972
			rs7992246	C	T	-0.104232	0.0230786	4.44723E-06	-0.0795	0.0286	0.00535698	0.001423791	20.39494333
	Genus	Odoribacter	rs10093869	A	G	-0.0577795	0.0125389	3.67443E-06	-0.0114	0.0283	0.687	0.001482062	21.23087834
			rs10423795	T	C	-0.0550695	0.0121164	6.5793E-06	0.0577	0.0287	0.0443598	0.001441884	20.65448367
			rs28417404	A	G	-0.0726896	0.0161372	3.68036E-06	-0.021	0.0471	0.6552	0.001416297	20.28745061
			rs4793970	A	G	-0.0576329	0.0129154	6.02698E-06	0.0613	0.0291	0.0353297	0.001389962	19.90969031
			rs6856150	A	G	-0.0881922	0.0194146	6.05954E-06	0.0157	0.0426	0.7123	0.001440321	20.63206699
			rs74553962	T	G	0.121449	0.0264106	9.48681E-06	-0.0505	0.0533	0.3438	0.00147595	21.14319581
			rs77779484	G	A	-0.133489	0.0268526	6.56251E-07	0.1065	0.0581	0.0666807	0.00172445	24.70913572
	Order	Actinomycetales	rs2889192	T	G	-0.0884052	0.0194997	3.96725E-06	0.0056	0.0392	0.8863	0.00143469	20.55128789
			rs34583783	G	T	0.123688	0.0264254	5.53886E-06	-0.0293	0.0583	0.6152	0.001529076	21.9054044
			rs35011108	A	G	0.241546	0.0503803	1.87659E-06	0.1365	0.0558	0.0144301	0.001604216	22.9835697
			rs4073240	G	A	0.074973	0.0164672	5.67898E-06	0.0487	0.0287	0.0893203	0.001446849	20.72571581
			rs58484246	T	C	0.075828	0.0168997	6.67483E-06	0.0383	0.0291	0.1893	0.00140531	20.12984789
SNP, single nucleotide polymorphism; SE, standard error.

