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吗啡和芬太尼诱导的肠道上皮抗菌活性损伤在肠道菌群失调及其对微生物群-肠-脑轴的影响中的作用。

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

机构信息

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.

Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.

出版信息

FASEB J. 2024 Apr 30;38(8):e23603. doi: 10.1096/fj.202301590RR.

Abstract

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

摘要

最近的证据表明,慢性暴露于吗啡等阿片类镇痛药会破坏肠道上皮层并导致肠道菌群失调。耗尽肠道细菌可以防止阿片类药物引起的镇痛耐受的发展,这表明肠道-大脑轴在介导阿片类药物的作用中起着重要作用。然而,阿片类药物引起的菌群失调的机制尚不清楚。宿主产生的抗菌肽(AMPs)对于肠道上皮屏障的完整性至关重要,因为它们可以防止肠道微生物群的发病机制。在这里,我们报告慢性吗啡或芬太尼暴露会降低回肠中的抗菌活性,导致细菌组成发生变化。接受吗啡治疗的小鼠的粪便样本中,阿克曼氏菌(Akkermansia muciniphila)的水平增加,厚壁菌门和拟杆菌门的丰度比例发生变化。来自吗啡-naive 小鼠的粪便微生物移植(FMT)或口服补充丁酸盐可恢复(a)抗菌活性,(b)抗菌肽 Reg3γ 的表达,(c)防止肠通透性增加,以及(d)防止吗啡依赖小鼠产生镇痛耐受。FMT 或丁酸盐改善上皮屏障功能可防止吗啡依赖小鼠中粘蛋白降解菌阿克曼氏菌(A. muciniphila)的富集。这些数据表明,肠道上皮抗菌活性的损害是阿片类药物破坏肠道微生物群-肠道-大脑轴的一种机制。

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