Alterations in the gut microbiome and metabolome profiles of septic rats treated with aminophylline

Yuanzhe Li,Lina Xie,Guiying Sun,Yongtao Duan,Xianfei Ding,Yanjun Guo,Huayan Zhao

doi:10.1186/s12967-022-03280-3

Abstract

The treatment of sepsis remains a major challenge worldwide. Aminophylline has been shown to have anti-inflammatory effects; however, the role of aminophylline in sepsis, a disease characterized by immune dysregulation, is unknown. In this study, we combined microbiome sequencing and metabolomic assays to investigate the effect of aminophylline administration on the intestinal flora and metabolites in septic rats. Sixty SD rats were randomly divided into three groups: a sham-operated (SC) group, a sepsis model (CLP) group and a CLP + aminophylline treatment (Amino) group. The intestinal flora and metabolic profile of rats in the CLP group were significantly different than those of the SC group, while aminophylline administration resulted in a return to a state similar to healthy rats. Differential abundance analysis showed that aminophylline significantly back-regulated the abundance of Firmicutes, unidentified_Bacteria, Proteobacteria, Lactobacillus, Escherichia-Shigella and other dominant bacteria (P < 0.05) and altered chenodeoxycholic acid, isolithocholic acid and a total of 26 metabolites (variable importance in the projection (VIP) > 1, P < 0.05). In addition, we found that there were significant correlations between differential metabolites and bacterial genera of the Amino and CLP groups. For example, Escherichia-Shigella was associated with 12 metabolites, and Lactobacillus was associated with two metabolites (P < 0.05), suggesting that differences in the metabolic profiles caused by aminophylline were partly dependent on its influence on the gutmicrobiome. In conclusion, this study identified a novel protective mechanism whereby aminophylline could regulate disordered intestinal flora and metabolites in septic rats.

Highlights

Sepsis is a dysregulated immune response to infection that leads to organ dysfunction, and sepsis affects more than 30 million people worldwide each year [1, 2]
The results showed a significant increase in 24-h mortality (55%) in CLP-induced septic rats compared to the shamoperated group (P = 0.002); the mortality rate decreased to 30% in the aminophylline treatment (Amino) group, the difference between the CLP and Amino groups was not statistically significant (P = 0.110)
The CLP group was distant from the SC group, but the Amino and SC groups were clustered together, indicating that the intestinal flora of rats was significantly altered by sepsis, but the flora structure became similar to that of healthy rats after aminophylline administration

Summary

Introduction

Sepsis is a dysregulated immune response to infection that leads to organ dysfunction, and sepsis affects more than 30 million people worldwide each year [1, 2]. Despite intensive research on the pathogenesis and treatment of sepsis in recent years, the morbidity and mortality of sepsis remain high in clinical practice [3,4,5]. The treatment of sepsis remains a major challenge worldwide. Inflammatory imbalance is one of the most critical bases for the pathogenesis of sepsis. Downregulating the inflammatory immune response early in sepsis is thought to potentially improve the patient’s prognosis. Aminophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor [8, 9], has been shown to have anti-inflammatory effects [10,11,12,13]. Aminophylline inhibits the hydrolysis of cyclic adenosine monophosphate (cAMP)

Methods

Results

Conclusion