Study on the effect of spleen deficiency on the pathogenesis of psoriasis based on intestinal microbiome

Psoriasis is an immune-mediated chronic inflammatory skin disease. According to the global report on psoriasis by the World Health Organization, this disease affects approximately 100 million individuals worldwide (1). Under the induction of various genetic and environmental factors, patients can cause recurrent and well-defined erythema and scale, which can seriously develop into life-threatening systemic erythroderma and arthritis. These symptoms not only reduce the quality of life, but also bring heavy financial burden to patients. The histological characteristics of psoriasis include keratinocytes excessive proliferation, parakeratosis, infiltration of inflammatory subsets such as neutrophils, dendritic cells and T lymphocytes. These characteristics reflect the differentiation of keratinocytes and the abnormal activation of the immune system.

Psoriasis and intestinal microecology

Gut-skin axis

Intestinal microecology is an important immunomodulatory environment for human body. The metabolic function of intestinal flora provides nutrition for the body and enhances the immune function of human body to resist the invasion of pathogenic bacteria. Many studies have found that the composition of intestinal flora and metabolites play an important role in immune and inflammatory response (2). These symbiotic bacteria can not only regulate intestinal immune function, but also affect the immune function of distant organs by stimulating the development of intestinal mucosa lymphoid tissue and regulating the activity of immune cells (3).

The “gut-skin axis” is based on the close correlation between the similar pathological structure of two kinds of tissues and the symptoms of clinical diseases (4): (I) both intestinal and skin tissues are rich in blood supply and dense innervation. As a complex epidemic-free and neuroendocrine organ, it is involved in the regulation of the overall immune and endocrine system. (II) As important organs in contact with the external environment, both of them have a large number of microbial communities. (III) Most of the patients with clinical intestinal dysfunction were accompanied by inflammatory rash. (IV) Dietetic changes and gastrointestinal diseases could affect the skin structure. The overall fur state and experimental dermatosis were significantly improved after probiotics feeding. (V) Specific dermatitis also indicates the occurrence of some gastrointestinal diseases.

Psoriasis is usually accompanied by inflammation of other organ systems, especially with gastrointestinal inflammation. 7–11% of inflammatory bowel disease (IBD) patients were diagnosed with psoriasis at the same time (5). Some common genetic and environmental factors and immune pathways are involved in the pathogenesis of these two diseases. For example, Th17 cells and their cytokines play a major role in the occurrence and development of psoriasis, and also participate in the pathophysiological process of IBD (6).

Changes of intestinal microbiota in patients with psoriasis

In addition to the skin inflammation symptoms of erythema and scales, there are also changes in intestinal tissue structure and intestinal microecology in patients with psoriasis. The intestinal mucosal permeability in patients with progressive psoriasis vulgaris was higher than that in normal subjects and patients after skin lesion regression, which was correlated with the severity of the disease (7). Comparing psoriasis patients with normal controls, it was found that there were significant changes in intestinal microflora of psoriasis patients (8). The quantity and variety of beneficial symbiotic bacteria in psoriasis decreased, including Bifidobacterium, lactic acid bacteria, prausnitzii, fecal bacteria and so on. However, the abundance of Salmonella, Escherichia coli, HP, campylobacter, mycobacteria, Alcaligenes and other pathogenic bacteria increased. Among them, the abundance of actinomycetes decreased in patients with psoriasis, and the proportion of actinomycetes was negatively correlated with the severity of the disease (9), while the ratio of Firmicute/Bacteroidetes increased, which was positively correlated with PASI score. The decrease of beneficial intestinal bacteria such as methamidophos, prausnitzii and fecal head bacteria in the intestinal flora of psoriasis leads to the weakening of the regulation of intestinal immune response, which further affects the distal organ system (10).

The role of intestinal microecological imbalance in the pathogenesis of psoriasis

In recent years, it has been found that intestinal microflora plays an important role in the pathogenesis of psoriasis. The changes of the bacteria quantity and variety in the intestines of psoriasis directly affect the skin inflammation. In the imiquimod-induced psoriasis model, mice treated with broad-spectrum antibiotics or metronidazole showed milder skin inflammation than mice without intervention (11). After treatment, the abundance of Lactobacillus, Bifidobacterium, Enterococcus and Parabacteroides distasonis increased significantly in intestine and skin. With the deepening of the study of intestinal microecology, the effect of intestinal microecology on psoriasis has been gradually clarified.

