Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism

Abstract

The intestinal microbiota has been associated with host immunity as well as psoriasis; however, the mechanism of intestinal microbiota regulating psoriasis needs to be demonstrated systematically. Here, we sought to examine its role and mechanism of action in the pathogenesis of psoriasis. We found that the severity of psoriasis-like skin phenotype was accompanied by changes in the composition of the intestinal microbiota. We performed co-housing and fecal microbial transplantation (FMT) experiments using the K14-VEGF transgenic mouse model of psoriasis and demonstrated that the transfer of intestinal microbiota from mice with severe psoriasis-like skin phenotype exacerbated psoriasiform skin inflammation in mice with mild symptoms, including increasing the infiltration and differentiation of Th17, and increased the abundance of Prevotella, while decreasing that of Parabacteroides distasonis, in the colon. These alterations affected fatty acid metabolism, increasing the abundance of oleic and stearic acids. Meanwhile, gentamicin treatment significantly reduced the abundance of Prevotella and alleviated the psoriasis-like symptoms in both K14-VEGF mice and imiquimod (IMQ)-induced psoriasis-like mice. Indeed, administration of oleic and stearic acids exacerbated psoriasis-like symptoms and increased Th17 and monocyte-derived dendritic cell infiltration in the skin lesion areas in vivo, as well as increased the secretion of IL-23 by stimulating DCs in vitro. At last, we found that, treatment of PDE-4 inhibitor alleviated psoriasis-like phenotype of K14-VEGF mice accompanied by the recovery of intestinal microbiota, including the decrease of Prevotella and increase of Parabacteroides distasonis. Overall, our findings reveal that the intestinal microbiota modulates host metabolism and psoriasis-like skin inflammation in mice, suggesting a new target for the clinical diagnosis and treatment of psoriasis.

Electroacupuncture promotes skin wound repair by improving lipid metabolism and inhibiting ferroptosis

“…17 Reactive oxygen species (ROS) generated by ultraviolet (UV) radiation can lead to skin barrier dysfunction, while sphingolipid-containing lacto-phospholipids can reduce skin barrier damage by regulating heme oxygenase-1 (HO-1) and reducing ROS levels through milk phospholipid-mediated activation of nuclear factor erythroid-2-related factor 2 (Nrf2). 18 Our study found acyl carnitine (CAR)-lipid acyl CoA under the action of carnitine lipid acyltransferase, and enter the matrix across the inner mitochondrial membrane to participate in oxidation 19,20 The decrease in fatty acids and complex phospholipids may be due to a dramatic decrease in 3-carbon intermediates (glycerol-based) in the glycolytic pathway, which generally provides the backbone for the synthesis of these lipids. 21 Palmitic acid, lauric acid and oleic acid in free fatty acids increase the release of antimicrobial peptides in the sebaceous glands, thus achieving an antimicrobial effect and preventing the entry of external harmful substances into the organism.…”

“…Fatty acids are oxidized through β‐oxidation to produce acetyl CoA, which is completely oxidized by the tricarboxylic acid cycle to produce CO2 and H2O and release energy. Fatty acid oxidation is divided into three stages, activation‐transfer‐oxidation and fatty acids need to be catalysed by lipid acyl CoA synthase to generate lipid acyl CoA first, then transported into mitochondria with the help of carnitine, and complete the transformation of lipid acyl CoA‐lipid acyl carnitine (CAR)‐lipid acyl CoA under the action of carnitine lipid acyltransferase, and enter the matrix across the inner mitochondrial membrane to participate in oxidation 19,20 The decrease in fatty acids and complex phospholipids may be due to a dramatic decrease in 3‐carbon intermediates (glycerol‐based) in the glycolytic pathway, which generally provides the backbone for the synthesis of these lipids 21 . Palmitic acid, lauric acid and oleic acid in free fatty acids increase the release of antimicrobial peptides in the sebaceous glands, thus achieving an antimicrobial effect and preventing the entry of external harmful substances into the organism 22 .…”

Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation

“…Consequently, VEGF has emerged as a promising therapeutic target for psoriasis [27]. Studies have also demonstrated that alterations in fatty acid metabolism can exacerbate the pathogenesis of psoriasislike symptoms [28]. Additionally, lysophosphatidic acid, a simple phospholipid found in nature, has been implicated in the development of psoriasis [29].…”

Cholesterol and low‐density lipoprotein as a cause of psoriasis: Results from bidirectional Mendelian randomization

“…Animal experiments have shown that abnormalities in lipid metabolism induced by a high-fat diet contribute to developing psoriasis, 16,21,22 and clinical studies have demonstrated abnormalities in lipid metabolism in patients with psoriasis. 17,23 However, the causal relationship between lipid metabolism and psoriasis remains unknown.…”