银屑病与肠道菌群(调研手稿一)

	树突状细胞	T细胞
肿瘤坏死因子-α（TNF-α）	√
白细胞介素-6(IL-6)	√
白细胞介素-12(IL-12)
白细胞介素-17(IL-17)		√
白细胞介素-20(IL-20)	√
白细胞介素-21(IL-21)		√
白细胞介素-22(IL-22)		√
白细胞介素-23(IL-23)	√
γ干扰素（IFN-γ）		√
IL-1β

Psoriasis is a chronic immune-mediated inflammatory disease that occurs in 2-4% of
people worldwide affecting skin and in 30% of cases joints (psoriatic arthritis)

Among these cytokines, IL-22, TNF-α, and IFN-γ are regarded as the major players in
psoriatic inflammation.

Furthermore, they are
the key molecules in the most commonly
reported immune mechanism associated with
psoriasis, namely IL-23/IL-17 axis [20,21]. IL-17,
which is produced by Th17 cells, was
numerously found to be upregulated in both
psoriatic lesions and bloodstream of patients
with psoriasis and psoriatic arthritis [22-29].(IL-23/IL-17在银屑病患者血液中显著上升，IL17是淋巴细胞T17产生的)

SCFAs(acetate, butyrate, propionate)

The findings of Chen et al., 2017 [57] revealed
that mice given L.pentosus GMNL-77 had
significantly less psoriasis-like skin lesions and
decreased hyperproliferation of keratinocytes
compared with the imiquimod only treated
group. The probiotic-treated mice had reduced
expre（喂食戊糖乳杆菌能明显降低皮损）

上述内容来自【1】

Th17 cells, as well as Th1 cells and keratinocytes, secrete TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17A, IL-22, IL-23 participating in pathophysiologic processes of psoriasis [5] and current biological therapies as T cell-directed agents have demonstrated excellent efficacy in psoriasis.

Among them, serum IL-6 and IL-22 levels were considered to be positively correlated with the severity of psoriasis inpatients [6, 7].

（Th17细胞以及Th1细胞和角质形成细胞分泌TNF-α、IFN-γ、IL-1β、IL-6、IL-12、IL-17A、IL-22、IL-23，参与银屑病的病理生理过程[5]，目前作为T细胞导向剂的生物疗法在银屑病中已显示出优异的疗效。其中，血清IL-6和IL-22水平被认为与银屑病住院患者的严重程度呈正相关[6,7]）

Intestinal permeability was more frequently was reported in plaque psoriasis patients, and the bacterial DNA from the gut can be detected in patients’ blood [13]（斑块型银屑病患者的肠道通透性更为常见，并且可以在患者血液中检测到肠道细菌DNA）

上述内容来自【11】

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菌群	作用	菌群比例-银屑病患者	菌群比例-正常对照组	睡眠障碍	Secukinumab (生物制剂)
拟杆菌门	抵抗炎症	9.2%	22%	下降	下降
放线杆菌	抵抗炎症	2.8%	3.9%
厚壁菌群	诱发炎症	83%	70%	增加	下降
变形菌

Finding	By
Alpha diversity（α多样性）	Increased	Gao et al. [19], Chang et al. [14]
Alpha diversity（α多样性）	Decreased	Fahlen et al. [18], Alexseyenko et al. [17], Tett et al. [16]
Beta diversity（β多样性）	Lower	Fahlen et al. [18]
Beta diversity（β多样性）	Higher	Alexseyenko et al. [17], Tett et al. [16], Loeshe et al. [12], Chang et al. [14]
Phylum level
Firmicutes（厚壁菌门）	Increased Firmicutes	Gao et al. [19], Fahlen et al. [18], Langan et al. [10]
Firmicutes（厚壁菌门）	Decreased Firmicutes	Loeshe et al. [12], Assarsson et al. [13], Drago et al. [15]
Actinobacteria（放线菌门）	Decreased Actinobacteria	Gao et al. [19], Fahlen et al. [18], Langan et al. [10]
Actinobacteria（放线菌门）	Increased Firmicutes and Actinobacteria	Alexseyenko et al. [17]
Proteobacteria(变形菌门)	Decreased Proteobacteria(放形)	Gao et al. [19]
Proteobacteria(变形菌门)	Increased Proteobacteria	Fahlen et al. [18], Drago et al. [15]
Genus level
Streptococcus（链球菌门）	Increased Streptococcus	Gao et al. [19], Fahlen et al. [18], Alexseyenko et al. [17], Stehlikova et al. [11], Drago et al. [15]
Streptococcus（链球菌门）	No correlation	Loeshe et al. [12]
Staphylococcus（葡萄球菌）	Increased Staphylococcus	Gao et al. [19], Tett et al. [16]
Staphylococcus（葡萄球菌）	Decreased Staphylococcus	Fahlen et al. [18]
Propionibacterium（丙酸杆菌）	Lower Propionibacterium	Gao et al. [19], Fahlen et al. [18], Drago et al. [15], Stehlikova et al. [11], Loeshe et al. [12]
Gram positives（革兰氏阳性）	Increased relative abundance of combined Gram positives: Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus	Alexseyenko et al. [17]
	Corynebacterium and Staphylococcus were significantly correlated with PASI scores	Langan et al. [10]
	Increased S. aureus, decreased P. acne	Gao et al. [19]
	Site-specific microbiota without related disease	Tett et al. [16]

It has been reported that B. longum strains exert pro-differentiating, as well as and pro-regenerating, effects on primary human epidermal keratinocytes [68]

