TMAO reductase, a biomarker for gut permeability defect induced inflammation, in mouse model of chronic kidney disease and dextran sulfate solution-induced mucositis
Sompong Boonhai,1 Kanthika Bootdee,2 Wilasinee Saisorn,2 Kullaya Takkavatakarn,3 Patita Sitticharoenchai,4 Somkanya Tungsanga,3 Khajohn tiranathanagul,3 Asada Leelahavanichkul2,3,5
Affiliations:
1 Master of Science Program in Molecular Science of Medical Microbiology and Immunology, Department of Transfusion Medicine and Clinical Microbiology Faculty of Allied Health Sciences, Chulalongkorn University
2 Department of Microbiology, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
3 Division of Nephrology, Department of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society and Faculty of Medicine, Chulalongkorn University
4 Division of Cardiology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
5 Translational Research in Inflammation and Immunology Research Unit (TRIRU), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
Abstract
Background: The excretion of trimethylamine N-oxide (TMAO) (uremic toxin) into the intestine might be enhanced, due to the limited renal elimination in chronic kidney disease (CKD), possibly induced TMAO reductase (a TMAO-neutralizing enzyme) in gut bacteria. Detection of TMAO reductase in serum could be used as a biomarker of gut permeability defect.
Objective: To explore the correlation between serum TMAO reductase, gut leakage, and systemic inflammation in CKD.
Methods: Mouse models of gut leakage; including 5/6 nephrectomy-induced chronic kidney disease (CKD), a model without colitis, and 1.5% dextran sulfate solution (DSS), a colitis model, were performed. In parallel, serum samples from patients with chronic hemodialysis (n = 48) and the healthy control (n = 20) were analyzed.
Results: Gut-leakage (FITC-dextran, endotoxemia, and reduced intestinal tight junction protein) was detected in both CKD and DSS models. While TMAO reductase and TMAO were elevated in the serum of both mouse models and patients, TMAO reductase correlated with TMAO, gut- leakage, and serum IL-6 only in mice but not in patients. Notably, endotoxemia was used as a surrogate marker of gut leakage in patients. In patients, TMAO reductase and TMAO did not correlate with serum IL-6 and vascular complications using the ankle-brachial index and cardio-ankle vascular index.
Conclusions: Serum TMAO reductase was elevated in CKD mice and patients with CKD. Serum TMAO reductase was correlated with TMAO and gut-leakage only in mice but not in patients. Further studies in patients are needed to determine the benefit of serum TMAO reductase in patients with CKD.
Key words: TMAO reductase, biomarker, inflammation, kidney disease, mucositis