4-乙基苯酚——与自闭症有关的肠道微生物组衍生神经调节剂的通量、代谢和排泄,Frontiers in Molecular Biosciences

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4-乙基苯酚——与自闭症有关的肠道微生物组衍生神经调节剂的通量、代谢和排泄
Frontiers in Molecular Biosciences ( IF 3.9 ) Pub Date : 2023-10-12 , DOI: 10.3389/fmolb.2023.1267754
Francesca Day ₁ , Justin O'Sullivan _{1,

2,

3,

4,

5} , Chris Pook ₁

Affiliation

肠道微生物组衍生的代谢物，例如 4-乙基苯酚 [4EP]，已被证明可以调节神经健康和功能。尽管人们对这些代谢物的来源有了更好的了解，但对于它们进入宿主循环的机制、它们如何在体内转运、它们如何代谢和排泄以及它们发挥作用的方式仍然存在知识差距。宿主修饰的 4EP（4-乙基苯酚硫酸盐 [4EPS]）的高血液浓度与自闭症个体的焦虑表型相关。我们回顾了现有文献并讨论了促进 4EP 从肠道微生物组流入、代谢和排泄的机制。我们注意到，肠道通透性增加在自闭症患者中很常见，这可能解释了 4EP 和/或 4EPS 穿过肠上皮和血脑屏障 [BBB] 的通量增加。同样，肾功能障碍（在自闭症患者中观察到的另一种并发症）会影响 4EP 及其衍生物从循环中的清除。有证据表明，小鼠大脑中 4EPS 的积累会影响子区域之间的连接，特别是那些与焦虑相关的区域。然而，我们没有发现有关人脑中 4EP 和/或 4EPS 的存在或数量的数据，无论神经系统状态如何，这可能是由于对该器官取样的挑战。我们认为，4EP 的渗透能力取决于其在 BBB 中的形式及其与内源性代谢物的理化相似性，以及跨 BBB 的专用主动转运机制。我们的结论是，未来的研究应侧重于物理（例如，吸收吸附剂）或代谢机制（例如，转化为 4EP-葡萄糖醛酸苷），这些机制能够用作干预措施，以减少 4EP 从肠道进入体内的流量，增加减少 4EP 和/或 4EPS 从大脑的流出，或增加肾脏的排泄，作为解决 4EP 神经系统影响的一种方法。

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4-Ethylphenol—fluxes, metabolism and excretion of a gut microbiome derived neuromodulator implicated in autism

Gut-microbiome-derived metabolites, such as 4-Ethylphenol [4EP], have been shown to modulate neurological health and function. Although the source of such metabolites is becoming better understood, knowledge gaps remain as to the mechanisms by which they enter host circulation, how they are transported in the body, how they are metabolised and excreted, and the way they exert their effects. High blood concentrations of host-modified 4EP, 4-ethylphenol sulfate [4EPS], are associated with an anxiety phenotype in autistic individuals. We have reviewed the existing literature and discuss mechanisms that are proposed to contribute influx from the gut microbiome, metabolism, and excretion of 4EP. We note that increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of 4EP and/or 4EPS across the gut epithelium and the Blood Brain Barrier [BBB]. Similarly, kidney dysfunction, another complication observed in autistic individuals, impacts clearance of 4EP and its derivatives from circulation. Evidence indicates that accumulation of 4EPS in the brain of mice affects connectivity between subregions, particularly those linked to anxiety. However, we found no data on the presence or quantity of 4EP and/or 4EPS in human brains, irrespective of neurological status, likely due to challenges sampling this organ. We argue that the penetrative ability of 4EP is dependent on its form at the BBB and its physicochemical similarity to endogenous metabolites with dedicated active transport mechanisms across the BBB. We conclude that future research should focus on physical (e.g., ingestion of sorbents) or metabolic mechanisms (e.g., conversion to 4EP-glucuronide) that are capable of being used as interventions to reduce the flux of 4EP from the gut into the body, increase the efflux of 4EP and/or 4EPS from the brain, or increase excretion from the kidneys as a means of addressing the neurological impacts of 4EP.

更新日期：2023-10-12

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