非常有意思，罗列了很多关于银屑病患者中“菌门增加还是减少”的结果截然相反的论文。

上述内容来自【12】，【13】也包含一张类似的比较表格

Pro- and prebiotics are commonly used to modulate the microbiome by promoting the growth of specific species. Three studies using three distinct probiotic species affecting distinct pathways of the pathomechanism of psoriasis [61, 62] have all shown improvement in the course of the disease. The probiotics resulted in the improvement of epithelial barrier function, increased production of TNF-alpha by epithelial cells, and regulated activation of the NF-ĸβ pathway [63]. An issue with probiotic supplementation is that the colonization of probiotic bacteria in the gut is mostly transient as they are only detectable for less than 2 weeks after cessation of intake [64]. However, a study by Maldonado-Gómez et al. demonstrated that a certain Bifidobacterium longum (B. longum) strain was able to persist for over 6 months in a subset of subjects where it was originally absent [65]. A recent, randomized, double-blind, placebo-controlled trial evaluated the effect of a probiotic mixture as co-adjutant treatment together with topical steroids in 90 patients with plaque psoriasis. The results showed a large reduction in the score of severity indexes in the probiotic group, compared with the placebo group. Gut microbiota analysis demonstrated the efficacy of the probiotic in modulation of the composition of the microbiota. After the end of the probiotic or placebo intake, patients were followed up for 6 months. The results showed a lower risk of relapse in patients in the probiotic group [66].（益生元和益生元通常用于通过促进特定物种的生长来调节微生物组。三项研究使用了三种不同的益生菌，它们影响银屑病发病机制的不同途径[61,62]，所有这些研究都表明银屑病的病程有所改善。益生菌可改善上皮屏障功能，增加上皮细胞产生TNF-α，并调节NF-β途径的激活[63]。益生菌补充的一个问题是，益生菌在肠道中的定植大多是短暂的，因为它们在停止摄入后的不到2周内才可检测到[64]。然而，Maldonado-Gómez等人的一项研究表明，某种长双歧杆菌（B.longum）菌株能够在最初不存在的一部分受试者中持续6个月以上[65]。最近的一项随机、双盲、安慰剂对照试验评估了益生菌混合物与局部类固醇联合治疗90例斑块型银屑病患者的疗效。结果显示，与安慰剂组相比，益生菌组的严重性指数得分大幅下降。肠道微生物群分析证明了益生菌在调节微生物群组成方面的功效。在服用益生菌或安慰剂结束后，对患者进行6个月的随访。）

上面的内容来自【13】

It is believed that, there are fractions of the gut microbiota with the ability to counteract inflammation(抵抗炎症) (Bacteroidetes and Actinobacterial), and others that are more prone to induce inflammation (Firmicutes) （导致炎症） and the disturbed microbiome ratio may be the cause for inducing psoriasis.

he human gut microbiota is dominated by only 2 of them: the Bacteroidetes and the Firmicutes (˃98%), whereas Actinobacteria, Proteobacteria, and others are present in minor proportions (Eckburg et al., 2005).

人类肠道拟杆菌和厚壁菌占据其中98%

Firmicutes was the commonest detected phyla in psoriasis patients (83%), while Bacteroidetes and Actinobacterial phyla were accounted for 9.2 and 2.8%, respectively. In the control group the detected percentage were 70, 22, and 3.9% for Firmicutes, Bacteroidetes, and Actinobacterial phyla, respectively.(厚壁菌是银屑病患者中最常见的菌门（83%），类杆菌和放线杆菌分别占9.2%和2.8%。在对照组中，厚壁菌门、拟杆菌门和放线菌门的检出率分别为70%、22%和3.9%。)

上述内容来自【2】

In favoring an increased Firmicutes to Bacteroidetes ratio and reduced abundance of short-chain fatty acid–producing bacteria, sleep dysfunction could be contributing to worsening psoriasis and cardiometabolic comorbidities through intestinal dysbiosis. Future studies are needed to determine whether gut- and sleep-targeting interventions could be therapeutic in patients with psoriasis having poor sleep.

上述内容来自【5】

Background and Objective

Immunotherapy could change the complex host-microbial interactions. We aimed to investigate the dynamics of gut microbiome in response to secukinumab [an interleukin (IL)-17 inhibitor] and ustekinumab (an IL-12/23 inhibitor) therapy and its association with treatment response in psoriasis.

Methods

This observational, longitudinal study collected a total of 114 fecal samples from 12 healthy controls and 34 patients with psoriasis at baseline and 3 and 6 months after secukinumab (n = 24) or ustekinumab treatment (n = 10) and gut microbiomes were investigated using next-generation sequencing targeting 16S ribosomal RNA.

Results

Secukinumab treatment causes more profound alterations in gut microbiome, including increases in the relative abundance of phylum Proteobacteria and decreases in Bacteroidetes and Firmicutes, than ustekinumab treatment. The relative abundance of family Pseudomonadaceae, family Enterobacteriaceae and order Pseudomonadales also increased significantly following secukinumab therapy. In contrast, there was no significant change in gut microbiome composition following ustekinumab treatment, and only genus Coprococcus significantly increased after 6 months of ustekinumab therapy. Moreover, we observed significant differences in baseline gut microbiome between responders and non-responders to secukinumab treatment.

Conclusion

These results indicate that gut microbiome is altered differently after anti-IL17 and anti-IL12/23 treatment. Secukinumab (anti-IL17) therapy is associated with distinct and more profound gut microbiome shifts than ustekinumab therapy (anti-IL 12/23) in patients with psoriasis. Moreover, gut microbiome would serve as potential biomarkers of response to secukinumab treatment.

