Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
Am J Physiol Gastrointest Liver Physiol. 2020 Jun 1;318(6):G1042-G1053. doi: 10.1152/ajpgi.00088.2020. Epub 2020 May 11.
The period during and immediately after weaning is an important developmental window when marked shifts in gut microbiota can regulate the maturation of the enteric nervous system (ENS). Because microbiota-derived signals that modulate ENS development are poorly understood, we examined the physiological impact of the broad spectrum of antibiotic, vancomycin-administered postweaning on colonic motility, neurochemistry of enteric neurons, and neuronal excitability. The functional impact of vancomycin on enteric neurons was investigated by Ca imaging in reporter mice to characterize alterations in the submucosal and the myenteric plexus, which contains the neuronal circuitry controlling gut motility. 16S rDNA sequencing of fecal specimens after oral vancomycin demonstrated significant deviations in microbiota abundance, diversity, and community composition. Vancomycin significantly increased the relative family rank abundance of , , and at the expense of and . In sharp contrast to neonatal vancomycin exposure, microbiota compositional shifts in weaned animals were associated with slower colonic migrating motor complexes (CMMCs) without mucosal serotonin biosynthesis being altered. The slowing of CMMCs is linked to disruptions in the neurochemistry of the underlying enteric circuitry. This included significant reductions in cholinergic and calbindin+ myenteric neurons, neuronal nitric oxide synthase+ submucosal neurons, neurofilament M+ enteric neurons, and increased proportions of cholinergic submucosal neurons. The antibiotic treatment also increased transmission and responsiveness in myenteric and submucosal neurons that may enhance inhibitory motor pathways, leading to slower CMMCs. Differential vancomycin responses during neonatal and weaning periods in mice highlight the developmental-specific impact of antibiotics on colonic enteric circuitry and motility.
断奶期间和之后是一个重要的发育窗口，在此期间，肠道微生物群的显著变化可以调节肠神经系统 (ENS) 的成熟。由于调节 ENS 发育的微生物衍生信号知之甚少，我们研究了广谱抗生素万古霉素在断奶后给药对结肠运动、肠神经元的神经化学和神经元兴奋性的生理影响。通过在报告小鼠中进行 Ca2+成像来研究万古霉素对肠神经元的功能影响，以表征对含有控制肠道运动的神经元回路的黏膜下和肌间神经丛的改变。口服万古霉素后的粪便标本 16S rDNA 测序表明微生物丰度、多样性和群落组成有显著偏差。万古霉素显著增加了 的相对家族等级丰度，而 的丰度则减少了。与新生儿万古霉素暴露形成鲜明对比的是，断奶动物的微生物组成变化与 CMMC（结肠移行性复合运动）变慢有关，而粘膜 5-羟色胺生物合成没有改变。CMMC 变慢与潜在肠电路的神经化学紊乱有关。这包括胆碱能和钙结合蛋白+肌间神经元、神经元型一氧化氮合酶+黏膜下神经元、神经丝 M+肠神经元的显著减少，以及胆碱能黏膜下神经元比例的增加。抗生素治疗还增加了肌间和黏膜下神经元的传递和反应性，这可能增强抑制性运动途径，导致 CMMC 变慢。在小鼠中，新生儿和断奶期万古霉素的不同反应突出了抗生素对结肠肠电路和运动的发育特异性影响。
