Psoriasis vulgaris is a systemic and chronic disease that primarily affects skin and joints. It causes serious harm to physical and mental health of patients, and brings heavy economic burden to the society as well. The definitive mechanism of psoriasis vulgaris is still unclear, but the researchers gradually noticed a significant imbalance in the ratio of Th17 to Treg in psoriasis patients [40, 41]. Th17 can produce abundant proinflammatory cytokines (IL-17 and IL-22) and induce psoriasis-like skin inflammation [40]. On the contrary, Treg can inhibit the function of Th17 through direct contact and release of inhibitory cytokines like IL-10 and TGF-β [41]. The over-activated Th17 and repressed Treg cells are the two dominant factors of psoriasis pathogenesis [42]. There is an interaction of reciprocal inhibition between Th17 and Treg, and maintaining the balance of Th17/Treg helps to effectively reduce inflammatory reaction of psoriasis and regulate immune homeostasis [43]. Recently, the relationship between psoriasis and gut microbiome has attracted attention. The gut microbiome can adjust the balance between effective T cells and Tregs and maintain the homeostasis of immunologic system [10]. It has been shown that the severity of psoriasis can be significantly improved by correcting the imbalance of gut microbiome, which may be a potential way of psoriasis treatment [44-46]. Therefore, exploring the relationship between gut microbiome and psoriasis vulgaris will help to reveal the pathogenesis of psoriasis and find some innovative therapies. In this study, we performed an MR analysis to identify the causal association between the gut microbiome and psoriasis vulgaris from a genetic perspective and we identified 7 bacterial taxa associated with psoriasis vulgaris.
In accordance with previous observational studies [47, 48], our MR study found that genus Lachnospira and genus Gordonibacter were associated with a lower risk of psoriasis vulgaris. We speculate that their protective effect on psoriasis vulgaris is associated with their metabolites, bile acids (BAs). The gut microbiota can further metabolize bile acids synthesized in the liver to form secondary BAs such as lithocholic acid (LCA). Varieties of BAs can bind to the Farnesoid X receptor and the G-protein-coupled BA receptor, thereby affecting the metabolism of the host [49]. Genus gordonibacter can convert LCA into 3-oxoLCA using the 3α-hydroxysteroid dehydrogenase and both of genus gordonibacter and genus Lachnospira can convert 3-oxoLCA into isoLCA using the 3β-hydroxysteroid dehydrogenase [50]. Retinoic acid-related orphan receptors-γt (RORγt) is a critical transcription factor of Th17, which can dominate the translation of Th17-specific genes, like IL-17A and IL-17F [51]. Both of 3-oxoLCA and isoLCA can surpress the differentiation of Th17 by binding to RORγt and blocking the transcription of RORγt [47]. Therefore, genus Lachnospira and genus Gordonibacter may inhibit the Th17-mediated inflammation in psoriasis through their metabolism of secondary bile acids.
Genus Alloprevotella, genus Lachnospira and genus Odoribacter, all butyrate secretors, were identified as protective factors of psoriasis vulgaris by our MR analysis [47, 52, 53]. The pattern of energy metabolism is closely associate with the differentiation of Treg and Th17 cells [51]. It has been shown that butyrate can influence Th17 and Treg differentiation by regulating T-cell energy metabolism [54]. Treg cells are primarily powered by oxidative phosphorylation, while Th17 cells rely on glycolysis to sustain their function [55]. Butyrate can increase the basal and maximal oxygen consumption rates and shift the energy metabolism towards oxidative phosphorylation in naive CD4+ T cells, thereby promoting Treg differentiation [54]. Butyrate, metabolite of genus Alloprevotella, genus Lachnospira and genus Odoribacter, can also affect T-cell energy metabolism by regulating hypoxia-inducible factor 1α (HIF-1α). HIF-1α enhances glycolysis metabolism by stimulating the transcription of pyruvate dehydrogenase kinase 1(PDK1) [56, 57]. Some research have shown that butyrate can downregulate the transcription of HIF-1α in naive CD4+ T cells, thereby inhibiting Th17 differentiation and Th17-skewed inflammation in psoriasis [54]. In addition, the effect of butyrate on the energy metabolic pattern of Treg and Th17 cells may also be related to peroxisome proliferator-activated receptors (PPARγ). PPARγ is widely distributed in the body, especially in adipose tissue and immune cells [58]. PPARγ is a ligand-activated transcription factor of mitochondrial gene, which is essential for the metabolism of glucose [59]. The recent study showed that butyrate can activate PPARγ in naive CD4+ T cells and the influence of butyrate on Th17 and Treg can be attenuated by GW9662, which is a selective PPARγ antagonist [54]. Therefore, butyrate produced by gut microbiome may promote the differentiation of anti-inflammatory Treg cell through activating PPARγ and switching the energy metabolism from glycolysis towards oxidative phosphorylation of naive CD4+ T cells.
