Antecedent Dietary Glutamine Supplementation Benefits Modulation of Liver Pyroptosis in Mice with Polymicrobial Sepsis

Abstract

The liver is the main organ responsible for bacterial and endotoxin clearance. Pyroptosis is a form of proinflammatory programmed cell death activated by caspase-1/11 and gasdermin D (GadD). Pyroptosis protects the host against bacterial infection; however, overactive pyroptosis can lead to organ injury. Glutamine (GLN) is a specific amino acid with anti-inflammatory and immunomodulatory properties. This study investigated the effects of GLN pretreatment on liver pyroptosis in a mouse model of polymicrobial sepsis. Mice were assigned to sham, sepsis control (Sepsis-C), and sepsis GLN (Sepsis-G) groups. The sham and Sepsis-C groups were fed the AIN-93G diet. The Sepsis-G group was provided with identical diet components except that part of the casein was replaced by GLN. After feeding the respective diets for 2 weeks, a cecal ligation and puncture (CLP) procedure was performed in the sepsis groups. An antibiotic was administered after CLP. Mice were sacrificed at either 24 or 72 h after CLP. The results showed that sepsis resulted in upregulated liver caspase-1/11 expression. Compared to the Sepsis-C group, the Sepsis-G group had higher liver caspase-11 and NLRP3 gene expressions at 24 h and lower active caspase-1/11 and cleaved GadD protein levels at 72 h after sepsis. Additionally, liver inflammatory cytokine gene expressions had decreased by 72 h post-CLP. The findings suggest that prophylactic administration of GLN initially upregulated liver pyroptosis to eradicate pathogens, yet the process of pyroptosis was suppressed in the late phase of sepsis. This may have beneficially attenuated liver inflammation and injury in an antibiotic-treated septic condition.

Maintenance of glutamine synthetase expression alleviates endotoxin‐induced sepsis via alpha‐ketoglutarate‐mediated demethylation

“…Our study revealed for the first time that macrophage Glul has an important protective effect on sepsis that can induce systemic organ failure. Studies have reported that glutamine can relieve different organs of sepsis, such as the intestine, kidney, lung, and liver 29–32 . Therefore, the high fatality rate of sepsis may be due to the different degrees of failure of various organs in the body, and whether Glul, the key enzyme for the synthesis of glutamine, has different alleviating effects on the pathological changes in different organs remains to be studied in depth.…”

Cardioprotective Effect of Tangeretin by Inhibiting PTEN/AKT/mTOR Axis in Experimental Sepsis-Induced Myocardial Dysfunction

“…Using 18-gauge needle, the exposed cecum was punctured at 2 places. Feces were gently extruded, and cecum was placed back in its anatomical position [16,17].…”

Glutamine Administration Attenuates Kidney Inflammation in Obese Mice Complicated with Polymicrobial Sepsis

“…Although a multicenter clinical study revealed that GLN administration was associated with an increased mortality among critical patients with multiorgan failure [ 12 ], subsequent clinical trials found that parenteral GLN supplementation is safe in surgical intensive care unit (ICU) patients and improved outcomes in stabilized patients with organ function [ 13 , 14 ]. Previous studies performed by our laboratory revealed that GLN administration attenuates inflammatory reaction and remote organ injury in sepsis [ 15 – 17 ]. GLN was found to elicit a more-balanced T helper cell polarization [ 16 ], decreased programmed cell death 1 expression on immune cells [ 18 ], and downregulated high-mobility group box protein-1- (HMGB-1-) mediated pathway [ 19 ], thus alleviating kidney injury in sepsis.…”