Opioids are commonly prescribed to patients with chronic pain. Chronic opioid usage comes with a slew of serious side effects, including opioid-induced hyperalgesia (OIH). The patients with long-term opioid treatment experience paradoxical increases in nociceptive hypersensitivity, namely, OIH. Currently, treatment options for OIH are extremely lacking. In this study, we show that the ketogenic diet recovers the abnormal pain behavior caused by chronic morphine treatment in male mice, and we further show that the therapeutic effect of the ketogenic diet is mediated through gut microbiome. Our 16S rRNA sequencing demonstrates that chronic morphine treatment causes changes in mouse gut microbiota, specifically a decrease in short-chain fatty acids-producing bacteria, and the sequencing data also show that the ketogenic diet rescues those bacteria in the mouse gut. More importantly, we show that supplementation with short-chain fatty acids (butyrate, propionate, and acetate) can delay the onset of OIH, indicating that short-chain fatty acids play a direct role in the development of OIH. Our findings suggest that gut microbiome could be targeted to treat OIH, and the ketogenic diet can be used as a complementary approach for pain relief in patients with chronic opioid treatment. We only used male mice in this study, and thus, our findings cannot be generalized to both sexes.

中文翻译：

---

生酮饮食通过恢复肠道中产生短链脂肪酸的细菌来减轻阿片类药物引起的痛觉过敏。

阿片类药物通常用于治疗慢性疼痛患者。长期使用阿片类药物会带来一系列严重的副作用，包括阿片类药物引起的痛觉过敏 (OIH)。长期接受阿片类药物治疗的患者会出现伤害性超敏反应（即 OIH）的矛盾增加。目前，OIH 的治疗方案极其缺乏。在这项研究中，我们证明生酮饮食可以恢复雄性小鼠因长期吗啡治疗引起的异常疼痛行为，并进一步表明生酮饮食的治疗效果是通过肠道微生物组介导的。我们的 16S rRNA 测序表明，长期吗啡治疗会导致小鼠肠道微生物群发生变化，特别是产生短链脂肪酸的细菌减少，测序数据还表明生酮饮食可以拯救小鼠肠道中的这些细菌。更重要的是，我们发现补充短链脂肪酸（丁酸盐、丙酸盐和乙酸盐）可以延缓 OIH 的发病，表明短链脂肪酸在 OIH 的发生中起直接作用。我们的研究结果表明，肠道微生物组可以作为治疗 OIH 的目标，而生酮饮食可以作为缓解慢性阿片类药物治疗患者疼痛的补充方法。我们在这项研究中只使用了雄性小鼠，因此，我们的研究结果不能推广到两性。