Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

Yu-Te Chou,Shiang-Fen Huang,Chia-Chang Huang,Ying-Ying Yang,Tzung-Yan Lee,Tze-Tze Liu,Chih-Wei Liu,Tzu-Hao Li,Ming-Chih Hou,Han-Chieh Lin,Hsuan-Miao Liu,Yi-Hsiang Huang,Ueng-Cheng Yang,Ming-Wei Lin

doi:10.3390/ijms22031233

Abstract

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

Highlights

Renal failure is a challenge in cirrhotic patients because the likelihood of mortality occurring increases with worsening renal function [1]
SIRT1 mice (Figure 5A and supplement Figure S1A–B). These results indicate that the overall mice. These results indicate that the overall mice microbial species diversity was lower in the mice and the intestinal epithelial cells (IEC) KO -bile duct ligated (BDL) mice microbial species diversity was lower in the mice and the
In addition to supporting the previous observation regarding the crosstalk between hepatic SIRT1 and tumor necrosis factor-α (TNFα) [28], this study suggests a link between SIRT1−TNFα crosstalk and intestinal SIRT1-related effects and renal dysfunction of cirrhosis

Summary

Introduction

Renal failure is a challenge in cirrhotic patients because the likelihood of mortality occurring increases with worsening renal function [1]. The search for new potential agents to treat patients with cirrhotic HRS whose responses to standard treatments are poor is ongoing [6,7]. Persistent increased circulating tumor necrosis factor-α (TNFα)related bacterial translocation and systemic (hepatic, intestinal, renal) inflammation are involved in the development of intestinal/renal dysfunction and HRS [3,5]. In cirrhotic patients at diagnosis and resolution of the infection, the development of renal impairment is associated with significantly high plasma and ascitic fluid TNFα levels [8]. Agents with anti-TNFα effects can prevent the development of systemic inflammation and renal dysfunction in cirrhotic rats with portal hypertension [9,10]

Methods

Results

Discussion

Conclusion