Invasion of bacteria and metabolites

Intestinal bacteria can enter the circulatory system through disordered intestinal barriers and directly target distant organs including the skin and joints to induce inflammation (12). There is some evidence that supports bacterial translocation in the context of psoriasis. It has been reported that bacterial intestinal DNA fragments can be found in the peripheral blood of psoriasis patients (13). In addition to the translocation and invasion of intestinal bacteria, bacterial metabolites also enter the circulatory system, affecting the homeostasis of the skin environment. Intestinal microflora has a huge ability to synthesize molecules, which is good or bad, can enter the blood circulation, and affect the skin and other distant parts. For example, free phenols and p-cresol produced by Clostridium difficult are metabolites of aromatic amino acids produced by intestinal bacteria, and p-cresol is a biomarker of intestinal disorders. Recent evidence suggests that free phenol and p-cresol in mice fed foods rich in l-tyrosine are able to enter the bloodstream and accumulate preferably in the skin (14). In vitro data showed that p-cresol and phenol decreased the expression of keratin 10 in keratinocytes cultured in vitro, thus affecting the differentiation and barrier function of epidermis.

Activation of the immune system

The intestinal microbiota metabolites have the potential of immune modification, which can change the balance between immune tolerance and inflammation by affecting the differentiation of T cells into regulatory T or Th17 lines. Effector T cells are usually anabolic and dependent on glycolysis as their source of adenosine triphosphate (ATP). However, memory and resting T cells are thought to be catabolic, using fatty acids and amino acids to produce ATP through oxidative phosphorylation in addition to glucose. The main transcription factors of adipogenesis pathway and glycolysis pathway are adenosine monophosphate activated kinase and rapamycin, respectively. Both act as energy sensors and are regulated by the availability of nutrients in the intestinal environment, which can be regulated by intestinal microflora.

Lipopolysaccharide (LPS), also known as endotoxin, is the product released after the death and lysis of Gram-negative bacteria. When the intestinal microecology is destroyed, the content of Gram-negative bacteria increases significantly in human body, which develops to the disorder of LPS metabolism, leading to the activation of dendritic cells and the proliferation of keratinocytes, thus causing or promoting the occurrence and development of psoriasis (15). It was found that probiotics could reduce the LPS concentration in vivo (16). Astragalus polysaccharides, an effective component of Astragalus membranaceus, can promote the growth of intestinal beneficial bacteria, adjust the intestinal flora imbalance and reduce the LPS content (17).

Reduced synthesis of short chain fatty acids

Recent results suggest that Intestinal symbiotic flora and its metabolites are regulated by the proliferation, differentiation and function of Treg cells, which plays an important role in maintaining the stability of the host immune system. Short chain fatty acids (SCFAs), the products of intestinal flora, play an important role in promoting the Treg maturation and inhibiting the T lymphocytes inflammatory response (18). It was found that SCFAs could enhance the histone H3 lysine 27 (H3K27) acetylation level of CNS1 and CNS3 enhancers in Foxp3, thus enhancing the effect of Fopx3. Moreover, SCFAs also enhance the function of DC to induce the differentiation of Treg cells by inhibiting histone acetylase. In addition, SCFAs can regulate Treg cells by stimulating G-protein-coupled receptors including GRP43, GRP41 and GRP109a (19).

Butyrate, for example, a form of SCFA, provides energy to colon cells, reduces oxidative stress, and acts as an anti-inflammatory material by triggering regulatory T cells to participate in immune tolerance which extends beyond the gastrointestinal system. Prausnitzii is one of the most common microorganisms in colon and an important source of butyrate. However, the number of such microorganisms in psoriasis decreased significantly (20). Some studies have shown that Sijunzi decoction can promote the significant proliferation of bacteria related to SCFA production. Therefore, the use of spleen-invigorating method has a positive impact on the production of SCFA.

Neuroendocrine network

The intestinal tract has a complex neuroendocrine network, which can regulate the function of the intestinal tract, and regulate the physiological and biochemical activities of the whole body by acting on extra-intestinal tissues and organs through endocrine factors, neuropeptides and “gut-brain axis”. Some neurotransmitters, neuropeptides, hormones and immune molecules in neuroendocrine immune network have also been closely related to the pathogenesis of psoriasis.

It was found that there was TLR4 on vagal afferent nerve and SCFA could significantly increase its responsiveness, which suggested that intestinal flora was involved in the regulation of “gut-brain axis” (21). For example, the imbalance of flora could significantly increase the substance P (SP) in the serum of rats (22). SP is one of the members of neurokinesis family, which plays a role in activating T cells, delaying apoptosis of neutrophils and prolonging inflammation, and can induce the expression of adhesion molecules and the production of IL-8 by endothelial cells and neutrophils. The contents of SP in the progressive and chronic plaque quiescent stage psoriasis lesions were significantly higher than that in convalescent patients and normal subjects, which played an important role in the occurrence, development and maintenance of psoriasis.

Spleen deficiency and intestinal flora

The spleen plays an important role in maintaining the stability of normal intestinal flora. Spleen deficiency is mostly caused by the diet disorder and emotional fatigue, which reflects the disorder of body function, and the main symptoms are loose, anorexia and abdominal distension (23). When the human body is in the state of spleen deficiency, gastrointestinal function will be abnormal, resulting in intestinal microecological imbalance, which has an impact on the occurrence and development of psoriasis and other diseases related to intestinal microecology.