Table 2

Mendelian randomization analysis results between Gut micriobiota and Psoriasis
Type of Psoriasis	Taxa	Gut microbiota	nSNP	Method of MR	SE	P-value	OR(95%CI)
Psoriasis	Genus	Odoribacter	7	MR Egger	0.468681544	0.727005492	0.84 (0.34–2.11)
				Weighted median	0.193021186	0.097235987	0.73 (0.50–1.06)
				Inverse variance weighted	0.149522127	0.024003258	0.71 (0.53–0.96)
				Simple mode	0.275616872	0.256385786	0.71 (0.41–1.21)
				Weighted mode	0.264522512	0.257840358	0.72 (0.43–1.21)
	Genus	Ruminiclostridium5	11	MR Egger	0.555343374	0.738329276	1.21 (0.41–3.60)
				Weighted median	0.185508687	0.557085239	1.12 (0.78–1.60)
				Inverse variance weighted	0.132980803	0.042978904	1.31 (1.01–1.70)
				Simple mode	0.313739279	0.701241893	1.13 (0.61–2.09)
				Weighted mode	0.304060473	0.762098653	1.10 (0.61–1.99)
Arthropathic psoriasis	Class	Verrucomicrobiae	11	MR Egger	0.574398065	0.793562314	1.17 (0.38–3.60)
				Weighted median	0.244563137	0.075803513	1.54 (0.96–2.49)
				Inverse variance weighted	0.171535894	0.006025337	1.60 (1.14–2.24)
				Simple mode	0.365432366	0.354447401	1.43 (0.70–2.92)
				Weighted mode	0.329487683	0.279373112	1.46 (0.76–2.78)
	Family	Rikenellaceae	17	MR Egger	0.52048819	0.026865417	0.28 (0.10–0.77)
				Weighted median	0.231094814	0.244132512	0.76 (0.49–1.20)
				Inverse variance weighted	0.167595229	0.032150723	0.70 (0.50–0.97)
				Simple mode	0.479631396	0.247494856	0.56 (0.22–1.44)
				Weighted mode	0.478217665	0.285657465	0.59 (0.23–1.51)
	Family	Verrucomicrobiaceae	11	MR Egger	0.574361801	0.79168493	1.17 (0.38–3.60)
				Weighted median	0.241690769	0.072359404	1.54 (0.96–2.48)
				Inverse variance weighted	0.171577639	0.006012542	1.60 (1.14–2.24)
				Simple mode	0.375891052	0.367623381	1.43 (0.68–2.98)
				Weighted mode	0.320986642	0.267768743	1.46 (0.78–2.73)
	Genus	Akkermansia	11	MR Egger	0.574045514	0.789131597	1.17 (0.38–3.61)
				Weighted median	0.232385661	0.061366384	1.54 (0.98–2.44)
				Inverse variance weighted	0.171515479	0.005994404	1.60 (1.14–2.24)
				Simple mode	0.36527646	0.355151184	1.42 (0.70–2.92)
				Weighted mode	0.325298686	0.274469597	1.46 (0.77–2.76)
	Order	Verrucomicrobiales	11	MR Egger	0.574398065	0.793562314	1.17 (0.38–3.60)
				Weighted median	0.233144023	0.062527403	1.54 (0.98–2.44)
				Inverse variance weighted	0.171535894	0.006025337	1.60 (1.14–2.24)
				Simple mode	0.378423083	0.370508536	1.43 (0.68–2.99)
				Weighted mode	0.335185439	0.287151332	1.46 (0.76–2.81)
Psoriasis vulgaris	Family	Actinomycetaceae	5	MR Egger	0.398479858	0.30483904	1.64 (0.75–3.57)
				Weighted median	0.213300825	0.012023107	1.71 (1.12–2.60)
				Inverse variance weighted	0.154221299	0.00845618	1.50 (1.11–2.03)
				Simple mode	0.285870978	0.115997099	1.77 (1.01–3.10)
				Weighted mode	0.241960557	0.078526551	1.77 (1.10–2.84)
	Genus	Eubacterium fissicatena group	9	MR Egger	0.47513716	0.702846081	1.21 (0.48–3.07)
				Weighted median	0.124570463	0.00272943	1.45 (1.14–1.85)
				Inverse variance weighted	0.091614312	7.57289E-05	1.44 (1.20–1.72)
				Simple mode	0.198510531	0.079438477	1.49 (1.01–2.20)
				Weighted mode	0.192937283	0.075243252	1.48 (1.02–2.17)
	Genus	Lactococcus	9	MR Egger	0.410672369	0.827821011	1.10 (0.49–2.45)
				Weighted median	0.125019737	0.063475786	1.26 (0.99–1.61)
				Inverse variance weighted	0.091538079	0.000490116	1.38 (1.15–1.65)
				Simple mode	0.178812978	0.24819944	1.25 (0.88–1.77)
				Weighted mode	0.16517465	0.204037115	1.26 (0.91–1.74)
	Genus	Odoribacter	7	MR Egger	0.678169598	0.551305788	0.65 (0.17–2.45)
				Weighted median	0.255970156	0.098444885	0.66 (0.40–1.08)
				Inverse variance weighted	0.197801429	0.016969706	0.62 (0.42–0.92)
				Simple mode	0.421330653	0.094016223	0.43 (0.19–0.99)
				Weighted mode	0.376008929	0.144454052	0.53 (0.25–1.11)
	Order	Actinomycetales	5	MR Egger	0.398482825	0.303376366	1.64 (0.75–3.58)
				Weighted median	0.20460834	0.008641524	1.71 (1.15–2.56)
				Inverse variance weighted	0.154414258	0.008419004	1.50 (1.11–2.03)
				Simple mode	0.282086246	0.112244761	1.77 (1.02–3.08)
				Weighted mode	0.232594511	0.070663371	1.77 (1.12–2.79)
SNP, single nucleotide polymorphism; MR, Mendelian randomization; SE, standard error; OR, odds ratio; CI, confidence interval.

Causal Effects of Gut Microbiota on Psoriasis

Psoriasis

The estimates of the IVWs test indicated that the genetically predicated relative abundance of two genera, namely, Odoribacter genus (OR: 0.71, 95% CI: 0.53–0.96, p = 0.024) and Ruminiclostridium5(OR: 1.31, 95% CI: 1.01–1.70, p = 0.043) was associated with an increased or reduced risk of psoriasis (Fig. 4). A higher genetically predicted abundance of Odoribacter genus was associated with a reduced risk of psoriasis. While a higher genetically predicted abundance of Ruminiclostridium5 was associated with an increased risk of psoriasis.

