Background and Aims

Visceral hypersensitivity and low grade mucosal inflammation are frequently observed in a subpopulation of irritable bowel syndrome (IBS) patients. The responsible mechanism is unclear. Resolvins are a novel class of anti-inflammatory lipid mediators that regulate resolution of inflammation and pain. We hypothesize that resolvin D1 (RvD1) synthesis is reduced in IBS-D colonic mucosa and contribute to the development of visceral hypersensitivity.

Methods

We used ELISA and qPCR to quantify the levels of RvD1 synthesis and the gene expression of LOX5 and LOX12 in colonic biopsy samples from healthy individuals (HC) or IBS-D patients. To evaluate the role of gut bacteria in regulating RvD1 synthesis, we colonized germ-free mice with different strains of bacteria, fecal microbiota from HC individuals or IBS-D patients. To evaluate the role of tuft cells in RvD1 synthesis, we examined the effect of fecal supernatant of IBS-D or HC subjects on human colonoids as well as colonoids from mice in which Chat-cre recombinase vector was used to knock-in diphtheria toxin sensitive receptor (DTR^f/f) or knock-out the expression of Tlr4^f/f or MyD88^f/f.

Results

We report that colonic biopsy samples from IBS-D patients generated significantly lower level of RvD1 and LOX5 mRNA. The conventionalization of germ-free mice with microbiota from IBS-D patients or gram-negative bacteria inhibited RvD1 biosynthesis and caused visceral hypersensitivity and mucosal inflammation. Colonic organoid studies demonstrate that Lps downregulated Lox5 mRNA expression and synthesis of RvD1 via Tlr4-MyD88 receptor signaling pathway in colonic tuft cells.

Conclusions

Our findings indicate that RvD1 is generated in colonic tuft cells to regulate gut sensitivity to mechanical stimulation. Colonic commensal bacterial composition regulates the synthesis of RvD1 in colonic mucosa which is reduced in IBS-D patients. This appears to be mediated by elevated fecal lipopolysaccharide secondary to gram-negative gut dysbiosis.

中文翻译：

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肠道微生物群通过调节结肠簇细胞中 Resolvin D1 的合成改变内脏痛觉和炎症。

背景和目标

在肠易激综合征 (IBS) 患者的亚群中经常观察到内脏超敏反应和低度粘膜炎症。责任机制尚不清楚。Resolvins 是一类新型的抗炎脂质介质，可调节炎症和疼痛的消退。我们假设 IBS-D 结肠粘膜中的分解素 D1 (RvD1) 合成减少，并有助于内脏超敏反应的发展。

方法

我们使用 ELISA 和 qPCR 来量化来自健康个体 (HC) 或 IBS-D 患者的结肠活检样本中RvD1 合成的水平以及LOX5和LOX12的基因表达。为了评估肠道细菌在调节 RvD1 合成中的作用，我们用不同的细菌菌株、来自 HC 个体或 IBS-D 患者的粪便微生物群对无菌小鼠进行了定殖。为了评估簇状细胞在 RvD1 合成中的作用，我们检查了 IBS-D 或 HC 受试者的粪便上清液对人类结肠样体以及小鼠结肠样体的影响，其中使用 Chat-c​​re 重组酶载体敲入对白喉毒素敏感的小鼠受体 ( DTR ^f/f ) 或敲除Tlr4 ^f/f的表达或我的 D88 ^f/f。

结果

我们报告说，来自 IBS-D 患者的结肠活检样本产生了显着较低水平的 RvD1 和LOX5 mRNA 。将来自 IBS-D 患者的微生物群或革兰氏阴性菌的无菌小鼠常规化会抑制 RvD1 生物合成并引起内脏超敏反应和粘膜炎症。结肠类器官研究表明，Lps在结肠丛细胞中通过 Tlr4-MyD88 受体信号通路下调Lox5 mRNA 表达和 RvD1 的合成。

结论

我们的研究结果表明，RvD1 在结肠簇细胞中产生，以调节肠道对机械刺激的敏感性。结肠共生细菌组成调节结肠粘膜中 RvD1 的合成，这在 IBS-D 患者中减少。这似乎是由继发于革兰氏阴性菌肠道菌群失调的粪便脂多糖升高介导的。