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

Man-Hui Pai,Po-Jen Yang,Jin-Ming Wu,Ming-Tsan Lin,Po-Chu Lee,Sung-Ling Yeh,Chun-Chieh Huang

doi:10.3390/nu12041086

Man-Hui Pai, Po-Jen Yang + Show 5 more

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https://doi.org/10.3390/nu12041086

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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.

Highlights

Sepsis is a clinical syndrome of a systemic inflammatory response that commonly occurs in critically ill patients
Some animals died at 72 h after cecal ligation and puncture (CLP); there was no difference in mortality rates between the two sepsis groups (Sepsis-C 25% vs. Sepsis-G 23%, p > 0.05)
The findings of this study showed that pretreatment with GLN increased liver caspase-11 and nod-like receptor family pyrin domain containing 3 (NLRP3) gene expressions at 24 h, while caspase-1/11 and gasdermin D (GadD) protein levels were downregulated at 72 h after sepsis

Summary

Introduction

Sepsis is a clinical syndrome of a systemic inflammatory response that commonly occurs in critically ill patients. It is defined as life-threatening multiorgan dysfunction triggered by a dysregulated immune response to infection [1]. The liver is the largest gland and a vital immune organ in the human body. This organ is responsible for various important physiological functions that makes it critical in the homeostasis of host metabolism and immunity [3,4]. The liver is one of the most frequently affected target organs in the clinical course of sepsis [5].

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