Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells

The maintenance of tissue-specific chronic inflammation results from the interplay of genetic and unidentified environmental factors. Here, we describe an immunoregulatory role for an environmentally driven microbial metabolite in Card14E138A/+-induced spontaneous psoriasis. Through metabolite screening, we demonstrate chronic skin inflammation is accompanied by alterations microbial metabolite. Notably, depletion of gut, not skin, microbes alleviates disease symptoms. We further identify indoxyl sulfate (I3S), a bacteriogenic metabolite, as a key driver of psoriatic inflammation and confirm that gut-resident indole-producing microbiota mediate this process. Mechanistically, indole-producing microbiota promote host I3S biothsynthesis via a metabolic relay, and I3S potentiates skin inflammation by reshaping chromatin accessibility in skin Th17 cells through AHR signaling. In human psoriasis cohorts, serum I3S levels correlate with disease severit. In summary, our study uncovers a mechanistic link between gut microbial factors and type 3 skin inflammation, highlighting targeting gut microbiota as a strategy for mitigating skin inflammation. CD45-positive immune cells were isolated from Card14E138A/+ mice and wild type littermates using flow cytometry and analyzed by scRNA-seq.

组织特异性慢性炎症的维持，源于遗传因素与未明确环境因素之间的相互作用。本研究阐明了环境诱导的微生物代谢物在Card14E138A/+诱导的自发性银屑病中的免疫调节作用。通过代谢物筛选实验，我们发现慢性皮肤炎症伴随微生物代谢物谱的改变。值得注意的是，清除肠道（而非皮肤）微生物可缓解疾病症状。我们进一步鉴定出吲哚硫酸酯（indoxyl sulfate, I3S）——一种细菌源性代谢物——作为银屑病炎症的关键驱动因子，并证实肠道定植的产吲哚微生物群介导了这一过程。从机制层面来看，产吲哚微生物群通过代谢接力途径促进宿主I3S的生物合成，而I3S则通过芳香烃受体（aryl hydrocarbon receptor, AHR）信号通路重塑皮肤Th17细胞的染色质开放状态，进而增强皮肤炎症。在人类银屑病队列研究中，血清I3S水平与疾病严重程度呈正相关。综上，本研究揭示了肠道微生物因素与3型皮肤炎症之间的机制性关联，提示靶向肠道微生物群可作为缓解皮肤炎症的治疗策略。研究人员通过流式细胞术从Card14E138A/+小鼠及其野生型同窝仔鼠中分离出CD45阳性免疫细胞，并采用单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）进行分析。