Except for its effect on energy metabolism, butyrate can also promote the proliferation of Treg cell by inhibiting the histone deacetylase (HDAC). Histone acetylation can activate the transcription of genes, while HDAC can collapse the DNA around histones and inhibit gene transcription. Forkhead box P3 (Foxp3) is an essential transcription factor of Treg cells, maintaining the differentiation and anti-inflammatory function of Treg [51]. As an inhibitor of HDAC, butyrate can induce histone H3 acetylation in the promoter of Foxp3 and activate the transcription of Foxp3 in naive CD4+T cells, inducing their differentiation into Treg cells [41].
Our MR analysis found that genus Terrisporobacter may be the protective factor of psoriasis vulgaris. The protective effect of genus Terrisporobacter on psoriasis vulgaris may be associated with its metabolites, acetate [60]. Acetate is the most abundant SCFAs in the intestinal tract which can regulate the immune system [61]. GPR43 is the main receptor of short-chain fatty acids, which is mainly expressed in immune cells and intestinal endocrine cells [62, 63]. Both of acetate and butyrate can stimulate the proliferation of tTreg by binding to GPR43 on the cell surface [64]. In addition, it has been shown that the level of acetate in colon was negatively associated with the level of proinflammatory cytokines like IL-17 and IL-23 in psoriatic lesions [45]. Both of them are important inflammatory cytokines of the IL-23/Th17 axis and they can both contribute to the aggravation of psoriasis. Therefore, genus Terrisporobacter may suppress the inflammatory response of psoriasis vulgaris by producing acetate.
Genus Eubacterium Fissicatena was judged as a risk factor for psoriasis vulgaris by the currant MR analysis. The casual association between this bacterial taxon and psoriasis vulgaris was also cross-validated by the IVW and WM models. However, the detail of Genus Eubacterium Fissicatena is little known. At present, there is no study on the association between this taxon and psoriasis vulgaris, and this specific bacterial taxon of psoriasis vulgaris was reported for the first time. Consequently, our MR research may provide an innovate perspective for the study of psoriasis vulgaris.
Strengths and Limitations
The present MR research has the following strengths. First of all, this research is the first bi-directional MR research to uncover the causality between intestinal microbiome and psoriasis vulgaris, which can avoid the disturbance of confounders or inversive causality. Secondly, rigorous criteria were applied for selecting IVs, and only when two or more MR models identify the causality can it be considered plausible. Moreover, we provide evidence for the study of the gut-skin axis from the genetic perspective.
This study has some weaknesses. For instance, the number of IVs included in the GWAS data of gut microbiome is limited, and there is a lack of available statistics at the species level. Besides, we are unable to judge whether there are any repetitive participants in the GWAS statistics of gut microbiome and psoriasis vulgaris involved in the present research. Lastly, there is a lack of demographic data in the original study, so we can't conduct subgroup analysis on factors like age. In subsequent research, we can expand the sample capacity and investigate the causality between gut microbiome and psoriasis vulgaris at the level of species.