Arthropathic Psoriasis

The genetically predicated relative abundance of Verrucomicrobiae class (OR: 1.60, 95% CI: 1.14–2.24, p = 0.006), Rikenellaceae family (OR: 0.70, 95% CI: 0.50–0.97, p = 0.032), Verrucomicrobiaceae family (OR: 1.60, 95% CI: 1.14–2.24, p = 0.006), Akkermansia genus (OR: 1.60, 95% CI: 1.14–2.24, p = 0.006), and Verrucomicrobiales order (OR: 1.60, 95% CI: 1.14–2.24, p = 0.006) were associated with the risk of arthropathic psoriasis (Fig. 5). The genetically predicted relative abundance of Verrucomicrobiae, Verrucomicrobiaceae, Akkermansia, Verrucomicrobiales were positively associated with arthropathic psoriasis. A higher genetically predicted abundance of Rikenellaceae served as protective factors for arthropathic psoriasis.

Psoriasis Vulgaris

The IVW estimate suggests that the genetically predicated relative abundance of five genera, namely, Actinomycetaceae family (OR: 1.50, 95% CI: 1.11–2.03, p = 0.00845618), Eubacterium fissicatena group genus (OR: 1.44, 95% CI: 1.20–1.72, p < 0.005), Lactococcus genus (OR: 1.38, 95% CI: 1.15–1.65, p < 0.005), Odoribacter genus (OR: 0.62, 95% CI: 0.42–0.92, p = 0.017), and Actinomycetales order (OR: 1.50, 95% CI: 1.11–2.03, p = 0.008) were associated with the risk of psoriasis vulgaris (Fig. 6). Specifically, a higher genetically predicted Atinomycetaceae, Eubacterium fissicatena group, Lactococcus, and Actinomycetales were associated with a higher risk of psoriasis vulgaris. In contrast, higher genetically predicted Odoribacter was a lower risk of psoriasis vulgaris.

Sensitivity Analyses

No significant effects were detected among the chosen SNPs based on the egger intercept and global tests of MR-Egger and MR-PRESSO (P > 0.05) (Fig. 7–9, Table 3–5). Furthermore, no significant heterogeneity and pleiotropy was observed between the selected IVs and psoriasis, psoriasis vulgaris and arthropathic psoriasis. Additionally, no causal relations were identified between the bacterial taxa and psoriasis, psoriasis vulgaris and arthropathic psoriasis driven by any single SNP.

Table 3

Directional pleiotropy results from Egger_intercept analysis
Type of Psoriasis	taxa	Gut microbiota	Egger_intercept	SE	P value
Psoriasis	Genus	Odoribacter	-0.012813054	0.034622851	0.726485058
Psoriasis	Genus	Ruminiclostridium5	0.005044615	0.034968184	0.888471541
Arthropathic psoriasis	Class	Verrucomicrobiae	0.026064829	0.045179275	0.5781363
	Family	Rikenellaceae	0.06906446	0.037078846	0.082215764
	Family	Verrucomicrobiaceae	0.02596015	0.045165432	0.579522792
	Genus	Akkermansia	0.025814788	0.04515692	0.58154065
	Order	Verrucomicrobiales	0.026064829	0.045179275	0.5781363
Psoriasis vulgaris	Family	Actinomycetaceae	-0.01024396	0.042702769	0.825872646
	Genus	Eubacterium fissicatena group	0.022858965	0.061353903	0.720488948
	Genus	Lactococcus	0.030640464	0.054183997	0.589398597
	Genus	Odoribacter	-0.003063587	0.05011813	0.953625974
	Order	Actinomycetales	-0.010358922	0.042649724	0.823754915
SE, standard error.

Table 4

Heterogeneity results from Cochran's Q test
Outcome	Taxa	Gut microbiota	MR-Egger		IVW
Outcome	Taxa	Gut microbiota	Q	P value	Q	P value
Psoriasis	Genus	Odoribacter	5	0.528742191	6	0.63858653
Psoriasis	Genus	Ruminiclostridium5	9	0.534354513	10	0.627005864
Arthropathic psoriasis	Class	Verrucomicrobiae	9	0.469345995	10	0.532896463
	Family	Rikenellaceae	15	0.752817227	16	0.564019842
	Family	Verrucomicrobiaceae	9	0.469476503	10	0.533260176
	Genus	Akkermansia	9	0.469656138	10	0.533777284
	Order	Verrucomicrobiales	9	0.469345995	10	0.532896463
Psoriasis vulgaris	Family	Actinomycetaceae	3	0.276939636	4	0.414951139
	Genus	Eubacterium fissicatena group	7	0.718002512	8	0.793082605
	Genus	Lactococcus	7	0.549635788	8	0.620882177
	Genus	Odoribacter	5	0.237372603	6	0.340998561
	Order	Actinomycetales	3	0.278028201	4	0.41603622
MR, Mendelian randomization; IVW, inverse variance weighted.