上述内容来自【6】

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【3】中提到菌群比例不平衡导致了银屑病

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An association between psoriasis and inflammation of the gut has also been observed; 7-11% of patients with inflammatory bowel disease (IBD) are also diagnosed with psoriasis. Further, the same pattern of dysbiosis (microbial imbalance) has been described in both IBD and psoriasis patients, regardless of whether the conditions are co-occurring. This dysbiosis has been shown to include a depletion in healthy bacteria, such as Lactobacillus spp., Bifidobacterium spp., and F. prausnitzii, as well as colonization of certain pathogenic bacteria, including E.coli and Salmonella sp. Additionally, evidence has shown that colonization of S. aureus, Malassezia, and C. albicans in the skin, gut, or both, exacerbates psoriasis.

上面内容来自【4】

	银屑病患者
Lactobacillus spp(双歧杆菌)	下降
Bifidobacterium spp（乳酸杆菌）	下降
Feacalibacterium prausnitzii	下降
双歧杆菌	下降
金黄色葡萄球菌	如果上升（则加重）
马拉色菌	如果上升（则加重）
白色念珠菌	如果上升（则加重）
丙酸杆菌	下降
链球菌	上升
棒状杆菌	上升
葡萄球菌	上升

Psoriasis is a chronic, inflammatory immune-mediated skin disease that affects about 2% of the world’s population. In 20% of patients with psoriasis, the characteristic skin lesions are accompanied by psoriatic arthritis (PsA). Psoriasis arises in genetically predisposed individuals who have a dysregulated immune response to various environmental factors. The human body is home to many microbial species, and both the skin and the gut microbiome influence the development and function of immune tissue development and function. Studies on the cutaneous microbiome show a trend toward an increased relative abundance of Streptococcus and a decreased level of Propionibacterium in patients with psoriasis compared to healthy controls. In the gut microbiome, the ratio of Firmicutes and Bacteroidetes was perturbed in psoriatic individuals compared to healthy controls. Actinobacteria was relatively underrepresented in patients with psoriasis compared to healthy individuals. A decrease in skin microbiome flora diversity seems to be a sign that a patient with psoriasis is at elevated risk for developing arthritis. Modulating the skin microbiota for therapeutic reasons can be achieved by antimicrobial (antibiotic) therapy, the application of prebiotics or probiotics, or the transplantation of an entire healthy microbial population.

（银屑病患者丙酸杆菌下降，链球菌丰度上升）

上述内容来自【10】

Curiously, studies in IBD also implicate these genera, with a decreased abundance of Ruminococcus and Akkermansia in both ulcerative colitis and Crohn disease27（瘤胃群菌和akk菌减少）【13】

Lower abundance of Propionibacterium in lesional skin was reported by Gao et al. [19], Fahlen et al. [18], Drago et al. [15], Stehlikova et al. [11], and Loeshe et al. [12], which is in contrast to Alexseyenko et al. [17] who reported an increase in the relative abundance of combined Gram positives such as Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus. In the subsequent study by Langan et al. [10], the presence of Corynebacterium and Staphylococcus was found to be significantly correlated with PASI scores while Anaerococcus and Propionibacterium were associated with non-lesional skin. These are consistent with the reports by Gao et al. [19] and Chang et al. [14] that at species level lesional skin psoriasis had an increased level of S. aureus but a decreased level of P. acne.（Gao等人[19]、Fahlen等人[18]、Drago等人[15]、Stehlikova等人[11]和Loeshe等人[12]报告了皮损皮肤中丙酸杆菌丰度较低的情况，这与Alexseyenko等人[17]报告的棒状杆菌、丙酸杆菌等组合革兰氏阳性菌相对丰度增加形成对比，葡萄球菌和链球菌。在Langan等人[10]的后续研究中，发现棒状杆菌和葡萄球菌的存在与PASI评分显著相关，而厌氧球菌和丙酸杆菌与非皮损皮肤相关。这与Gao等人[19]和Chang等人[14]的报告一致，即在物种水平上，皮损性银屑病的金黄色葡萄球菌含量增加，但痤疮杆菌含量减少。）

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Compelling new research from Spain demonstrates that the answer to this question may, in fact, lie within the gut. These researchers have demonstrated higher levels of a specific chemical, LPS, in the blood of patients with psoriasis who also have metabolic syndrome, an ever increasing situation here in America characterized by excess body fat, high blood sugar, elevated blood pressure, etc.

LPS happens to be a chemical that makes up part of the cell membrane of a large number of bacteria that live within the gut. Finding elevated LPS levels in the bloodstream is an indication of two things. First, it means that the gut has become permeable or leaky, which has allowed the LPS to get into the bloodstream. Second, it means that the process of inflammation has been enhanced as LPS acts as a powerful switch, turning on the inflammatory cascade.

What I found most compelling about the study was the fact that even when the skin condition improved using phototherapy, again a treatment based exclusively on dealing with the skin, the elevation of the LPS did not change. What this means is that the phototherapy was basically treating the smoke while the fire was being ignored. The fire is the inflammatory cascade brought on by this LPS chemical that leeches its way into the bloodstream because the gut is permeable.

So, you might then ask, what causes the gut to become permeable in the first place? Several important factors should be considered to answer this question. First and foremost, understand that it is the role of various probiotic bacteria to maintain the integrity of the gut lining. When the balance of bacteria within the gut is threatened by such things as overuse of antibiotics, or even dietary choices, the ability of the good bacteria to maintain the gut wall lining is challenged. In addition, it is known that gliadin, a protein found in gluten, may also threaten the integrity of the gut lining.

