The Host CYP1A1-Microbiota Metabolic Axis Promotes Gut Barrier Disruption in Methicillin-Resistant Staphylococcus aureus-Induced Abdominal Sepsis

Xiaoyuan Ma; Huaijian Jin; Xiang Chu; Weihong Dai; Wanqi Tang; Junyu Zhu; Fangjie Wang; Xue Yang; Wei Li; Guodong Liu; Xia Yang; Huaping Liang

doi:10.3389/fmicb.2022.802409

The Host CYP1A1-Microbiota Metabolic Axis Promotes Gut Barrier Disruption in Methicillin-Resistant Staphylococcus aureus-Induced Abdominal Sepsis

Front Microbiol. 2022 Apr 27:13:802409. doi: 10.3389/fmicb.2022.802409. eCollection 2022.

Authors

Xiaoyuan Ma¹, Huaijian Jin^{1

2}, Xiang Chu¹, Weihong Dai³, Wanqi Tang¹, Junyu Zhu¹, Fangjie Wang¹, Xue Yang¹, Wei Li¹, Guodong Liu^{1

4}, Xia Yang¹, Huaping Liang¹

Affiliations

¹ State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, China.
² Department of Spine Surgery, Center of Orthopedics, Daping Hospital, Army Medical University, Chongqing, China.
³ Trauma Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, China.
⁴ State Key Laboratory of Trauma, Burn and Combined Injuries, Medical Center of Trauma and War Injuries, Daping Hospital, Army Medical University, Chongqing, China.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1800018646].

Keywords: CYP1A1; cadaverine; enterocytes junction; gut microbiota; intestinal barrier; methicillin-resistant Staphylococcus aureus; sepsis.