Table 5

The pleiotropy results from MR-PRESSO
Outcome	Taxa	Gut microbiota	Causal Estimate	SD	T-stat	P-value	RSS_obs	Global test P-value
Psoriasis	Genus	Odoribacter	-0.337483	0.126313	-2.671799	0.03693782	5.51931	0.75
Psoriasis	Genus	Ruminiclostridium5	0.2691418	0.1190809	2.260159	0.04735568	9.958527	0.68
Arthropathic psoriasis	Class	Verrucomicrobiae	0.4711061	0.1626577	2.896303	0.01593418	10.51682	0.5
	Family	Rikenellaceae	-0.3590781	0.1593603	-2.253247	0.03862774	16.61837	0.51
	Family	Verrucomicrobiaceae	0.4713403	0.1626626	2.897656	0.0158973	10.5124	0.63
	Genus	Akkermansia	0.4713395	0.1625544	2.899579	0.01584501	10.50527	0.51
	Order	Verrucomicrobiales	0.4711061	0.1626577	2.896303	0.01593418	10.51682	0.55
Psoriasis vulgaris	Family	Actinomycetaceae	0.4061096	0.1529522	2.65514	0.05667691	6.010643	0.46
	Genus	Eubacterium fissicatena group	0.3625663	0.06993167	5.18458	0.000838045	6.187024	0.78
	Genus	Lactococcus	0.319111	0.08081443	3.948688	0.004243823	7.785787	0.7
	Genus	Odoribacter	-0.4722239	0.1978014	-2.387363	0.05422082	9.001224	0.48
	Order	Actinomycetales	0.4068487	0.1529902	2.659313	0.05643076	5.997236	0.51
MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; SD, standard deviation; RSSobs, observed residual sum of squares.

We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between gut microbes (GMs) and psoriasis. To our knowledge, this is the first large-scale MR analysis utilizing the latest and most extensive GWAS gene-level data to investigate the association between GMs and psoriasis, which could provide valuable insights for preventing, treating, and managing psoriasis with specific GMs.

The gut microbiota plays a role in host homeostasis, stress response, and disease pathogenesis[26] [27]. It is currently believed that dysbiosis of the gut microbiota in the gut-microbiota-skin axis leads to an increase in harmful bacteria, disruption of the intestinal mucosal barrier function, and the development of gut inflammation and leakiness, as well as bacterial translocation[28, 29]. This leads to excessive activation of Th1 and Th17 cells and a decrease in Treg cell numbers, with Th17 cells being the main effector cells[30, 31]. Bacteria and their metabolites migrate outside the gut and disrupt skin homeostasis, creating a microenvironment conducive to the development of psoriasis.

Previous studies have identified specific bacterial groups that are associated with psoriasis, including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia, and Tenerictes Bacteroides[14, 16]. In patients with psoriatic arthritis, there was a decrease in the abundance of certain bacteria such as Akkermansia, Ruminococcus, Pseudobotyrivibrio, Paraacteroides, Alistipes, and Coprococcus[14, 16, 32]. In patients with psoriasis vulgaris showed changes in the proportions of Firmicutes and Bacteroides, and a decrease in the abundance of Actinomyces, Vitallis, and Coprococcus[11, 14, 33]. However, the conclusions of various studies are not consistently the same. Therefore, we conducted MR analysis to study the causal relationship between Gut microbiota and psoriasis, arthropathic psoriasis and psoriasis vulgaris. This MR study found that Odoribactor can serve as a protective factor for psoriasis and psoriasis vulgaris, Rikenellaceae can serve as a protective factor for arthropathic psoriasis. This study also suggested that increased abundance of Ruminiclostridium5 was causally related to a higher risk of psoriasis, increased abundance of Verrucomicrobiaceae and Akkermansia was causally related to a higher risk of arthropathic psoriasis, increased abundance of Actinomycetales, Eubacterium fissicatena group and Lactococcus was causally related to a higher risk of psoriasis vulgaris, respectively.

