The Host CYP1A1-Microbiota Metabolic Axis Promotes Gut Barrier Disruption in Methicillin-Resistant Staphylococcus aureus-Induced Abdominal Sepsis.
The Host CYP1A1-Microbiota Metabolic Axis Promotes Gut Barrier Disruption in Methicillin-Resistant Staphylococcus aureus-Induced Abdominal Sepsis.
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宿主 CYP1A1-微生物群代谢轴促进耐甲氧西林金黄色葡萄球菌引起的腹部脓毒症的肠道屏障破坏
DOI：
10.3389/fmicb.2022.802409
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发表时间：
2022
影响因子：
5.2
通讯作者：
Liang, Huaping
中科院分区：
文献类型：
--
作者：
Ma, Xiaoyuan;Jin, Huaijian;Chu, Xiang;Dai, Weihong;Tang, Wanqi;Zhu, Junyu;Wang, Fangjie;Yang, Xue;Li, Wei;Liu, Guodong;Yang, Xia;Liang, Huaping
关键词：
宿主-微生物群串扰涉及调节肠屏障功能的多个宿主代谢途径轴。虽然组成型细胞色素P4501 A1（CYP 1A 1）表达扰乱肠道感染后微生物组衍生的自动调节回路，但对宿主CYP 1A 1在耐甲氧西林金黄色葡萄球菌（MRSA）诱导的腹部脓毒症期间调节肠道微生物组介导的信号传导及其对肠道屏障完整性的影响知之甚少。腹腔注射MRSA诱导小鼠腹腔脓毒症。使用RNA测序、微生物组分析和靶向代谢组学研究了CYP 1A 1缺乏对肠道屏障完整性的影响。微生物群产生的代谢产物在脓毒症和持续性MRSA感染患者中得到验证。缺乏CYP 1A 1的小鼠表现出改变的肠道微生物组，盲肠内容物中从赖氨酸到尸胺的代谢转变和抗微生物分子产生（Retnlb、Gbp 7和Gbp 3）减少，并且当经受MRSA攻击时，它们受到保护免受肠道屏障破坏。通过与CYP 1A 1 KO小鼠共饲养，在芳烃受体（AHR）敲除（KO）小鼠中验证了这些有益作用，并在补充尸胺或粪肠球菌（尸胺合成的主要微生物群属）后消除。抗生素驱动的肠道菌群失调损害了MRSA感染后CYP 1A 1 KO小鼠的生存益处并破坏了肠道屏障完整性。此外，在持续MRSA感染期间肠漏的危重患者中检测到粪便和血清中尸胺水平升高，而在健康对照组中未检测到尸胺。此外，微生物来源的尸胺通过激活组胺H4受体/核因子-κB/肌球蛋白轻链激酶信号通路诱导肠上皮细胞连接破坏。这项研究揭示了宿主CYP 1A 1在微生物群介导的尸胺代谢中的意想不到的功能，对MRSA诱导的腹部脓毒症后的菌群失调具有重要影响，表明抑制CYP 1A 1或阻断尸胺-组胺H4受体信号传导可能是腹部脓毒症的潜在治疗靶点。[http：//www.chictr.org.cn/index.aspx]，标识符[ChiCTR 1800018646]。
Host-microbiota crosstalk has been implicated in multiple host metabolic pathway axes that regulate intestinal barrier function. Although constitutive cytochrome P4501A1 (CYP1A1) expression perturbs the microbiome-derived autoregulatory loop following enteric infection, little is known about the role of host CYP1A1 in modulating gut microbiome-mediated signaling during methicillin-resistant Staphylococcus aureus (MRSA)-induced abdominal sepsis and its effects on intestinal barrier integrity. Abdominal sepsis was induced by the intraperitoneal injection of MRSA in mice. The effect of CYP1A1 deficiency on gut barrier integrity was investigated using RNA sequencing, microbiome analyses, and targeted metabolomics. The microbiota-produced metabolites were validated in patients with sepsis and persistent MRSA infection. Mice lacking CYP1A1 exhibited an altered gut microbiome, a reduced metabolic shift from lysine to cadaverine in the caecal contents and antimicrobial molecule production (Retnlb, Gbp7, and Gbp3), and they were protected against gut barrier disruption when subjected to MRSA challenge. These beneficial effects were validated in aryl hydrocarbon receptor (AHR) knockout (KO) mice by cohousing with CYP1A1 KO mice and abrogated after supplementation with cadaverine or Enterococcus faecalis, the primary microbiota genus for cadaverine synthesis. Antibiotic-driven gut dysbacteriosis impaired the survival benefit and disrupted the intestinal barrier integrity in CYP1A1 KO mice after MRSA infection. Furthermore, increased cadaverine levels in feces and serum were detected in critically ill patients with gut leakiness during persistent MRSA infection, whereas cadaverine was not detected in healthy controls. Additionally, microbiota-derived cadaverine induced enterocyte junction disruption by activating the histamine H4 receptor/nuclear factor-κB/myosin light-chain kinase signaling pathway. This study revealed the unexpected function of host CYP1A1 in microbiota-mediated cadaverine metabolism, with crucial consequences for dysbacteriosis following MRSA-induced abdominal sepsis, indicating that inhibiting CYP1A1 or blocking cadaverine-histamine H4 receptor signaling could be a potential therapeutic target against abdominal sepsis. [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1800018646].
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影响因子：
12.2
作者：
Agudelo-Ochoa GM;Valdés-Duque BE;Giraldo-Giraldo NA;Jaillier-Ramírez AM;Giraldo-Villa A;Acevedo-Castaño I;Yepes-Molina MA;Barbosa-Barbosa J;Benítez-Paéz A
通讯作者：
Benítez-Paéz A
DOI：
10.1016/j.bbadis.2017.03.005
发表时间：
2017-10
期刊：
Biochimica et biophysica acta. Molecular basis of disease
影响因子：
--
作者：
Fay KT;Ford ML;Coopersmith CM
通讯作者：
Coopersmith CM
影响因子：
3.9
作者：
Fu, Zidong Donna;Selwyn, Felcy P.;Klaassen, Curtis D.
通讯作者：
Klaassen, Curtis D.
影响因子：
64.5
作者：
Levy M;Thaiss CA;Zeevi D;Dohnalová L;Zilberman-Schapira G;Mahdi JA;David E;Savidor A;Korem T;Herzig Y;Pevsner-Fischer M;Shapiro H;Christ A;Harmelin A;Halpern Z;Latz E;Flavell RA;Amit I;Segal E;Elinav E
通讯作者：
Elinav E
影响因子：
6.7
作者：
Cheung GYC;Bae JS;Liu R;Hunt RL;Zheng Y;Otto M
通讯作者：
Otto M