The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota.
The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota.
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DOI：
10.1186/s40168-021-01103-z
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发表时间：
2021-07-08
期刊：
影响因子：
15.5
通讯作者：
Davidovic L
中科院分区：
文献类型：
--
作者：
Bermudez-Martin P;Becker JAJ;Caramello N;Fernandez SP;Costa-Campos R;Canaguier J;Barbosa S;Martinez-Gili L;Myridakis A;Dumas ME;Bruneau A;Cherbuy C;Langella P;Callebert J;Launay JM;Chabry J;Barik J;Le Merrer J;Glaichenhaus N;Davidovic L
自闭症谱系障碍（ASD）与微生物群-肠-脑轴的失调、微生物群组成的变化以及微生物代谢物的粪便、血清和尿液水平的变化相关。然而，微生物群-肠-脑轴失调与ASD之间的因果关系仍有待证实。在这里，我们假设微生物代谢物对甲酚，这是更丰富的ASD患者相比，神经典型的个人，可以诱导ASD样行为的小鼠。在饮用水中暴露于对甲酚4周的小鼠表现出社会行为缺陷、刻板和持续行为，但焦虑、运动或认知没有变化。对甲酚诱导的异常社会行为与参与社会奖励回路的中枢多巴胺神经元活性降低有关。此外，对甲酚诱导的微生物群组成和社会行为缺陷的变化可以通过粪便微生物群移植（FMT）从对甲酚处理的小鼠转移到对照小鼠。我们还表明，与移植对照小鼠微生物群的小鼠相比，移植对甲酚处理小鼠微生物群的小鼠表现出粪便对甲酚排泄增加。此外，我们确定了可能的对甲酚细菌生产者。最后，当移植到对甲酚治疗的小鼠时，对照小鼠的微生物群拯救了社会互动，多巴胺神经元兴奋性和粪便对甲酚水平。微生物代谢产物对甲酚选择性诱导小鼠ASD核心行为症状。对甲酚诱导的社会行为缺陷取决于微生物群组成的变化。我们的研究为针对微生物群和对甲酚生产的治疗干预铺平了道路，以治疗ASD患者。视频摘要在线版本包含补充材料，可在10. 1186/s40168-021-01103-z获得。
Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract The online version contains supplementary material available at 10.1186/s40168-021-01103-z.
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影响因子：
11.1
作者：
Golubeva AV;Joyce SA;Moloney G;Burokas A;Sherwin E;Arboleya S;Flynn I;Khochanskiy D;Moya-Pérez A;Peterson V;Rea K;Murphy K;Makarova O;Buravkov S;Hyland NP;Stanton C;Clarke G;Gahan CGM;Dinan TG;Cryan JF
通讯作者：
Cryan JF
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
DOI：
10.1016/j.bbadis.2020.165859
发表时间：
2020-10-01
影响因子：
6.2
作者：
Gevi, Federica;Belardo, Antonio;Zolla, Lello
通讯作者：
Zolla, Lello
影响因子：
4.3
作者：
Emond, Patrick;Mavel, Sylvie;Andres, Christian R.
通讯作者：
Andres, Christian R.
影响因子：
7.6
作者：
Becker, Jerome A. J.;Clesse, Daniel;Kieffer, Brigitte L.
通讯作者：
Kieffer, Brigitte L.