(光疗法治标不治本，银屑病本质是血液中LPS浓度的上升)

上述内容来自【7】

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The results from this promising animal model prompted a series of human studies. In one, administering medium-chain fatty acids as a prebiotic in healthy individuals appeared to diversify their gut microbiota and to expand the population of regulatory T cells in their blood. “We saw more bacteria overall, and in particular, more reportedly beneficial bacteria,” Dr. Scher says. “So now we have a proof of principle that a single modification correlates with an increase in your body’s inflammation regulators,” he says(中链脂肪酸所谓益生元能使得肠道菌群更加多样化)

A Potential Explanation for IL-17i-Mediated Gut Inflammation
The same concept can be applied to other medications like the interleukin-17 inhibitor, or IL-17i. The drug class, commonly prescribed to patients with psoriatic arthritis and spondyloarthritis, has the well-known and seemingly paradoxical side effect of exacerbating Crohn’s disease in some patients.

At the gut level, research led by Julia Manasson, MD, post-doctoral T32 research fellow, and colleagues suggests significant shifts in the microbiota of patients with spondyloarthritis receiving IL-17i therapy, with some showing a significant increase in the abundance of Candida albicans yeast in the intestinal lumen. The same shift was not observed in patients receiving TNF blockade therapy. The increase, Dr. Scher says, may explain why certain patients who already have subclinical gut inflammation develop clinically overt inflammation and Crohn’s disease upon treatment with an IL-17 inhibitor.(其中一些患者的肠腔中白色念珠菌酵母菌的丰度显著增加。在接受TNF阻断治疗的患者中未观察到同样的变化。Scher博士说，这种增加可能解释了为什么某些已经患有亚临床肠道炎症的患者在使用IL-17抑制剂治疗后会出现临床上明显的炎症和克罗恩病)

上述内容来自【8】

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Food is one of the major modifiable factors regulating the gut microbiota, the community of microorganisms living in the intestines. Eating a Western diet can cause rapid change to the gut’s microbial community and its functions. This disruption in microbial balance—known as dysbiosis—contributes to gut inflammation.（西餐会迅速破坏肠道菌群）

上述内容来自【9】

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The two most dominant phyla in intestinal
microbiome are Bacteroidetes and Firmicutes [11]. Bacteria from these two phyla may
secrete short-chain fatty acids (SCFA), which are the end products of bacterial anaerobic
fermentation of dietary fibre. Many studies suggested that SCFA have anti-inflammatory
properties, can induce regulatory T cells in the colon and maintain its homeostasis, and are
able to modulate the function of intestinal macrophages [12]. A study conducted in 2011
by Arumugam et al. determined three robust clusters of intestinal microbiome, named
enterotypes, depending on dominant genera: enterotype 1—Bacteroides, enterotype 2—
Prevotella, enterotype 3—Ruminococcus. The most often occurring is enterotype three
which, besides Ruminococcus, also includes Akkermansia genus [13].

（肠道中两个最主要的门

微生物群是拟杆菌和厚壁菌[11]。来自这两个门的细菌可能

分泌短链脂肪酸（SCFA），这是细菌厌氧发酵的最终产物

膳食纤维的发酵。许多研究表明，SCFA具有抗炎作用

特性，可以诱导结肠中的调节性T细胞并维持其体内平衡，并且

能够调节肠道巨噬细胞的功能[12]。2011年进行的一项研究

由Arumugam等人确定了三个强大的肠道微生物群，命名为

肠型，取决于优势属：肠型1-类杆菌，肠型2-

普雷沃特菌，肠型3-瘤胃球菌。最常见的是肠三型

除瘤胃球菌外，还包括Akkermansia属[13]）

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Treatments
According to Natural Medicine Journal, the first step is to treat the underlying cause of a leaky gut. For example, changes in diet that reduce gut inflammation due to Crohn’s disease or ulcerative colitis may improve intestinal barrier function.

Research shows the following treatments may help heal leaky gut:

antioxidant supplements, such as quercetin, Ginkgo biloba, vitamin C, and vitamin E
zinc supplementation with nutrients that support healthy intestinal mucosa, such as L-glutamine, phosphatidylcholine, and gamma-linolenic acid
plant enzymes
probiotics
dietary fiber
Eating healing foods is said to mend leaky gut. These can include:

bone broth
raw dairy products
fermented vegetables
coconut products
sprouted seeds
Speaking with your doctor
Despite the lack of evidence supporting this syndrome, there’s little doubt that it’s a real condition. Proponents of this syndrome are confident it’s only a matter of time before clear evidence confirms that it causes systemic health issues.（

根据《自然医学杂志》，第一步是治疗肠道渗漏的根本原因。例如，改变饮食以减少克罗恩病或溃疡性结肠炎引起的肠道炎症可能会改善肠道屏障功能。

研究表明，以下治疗方法可能有助于治愈肠道渗漏：

抗氧化剂补充剂，如槲皮素、银杏叶、维生素C和维生素E

补充营养素，如L-谷氨酰胺、磷脂酰胆碱和γ-亚麻酸，以支持健康的肠粘膜

植物酶

益生菌

膳食纤维

据说吃有治疗作用的食物可以修复肠道的渗漏。这些措施可包括：

骨头汤

生乳制品

发酵蔬菜

椰子制品

发芽种子

）

以上内容来自【14】

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One study described how administrating Lactobacillus pentosus GMNL-77 as a probiotic to psoriatic mice significantly reduced erythema, scaling, and epidermal thickening compared with mice in the control group. Another group of mice which received Lactobacillus reuteri（罗伊式乳杆菌） exhibited an accelerated wound healing time.（伤口愈合快）

