Background & Aims

Despite achieving endoscopic remission, more than 20% of inflammatory bowel disease patients experience chronic abdominal pain. These patients have increased rectal transient receptor potential vanilloid-1 receptor (TRPV1) expression, a key transducer of inflammatory pain. Because inflammatory bowel disease patients in remission exhibit dysbiosis and microbial manipulation alters TRPV1 function, our goal was to examine whether microbial perturbation modulated transient receptor potential function in a mouse model.

Methods

Mice were given dextran sodium sulfate (DSS) to induce colitis and were allowed to recover. The microbiome was perturbed by using antibiotics as well as fecal microbial transplant (FMT). Visceral and somatic sensitivity were assessed by recording visceromotor responses to colorectal distention and using hot plate/automated Von Frey tests, respectively. Calcium imaging of isolated dorsal root ganglia neurons was used as an in vitro correlate of nociception. The microbiome composition was evaluated via 16S rRNA gene variable region V4 amplicon sequencing, whereas fecal short-chain fatty acids (SCFAs) were assessed by using targeted mass spectrometry.

Results

Postinflammatory DSS mice developed visceral and somatic hyperalgesia. Antibiotic administration during DSS recovery induced visceral, but not somatic, hyperalgesia independent of inflammation. FMT of postinflammatory DSS stool into antibiotic-treated mice increased visceral hypersensitivity, whereas FMT of control stool reversed antibiotics’ sensitizing effects. Postinflammatory mice exhibited both increased SCFA-producing species and fecal acetate/butyrate content compared with controls. Capsaicin-evoked calcium responses were increased in naive dorsal root ganglion neurons incubated with both sodium butyrate/propionate alone and with colonic supernatants derived from postinflammatory mice.

Conclusions

The microbiome plays a central role in postinflammatory visceral hypersensitivity. Microbial-derived SCFAs can sensitize nociceptive neurons and may contribute to the pathogenesis of postinflammatory visceral pain.

中文翻译：

---

结肠炎引起的微生物扰动促进炎症后内脏过敏。

 背景与目标

尽管实现了内镜缓解，但仍有超过 20% 的炎症性肠病患者经历慢性腹痛。这些患者的直肠瞬时受体电位 vanilloid-1 受体 (TRPV1) 表达增加，这是炎性疼痛的关键传导因子。由于炎症性肠病缓解期患者表现出生态失调，并且微生物操作会改变 TRPV1 功能，因此我们的目标是在小鼠模型中检查微生物扰动是否调节瞬时受体电位功能。

 方法

给予小鼠右旋糖酐硫酸钠（DSS）以诱导结肠炎并使其康复。使用抗生素和粪便微生物移植（FMT）会扰乱微生物组。通过记录内脏运动对结直肠扩张的反应并分别使用热板/自动冯弗雷测试来评估内脏和躯体敏感性。分离的背根神经节神经元的钙成像被用作伤害感受的体外相关性。通过 16S rRNA 基因可变区 V4 扩增子测序评估微生物组组成，而通过靶向质谱法评估粪便短链脂肪酸 (SCFA)。

 结果

炎症后 DSS 小鼠出现内脏和躯体痛觉过敏。 DSS 恢复期间使用抗生素会引起内脏痛觉过敏，但不会引起躯体痛觉过敏，与炎症无关。对抗生素处理的小鼠进行炎症后 DSS 粪便的 FMT 会增加内脏过敏，而对照粪便的 FMT 则逆转了抗生素的致敏作用。与对照组相比，炎症后小鼠的 SCFA 产生种类和粪便乙酸/丁酸盐含量均有所增加。在单独使用丁酸钠/丙酸钠和来自炎症后小鼠的结肠上清液孵育的幼稚背根神经节神经元中，辣椒素诱发的钙反应增加。

 结论

微生物组在炎症后内脏超敏反应中发挥着核心作用。微生物衍生的 SCFA 可以使伤害性神经元敏感，并可能导致炎症后内脏疼痛的发病机制。