The loss of beneficial bacteria and diversity of gut microbiota may affect psoriasis development through various mechanisms such as the gut-skin axis[10, 11, 16, 34]. In recent years, rebuilding gut microbiota balance to prevent and treat diseases has been a hot topic of research. Supplementation with probiotics to correct gut dysbiosis and fecal microbiota transplantation to rebuild gut microbiota balance has been found to be effective in relieving psoriasis symptoms and reducing recurrence in many clinical studies. Researchers have also found that probiotics have an impact on psoriatic arthritis activity and intestinal permeability, indicating that taking probiotics can improve gut permeability and reduce disease activity. Gut dysbiosis exists in psoriasis patients, and microbial-based studies can provide further insight into the pathogenesis of psoriasis, offering new strategies for its prevention and treatment.

One of the primary benefits of our research is the implementation of MR analysis to investigate the correlation between GM and psoriasis in humans. This approach allows us to obtain reliable causal relationships by minimizing the impact of external factors and avoiding confounding or reverse causality. Furthermore, we leverage data from the largest microbiome consortium GWAS meta-analysis, which provides us with gut microbiome data with high statistical strength. To ensure our MR analysis instrument variables are free of pleiotropy, we utilize both MR-PRESSO and MR-Egger regression intercept tests. Additionally, our research utilizes the cML MA method to eliminate both correlated and uncorrelated multiplicative biases, ultimately improving the accuracy of our results.

Despite the rigorous research process, there are some limitations to consider. The study is hindered by database constraints as it was unable to thoroughly investigate the correlation between gut microbiota and pustular-type psoriasis and erythrodermic psoriasis. Moreover, although the sample size of gut microbiota in the GWAS database was adequate, the provided information regarding bacterial strains is insufficient. The absence of demographic information in the aggregated statistical data used in the analysis precludes subgroup analysis, leading to the potential for biased results. The study has a limited focus on participants of European descent, and the findings may not be applicable to other ethnic groups.

In brief, this MR study presents the initial comprehensive investigation of the causative impacts of gut microbiota on psoriasis and its subtypes. Our discoveries offer novel perspectives regarding the prevention, advancement, and therapy of psoriasis by concentrating on specific bacterial groups. Additional research is required to specify the exact mechanism relating the association between gut microbiota and psoriasis along with its classifications.

WHO, The World Health Organization;

MR, Mendelian randomization;

IV, instrumental variable;

GWAS, genome-wide association study;

IVW, inverse variance weighting;

SNP, single nucleotide polymorphism;

MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier.

Ethics approval and consent to participate

This research has been conducted using published studies and consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent. In addition, no individual-level data was used in this study. Therefore, no new ethical review board approval was required.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study are available in the MiBioGen repository( https://mibiogen.gcc.rug.nl/ ) and the FinnGen repository (https://r7.finngen.fi/ ).

Competing Interest

The authors have no relevant financial or non-financial interests to disclose.

Funding

This work was supported by Development of standardized clinical trials and establishment of follow-up evaluation system for in situ regeneration of intelligent biomaterials (2019YFA0110603) and key research project "Research on key technologies and equipment for early treatment of naval battle injuries in 2019” (2019YSL010).

Authors’ Contributions

JZ and YX designed the study; JZ, YX and YS contributed to data analysis. JZ and YX wrote the initial draft of the manuscript; JZ, YX, YS, QC, LL, JJ, QL and SZ reviewed and edited the manuscript. All authors read and approved the manuscript.

Jin Zhang, Yang Xiang and Yingjie Shen contributed equally to this work.

Acknowledgements

Not applicable.

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No competing interests reported.

Association between gut microbiota and psoriasis: a bidirectional two-sample Mendelian randomization study

Status:

Version 1

Abstract

Background:

Methods:

Results:

Conclusion:

Figures

Introduction

Methods

Data source

Assumption of Mendelian randomization

Selection of Instrumental Variables

Statistical analysis of Mendelian randomization

Results

Selection of Instrumental Variable

Causal Effects of Gut Microbiota on Psoriasis

Psoriasis

Arthropathic Psoriasis

Psoriasis Vulgaris

Sensitivity Analyses

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1