A study conducted with humans diagnosed with severe pustular psoriasis emphasized the effectiveness of probiotic treatments in patients. Previously these patients were unresponsive to several treatments including steroids, dapsone, and methotrexate. However, “after initiating Lactobacillus sporogenes（芽孢乳酸杆菌） supplementation 3 times per day, the patients showed significant clinical improvement within 2 weeks, with almost complete remission after 4 weeks,” the authors said.（迅速缓解）【15】

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Psoriasis patients differ from controls in the observed community structure. The dominant phyla in psoriasis patients were Bacteroidetes 47.1%, Firmicutes 44.6%, Proteobacteria 5.4%, Actinobacteria 0.8% and Fusobacteria 0.7%, while the principal phyla found in controls were Bacteroidetes 59.9%, Firmicutes 33.0%, Proteobacteria 4.2%, Verrucomicrobia 1.4% and Actinobacteria 0.8% (Fig. 2).

	psoriasis	controls
Bacteroidetes	47.1%	59.9%
Firmicutes	44.6%	33.0%
Proteobacteria	5.4%	4.2%
Actinobacteria	0.8%	1.4%
Fusobacteria	0.7%	0.8%

The fact that most relevant genus in psoriasis patients that discriminated against non-psoriasis controls were Faecalibacterium and Blautia, taxa producing high levels of butyrate, contradicts the traditional association of butyrate producers observed in diseases such as IBD66,67. Therefore, results highlight the need for additional research given the observational nature and limits of 16S used in this study.

In our control group, the predominant genus were Bacteroides and Paraprevotella. These bacteria differ only in family (Bacteroideaceae for Bacteroides and Prevotellaceae for Paraprevotella)68,69. Increasing evidence proposes that Bacteroides harness complex recalcitrant glycans70. SCFAs are the major metabolic products of anaerobic fermentation of glycans by gut bacteria and have been shown to impact on the host physiology71. The beneficial effect of Bacteroides is consistent with our findings, where this genus was increased in controls and depleted in psoriasis patients.（

银屑病患者中与非银屑病对照组最相关的属是粪便杆菌属和Blautia属，即产生高水平丁酸的分类群，这一事实与在IBD66、67等疾病中观察到的丁酸产生者的传统关联相矛盾。因此，鉴于本研究中使用的16秒的观测性质和局限性，研究结果强调了进行额外研究的必要性。

在我们的对照组中，主要属为类杆菌和副雷沃杆菌。这些细菌仅在科（拟杆菌科为拟杆菌属，Prevotellaceae为Pararevotella）68,69中有所不同。越来越多的证据表明类杆菌利用复杂的难降解聚糖70。SCFA是肠道细菌厌氧发酵聚糖的主要代谢产物，已被证明对宿主生理有影响71。类杆菌的有益作用与我们的研究结果一致，在对照组中，该属菌数量增加，而在银屑病患者中，该属菌数量减少。

）

上面内容来自【17】

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For example, Lactobacillus rhamnosus GG, a commensal species, secretes p40, a protein that suppresses cytokine-mediated apoptosis and epithelial barrier disruption.[22]

Many studies on human and other animals mention that the intestinal microbiome's influence extends to extracolonic sites and contributes to the function, and dysfunction, of distant organ systems.[2,28] For instance, short-chain fatty acids (SCFAs), which are produced from dietary fibers fermented by the gut microbiome, have a protective role against the progression of some inflammatory disorders, including allergy and arthritis, in addition to colitis.（例如，鼠李糖乳杆菌GG，一种共生物种，分泌p40，一种抑制细胞因子介导的凋亡和上皮屏障破坏的蛋白质

许多关于人类和其他动物的研究提到，肠道微生物组的影响延伸到结肠外部位，并导致远处器官系统的功能和功能障碍。[2,28]例如，短链脂肪酸（SCFA），由肠道微生物组发酵的膳食纤维产生，除结肠炎外，对某些炎症性疾病的进展具有保护作用，包括过敏和关节炎。）

.[33] Another class of metabolites, SCFAs, regulates both the activation and apoptosis of immune cells（SCFA会调节细胞的激活和凋亡）

The beneficial effects of intestinal bacteria on skin health and appearance have been documented in several studies on rodents and humans. In rats, oral administration of Lactobacillus brevis SBC8803 resulted in decreased tone of cutaneous arterial sympathetic nerve and increased cutaneous blood flow.[37] Such effects were possibly caused by increased serotonin release from intestinal enterochromaffin cells followed by activation of parasympathetic pathways.[37] A considerable decrease in transepidermal water loss (TEWL), a marker of skin barrier function, was noted as well.[37] Noteworthy, similar outcomes were observed in human clinical research. After taking L. brevis SBC8803 orally for 12 weeks, human subjects had significantly decreased TEWL and increased corneal hydration.[38] In another study, it was shown that bacterial supplementation positively affects skin barrier function.[39]（肠道细菌对皮肤健康和外观的有益影响已在几项关于啮齿动物和人类的研究中得到证实。在大鼠中，口服短乳杆菌SBC8803导致皮肤动脉交感神经张力降低和皮肤血流量增加。[37]这种效应可能是由肠嗜铬细胞释放的5-羟色胺增加，然后激活副交感神经通路引起的。[37]经皮皮肤失水（TEWL）显著减少，这是皮肤屏障功能的标志。[37]值得注意的是，在人类临床研究中也观察到类似的结果。在口服短乳杆菌SBC8803 12周后，人类受试者的TEWL显著降低，角膜水合作用增加。[38]另一项研究表明，补充细菌对皮肤屏障功能有积极影响。[39]）

Although the healing process through microscopic examination of wounds revealed the usual histomorphologic stages of wound healing in both probiotic-treated and untreated mice, the time required for complete healing was markedly reduced in the treated group（罗伊氏乳杆菌能加速皮损愈合）