Studies have shown that the number of intestinal beneficial bacteria is significantly reduced with spleen deficiency and the pathogenic bacteria are relatively abundant, leading to the imbalance and disorder of intestinal flora (24). When the spleen and stomach function was abnormal, the number of intestinal beneficial anaerobes such as Bifidobacterium and Lactobacillus decreased significantly, while the content of Enterobacter and other pathogenic bacteria increased (25). On the other hand, the disorder of intestinal flora leads to gastrointestinal discomfort, decreased digestive function, diarrhea, abdominal distension and other TCM spleen deficiency syndrome. The balance of intestinal flora can be restored by invigorating the spleen, such as Shenling baizhu Powder can restore the number of anaerobes such as Bifidobacterium to normal, and can obviously inhibit the number of aerobic bacteria represented by enterococci, so as to enhance the role of normal intestinal flora (26).

From the above, it can be seen that the imbalance of intestinal flora can aggravate spleen deficiency, and can be adjusted by using traditional Chinese medicine, through the regulation of the quantity and variety of intestinal flora, SCFA, LPS, neuropeptide and so on. It is also contributes to Inhibit the pathogenesis of psoriasis.

Spleen deficiency is the basis of difficult recovery and recurrence of psoriasis

Psoriasis patients often suffer from chronic course of disease due to weak body and spleen qi deficiency, or exogenous dampness and heat, or emotional disorders and improper diet, or overwork disorders, or excessive use of cold drugs, accompanied by spleen deficiency.

Traditional Chinese medicine believes that the spleen and stomach are the postnatal foundation and the source of qi and blood. The absorption and transportation of nutrition rely on spleen transfer and dispersion. Spleen deficiency can lead to the occurrence of a variety of diseases. Since deficiency in the spleen causes failure of the usable refined essence to be transported to the lung and nourish the body, there present such symptoms as a pallid complexion, cold hand and feet, fatigue, poor appetite, loose stools and cough. The performance of spleen deficiency in psoriasis is: qi cannot fix blood into blood vessel to cause megascopic erythema; disorder of qi and blood transport cause dry skin, scale, psoriasis nail and pale erythema. In addition, the health table is not solid, easy to be affected by wind evil, so there is pruritus. Spleen deficiency result in abnormal body fluids metabolism which stopped in middle-energizer to impede qi’s ascending and descending function, and make the disease difficult to heal.

Invigorating the spleen and draining dampness to improve the symptoms and prognosis of psoriasis

Many modern doctors realize the importance of spleen deficiency in the pathogenesis of psoriasis. Chushiweiling decoction has achieved good clinical results in the treatment of psoriasis patients with chronic course by using. Taken Sijunzi decoction as the main prescription, combined with drugs for clearing heat, psoriasis was treated by dehumidifying and detoxifying, nourishing yin, replenishing qi and fixing the surface. Psoriasis vulgaris with blood heat and blood dryness syndrome was ameliorated by treat with modified Xiaoyin jiedu Yin which added the product of invigorating spleen and replenishing yin. Doctor Hongxia Liu analyzed the physique of 583 psoriasis patients in Xinjiang Uygur Autonomous region. It was found that the treatment of invigorating spleen and detoxification was effective in clinic, and the condition of skin lesions and quality of life were significantly improved.

Generally speaking, it is advised to strengthen the spleen to treat psoriasis chronic course accompanied by spleen disorders. Reinforcing the health qi to eliminate pathogenic factors is the key to treatment, though invigorating the spleen and nourishing blood for reinforcing the health qi, and clearing heat and detoxification and removing toxic materials for eliminating pathogenic factors.

Summary

The imbalance of intestinal flora in patients with spleen deficiency leads to abnormal metabolism of SCFA, LPS and growth factors. On the one hand, invigorating the spleen can regulate SCFA, LPS and growth factors, on the other hand, it can maintain the ecological balance of intestinal flora. Jianpi recipe can promote the growth of intestinal beneficial bacteria in patients with spleen deficiency, adjust intestinal microecology, and restore the balance of unbalanced intestinal flora. Stable intestinal flora can increase the level of SCFA and decrease the level of LPS in patients with psoriasis and improve the clinical symptoms of psoriasis.

Acknowledgments

Beijing Key Laboratory of Clinic and Basic Research with Traditional Chinese Medicine on Psoriasis provided experimental research platform.

Funding: This study was supported by the National Natural Science Foundation of China [No. 81573974], Special subject of scientific research of National Clinical Research Base National Administration of traditional Chinese Medicine [JDZX2015190]. Beijing Excellent Talents Individual Project [No. 2017000021469G299].

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Bo Li) for the series “Holistic Traditional Chinese Medicine: the synergy of spleen and stomach in health” published in Longhua Chinese Medicine. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/lcm.2019.09.02). The series “Holistic Traditional Chinese Medicine: the synergy of spleen and stomach in health” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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