Recently, after the discovery of elevated IL-17 levels in psoriatic lesions, therapies shifted the focus to Th17 cells. Cytokines released by Th17 cells promote the expression of the IL-10 cytokine family, including IL-20 and IL-22 cytokines, which causes keratinocyte hyperproliferation. After the discovery of the Th17 pathway, most clinical and mechanistic evidence indicate that psoriasis is primarily driven by the IL-23/IL-17/Th17 axis.[63,64,65,66,67,68,69](最近，在银屑病皮损中发现IL-17水平升高后，治疗的重点转移到Th17细胞。Th17细胞释放的细胞因子促进IL-10细胞因子家族的表达，包括IL-20和IL-22细胞因子，导致角质形成细胞过度增殖。在发现Th17通路后，大多数临床和机制证据表明银屑病主要由IL-23/IL-17/Th17轴驱动)

Faecalibacterium prausnitzii, a beneficial microbial inhabitant of the large intestine, provides many benefits to the host. It serves as a significant source of butyrate, an SCFA that provides energy for colonocytes, reduces oxidative stress, and exerts anti-inflammatory action by triggering regulatory T cells, thereby conferring immune tolerance beyond the GI system.[75,76] This species is much less abundant in the gut of psoriatic patients than in healthy ones.[77] Furthermore, intestinal dysbiosis generates endotoxin-peptidoglycan superantigens that induce autoimmune and inflammatory conditions associated with psoriasis. An immune response is triggered in response to the toxins produced by microorganisms in the gut and psoriatic patients exhibit positive skin test to gut bacterial antigens.(prausnitzii粪杆菌是大肠中有益的微生物，为宿主提供许多益处。它是丁酸的重要来源，丁酸是一种SCFA，为结肠细胞提供能量，减少氧化应激，并通过触发调节性T细胞发挥抗炎作用，从而赋予免疫耐受性在胃肠道系统之外。[75,76]银屑病患者肠道中的该物种数量远少于健康患者.此外，肠道生态失调产生内毒素肽聚糖超抗原，诱导银屑病相关的自身免疫和炎症条件。对肠道微生物产生的毒素会触发免疫反应，银屑病患者对肠道细菌抗原的皮肤试验呈阳性)

Probiotics and psoriasis
Although data on probiotic supplementation in psoriasis treatment are limited, promising outcomes have been documented. Psoriasis is often associated with intestinal inflammation, such as IBD, the pathophysiology is closely associated with the dysbiosis of the gut.[90] Moreover, a recent study showed that psoriasis has been associated with gut dysbiosis.[91] One study was shown that Lactobacillus pentosus GMNL-77 administration (as a probiotic) in an imiquimod-induced psoriasis mouse model results in significantly less erythema, scaling, and epidermal thickening when compared with untreated control mice.[41] In another study, the same probiotic suppressed the expression of TNF-α, IL-6, and proinflammatory cytokines in the IL-23/IL-17 cytokine axis.[92] Though the mechanism for reduced T-cell activity was unclear, the authors proposed that this effect was mediated by the suppression of CD103+ dendritic cells, intestinal antigen-presenting cells that modulate regulatory T cells in the GI tract.[93] Furthermore, in a placebo-controlled study of psoriasis patients, Bifidobacterium infantis 35624 supplementations led to significantly decreased plasma levels of TNF-α when compared with the placebo group.[92] The effectiveness of probiotic treatment was highlighted in a case severe pustular psoriasis that had been unresponsive to steroids, dapsone, and methotrexate. After initiating Lactobacillus sporogenes supplementation 3 times per day, the patients showed significant clinical improvement within 2 weeks, with almost complete remission after 4 weeks.[94](双歧杆菌+戊糖乳杆菌)

More than 70 clinical studies on food containing microbial ingredients have been conducted to investigate the potential side effects of probiotics and none has shown any adverse effects.[97]（已经对含有微生物成分的食品进行了70多项临床研究，以调查益生菌的潜在副作用，但没有发现任何副作用。）调查益生菌副作用的文章是下面一篇

Use of probiotics in pediatrics: rationale, mechanisms of action, and practical aspects - PubMed

上述内容来自【18】

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Recently, a study focused on autism and accompanying GI symptoms12, found that autism patients had a distinct and less diverse gut microbial composition with lower levels of Prevotella, Coprococcus, and an unclassified Veillonellaceae. All these results suggest a potentially important role of the gut microbiome in illnesses that are not directly related to the digestive tract.（孤独症患者的肠道菌群多样性较低）

The intestinal bacterial composition was compared based on BT detection and enterotype classification (Arumugam et al.)13: enterotype 1 (predominance of Bacteroides, Fig. 2A), enterotype 2 (predominance of Prevotella) (Fig. 2B) and enterotype 3 (predominance of Ruminococcus) (Fig. 2C)

肠型分类：

	主要细菌
肠型1	类杆菌
肠型2	普氏杆菌
肠型3	瘤胃球菌

Butyrate and propionate are short chain fatty acids produced by gut microbial and with a demonstrated anti-inflammatory role19 and, furthermore, butyrate has shown to be a key-player for maintaining barrier integrity20.（肠道需要丙酸盐和丁酸盐来抗炎）

上述内容来自【19】

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In particular, the relationship between psoriasis and obesity is bidirectional, with obesity favoring psoriasis and psoriasis predisposing individuals to obesity (Shipman and Millington, 2011; Cooksey et al., 2018; Dauden et al., 2018). (肥胖有利于银屑病)

S. aureus, another common pathogen, may also be a pathogenic factor of psoriasis, given the increase in Th17 polarization and exacerbated cutaneous inflammation during early colonization of newborn mouse skin (Chang et al., 2018).（Th17极化增加，皮肤炎症加剧）

上述内容来自【20】

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A 2018 study looked at the effects of probiotics on skin conditions such as eczema in mice.

The researchers found that certain probiotics reduced and may even prevent chronic skin inflammation, including:

Lactobacillus salivarius LA307(唾液乳杆菌)
Lactobacillus rhamnosus LA305（鼠李糖乳杆菌）

Another study in mice considered the effects of Lactobacillus pentosus GMNL-77 on psoriasis. The authors found that this strain prevented skin inflammation and reduced biomarkers of inflammation.（戊糖乳杆菌GMNL-77）

yogurt（奶绕）
kefir, which is a fermented, probiotic dairy drink
kombucha, a fermented tea made with bacteria and yeast
fermented cheeses
pickles
miso, a Japanese seasoning paste（其实就是国内豆瓣酱，但是国内的豆瓣酱太咸了，不利于健康） made with fermented soybeans
fermented vegetables, such as kimchi and sauerkraut
Probiotic supplements are another good option

Treatments for mild to moderate outbreaks include:

topical corticosteroids
topical retinoids, which contain vitamin A
vitamin D analogs, which contain a topical synthetic form of vitamin D
salicylic acid
coal tar（水杨酸、维生素D）

Research suggests that probiotics may reduce symptoms of psoriasis. However, probiotics are still not well understood, and they can harm people with weakened immune systems.

Confirming the benefits and risks of taking probiotics will require further research.

Everyone’s microbiome is unique, so a person may need a particular combination of probiotic strains. Consult a healthcare provider before taking probiotic supplements.

Probiotic supplements are available for purchase online.（益生菌可能伤害免疫系统薄弱的人，目前人类依然没有很好地理解益生菌，所以一个人可能需要一种特殊的益生菌菌株组合）

上述内容来自【21】

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In mice with an experimental model of psoriasis induced by imiquimod, oral treatment with broad-spectrum antibiotic reduces the severity of skin inflammation through downregulation of Th17 immune response [12,13]. （光谱抗生素能抑制Th17）

We searched four electronic databases from their inception to March 2020: MEDLINE (via PubMed), Embase (via OvidSP), Web of Science Core Collection, and Scopus（作者提到了自己的电子数据库）

All studies confirmed the association of psoriasis and gut microbiota dysbiosis. At the phylum level, Bacteroidetes had a lower relative abundance and Firmicutes a higher relative abundance in patients with psoriasis than in healthy controls [20,22,23]. However, in a study by Huang et al., Bacteroidetes was reported to be increased and Firmicutes decreased in psoriasis [21]. Additionally, two studies showed decreased amounts of Proteobacteria in psoriatic cohort [20,22]. Studies for Actinobacteria provide conflicting results—an increase in two studies [20,22] and decrease in the other two studies [27,28].

At the family level, the relative abundance of Ruminococcaceae, Lachnospiraceae, Clostridiales Family XIII, Peptostreptococcaceae, Enterococcaceae, Coriobacteriaceae, and Eggerthellaceae was increased in psoriasis, whereas Prevotellaceae, Barnesiellaceae, Tannerellaceae, Rikenellaceae, Porphyromonadaceae, Marinifilaceae, S24-7, Lactobacillaceae, Streptococcaceae, Pasteurellaceae, Burkholderiaceae, Desulfovibrionaceae, Victivallaceae, and Verrucomicrobiaceae decreased. There were conflicting results for Bacteroidaceae, Erysipelotrichaceae, Veillonellaceae and Bifidobacteriaceae. Some studies reported these families to be decreased in psoriasis [22,23,28] while others showed their increase [22,25].

At the genus level, Paraprevotella, Barnesiella, Alistipes, Allobaculum, Coprobacillus, Carnobacterium, Granulicatella, Rothia, Gordonibacter, Thermus were found to be decreased. Following genera were relatively increased in psoriasis: Ruminococcus, Subdoligranulum, Blautia, Coprococcus, Dorea, Christensenella, Streptococcus, Lactococcus, Enterococcus, Bacillus, Collinsella, Slackia. Divergent findings were reported for Bacteroides, Parabacteroides, Faecalibacterium, Lachnospira, Akkermansia, Sutterella, and Bifidobacterium.

At the species level, Prevotella copri, Faecalibacterium prausnitzii and Akkermiansia muciniphila were found to be significantly decreased, while Ruminococcus gnavus, Dorea formicigenerans, Clostridium citroniae, Escherichia coli, and Collinsella aerofaciens were increased in patients with psoriasis compared to control group. However, these alterations have not been confirmed in more than one study. Details indicating the altered bacteria are shown in Table 4.

（

所有研究都证实了银屑病与肠道微生物群失调的关系。在门水平上，银屑病患者的类杆菌相对丰度低于健康对照组，厚壁菌相对丰度高于健康对照组[20,22,23]。然而，Huang等人的一项研究表明，银屑病患者类杆菌增多，厚壁菌减少[21]。此外，两项研究表明银屑病队列中的变形菌数量减少[20,22]。对放线菌的研究提供了相互矛盾的结果：两项研究[20,22]增加，另两项研究[27,28]减少。

在家族水平上，银屑病患者的反刍菌科、丝状菌科、梭状芽孢杆菌科、消化链球菌科、肠球菌科、科里奥巴氏菌科和蛋壳菌科的相对丰度增加，而普雷沃菌科、巴氏菌科、单宁菌科、里肯菌科、卟啉单胞菌科、海洋菌科、S24-7、乳酸杆菌科、，链球菌科、巴氏杆菌科、伯克霍尔德菌科、脱硫弧菌科、维克托菌科和疣状菌科减少。对于类杆菌科、丹毒菌科、脉内尔菌科和双歧杆菌科，结果存在矛盾。一些研究报告这些家族在银屑病[22,23,28]中有所减少，而另一些则显示其增加[22,25]。

在属水平上，发现副革兰氏菌、巴氏杆菌、阿利斯蒂普斯菌、异杆菌、粪杆菌、肉杆菌、颗粒杆菌、罗氏菌、戈登杆菌、热杆菌数量减少。银屑病中的以下属相对增多：瘤胃球菌、鼻下角膜炎、布劳提氏菌、粪球菌、Dorea、Christensenella、链球菌、乳球菌、肠球菌、芽孢杆菌、柯林斯菌、松驰菌。对于类杆菌、类副杆菌、粪杆菌、拉奇诺匹拉菌、阿克曼菌、苏特莱拉菌和双歧杆菌，报告了不同的发现。

在物种水平上，发现银屑病患者与对照组相比，copri普氏菌、prausnitzii粪杆菌和粘质Akkermianiasia显著减少，而gnavus瘤胃球菌、Dorea formicigeneras、柠檬酸梭菌、大肠杆菌和产气柯林斯菌增加。然而，这些改变尚未在一项以上的研究中得到证实。表4显示了改变细菌的详细信息。）

文中的Table4提供了一张有矛盾的研究结果的列表

We presented several taxa that differed in their relative abundance in psoriasis. For instance, a reduction in Bacteroides and Proteobacteria with increased proportions of Firmicutes and Actinobacteria, at phylum level was reported in more than one study. These four phyla constitute > 98% of the gut microbiota. Therefore, the Firmicutes/Bacteroidetes (F/B) ratio is considered as an important marker of gut microbiota state. Several studies have shown that an altered F/B ratio in gut microbiome is associated with psoriasis comorbidities, such as cardiovascular diseases [34], obesity [35], insulin resistance [36] and nonalcoholic fatty liver disease [37]. Only one study by Huang et al. reported opposite changes in Bacteroides and Firmicutes [21]. This dissimilarity partially may be related to a small number of participants and very diverse group, which consisted of people with plaque psoriasis, pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis.

The tendencies for the change of Firmicutes and Bacteroidetes in patients with psoriasis are also present at the lower taxonomic levels. Families Bacteroidaceae and Prevotellaceae are two important subgroups in phylum Bacteroides. While alterations in Bacteroidaceae and Bacteroides have been confirmed in psoriasis, there is no agreement about the direction of these changes. Similarly, the role of these bacteria is also controversial. Bacteroides fragilis, can produce enterotoxins responsible for inflammation and impairment of the intestinal barrier [38]

（我们介绍了银屑病中几个相对丰度不同的分类群。例如，不止一项研究报告了类杆菌和变形杆菌的减少，以及厚壁菌门和放线菌门的比例增加。这四个门构成 > 98%的肠道微生物群。因此，厚壁菌/拟杆菌（F/B）比率被认为是肠道微生物群状态的重要标志。几项研究表明，肠道微生物群中F/B比率的改变与银屑病共病有关，如心血管疾病[34]、肥胖[35]、胰岛素抵抗[36]和非酒精性脂肪肝[37]。只有Huang等人的一项研究报告了类杆菌和厚壁菌的相反变化[21]。这种差异部分可能与少数参与者和非常多样化的群体有关，其中包括斑块型银屑病、脓疱型银屑病、红皮病型银屑病和银屑病关节炎患者。

银屑病患者厚壁菌和类杆菌的变化趋势也存在于较低的分类水平。类杆菌科和类杆菌科是类杆菌门的两个重要亚类。虽然类杆菌科和类杆菌科的改变已在银屑病中得到证实，但这些改变的方向尚不一致。同样，这些细菌的作用也存在争议。脆弱类杆菌可产生肠毒素，导致肠道屏障的炎症和损伤[38]）

Regarding the second important phylum, Firmicutes, at least two studies have found increased abundance of families Ruminococcaceae and Lachnospiraceae, with depletion of Faecalibacterium prausnitzii and augmentation of Ruminococcus gnavus at the species level. F. prausnitzii metabolites exert a protective effect on the gut barrier and inhibit the activation of the NF-κB, altering the pro-inflammatory response [43]. The depletion of F. prausnitzii has been associated with inflammatory disorders, such as inflammatory bowel disease or ankylosing spondylitis [26,39]. On the other hand, R. gnavus produces an inflammatory polysaccharide and contributes to gut barrier dysfunction. Its increased abundance was observed in inflammatory bowel disease, spondyloarthritis, eczema and coronary artery disease [44].

It is still not clear whether psoriasis is an effect or a cause of the observed disbalance between beneficial and pathogenic microbes.（关于第二个重要的门，厚壁菌门，至少有两项研究发现，瘤胃球菌科和拉克诺菌科的数量增加，在物种水平上，prausnitzii粪杆菌的减少和gnavus瘤胃球菌的增加。F.prausnitzii代谢物对肠道屏障具有保护作用，并抑制NF-κB的激活，从而改变促炎症反应[43]。prausnitzii的缺失与炎症性疾病有关，如炎症性肠病或强直性脊柱炎[26,39]。另一方面，gnavus弧菌产生一种炎性多糖并导致肠道屏障功能障碍。在炎症性肠病、脊椎关节炎、湿疹和冠状动脉疾病中观察到其含量增加[44]。

目前尚不清楚银屑病是有益微生物和致病微生物之间失衡的结果还是原因。）

上述内容来自【22】

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Reference:

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