High-Fat Diet Aggravates the Intestinal Barrier Injury via TLR4-RIP3 Pathway in a Rat Model of Severe Acute Pancreatitis

Abstract

Objective. For patients with severe acute pancreatitis (SAP), a high body mass index (BMI) increases the possibility of infection derived from the intestine. In this study, we evaluate whether TAK242 can alleviate severe acute pancreatitis-associated injury of intestinal barrier in high-fat diet-fed rats. Methods. A SAP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty Sprague-Dawley (SD) adult rats were randomly divided into five groups: standard rat chow (SRC) normal (SN), SRC SAP (SAP), high-fat diet normal (HN), HFD SAP (HSAP), and TLR4 inhibitor pretreatment HFD SAP (HAPT) groups. Intraperitoneal injection of 3 mg/kg TAK242 was administered 30 minutes before SAP model establishment in the HAPT group. Rats were sacrificed 12 hours after SAP modeling, followed by blood and pancreatic and distal ileum tissue collection for further analyses. Changes in the pathology responses of the rats in each group were assessed. Result. Analyses of serum amylase, lipase, cholesterol, triglyceride, IL-1β, IL-6, DAO, and serum endotoxin as well as tight junction protein expression including zonula occluden-1 and occludin indicated that high-fat diet aggravated SAP-induced intestinal barrier injury via increasing inflammatory response. In addition, the level of necroptosis was significantly higher in the SAP group compared with the SN group while the HSAP group exhibited more necroptosis compared with the SAP group, indicating the important role of necroptosis in pancreatitis-associated gut injury and illustrating that high-fat diet aggravated necroptosis of the ileum. Pretreatment with TLR4 inhibitor significantly alleviated inflammatory response and reduced necroptosis and level of oxidative stress while improving intestinal barrier function. Conclusion. High-fat diet aggravated SAP-induced intestinal barrier injury via inflammatory reactions, necroptosis, and oxidative stress. Inhibition of TLR4 by TAK242 reduced inflammation, alleviated necroptosis, and lowered the level of oxidative stress and then protected the intestinal barrier dysfunction from SAP in high-fat diet-fed rats.

Emodin protects against intestinal and lung injury induced by acute intestinal injury by modulating SP-A and TLR4/NF-κB pathway

“…Among all TLRs, the ligand of TLR4 is lipopolysaccharide, a cell wall component of Gram-negative bacteria. It has been confirmed that TLR4 is closely related to acute intestinal injury and intestinal infection [24]. Consistent with previous studies, in our study, we found that TLR4 levels were remarkedly decreased in serum, intestinal and lung tissues of rats with acute intestinal injury, which were ameliorated by emodin treatment.…”

CaMK II Inhibition Attenuates ROS Dependent Necroptosis in Acinar Cells and Protects against Acute Pancreatitis in Mice

“…Additionally, the caerulein-induced AP model and PDL-induced SAP are essentially caused by hypersecretion of digestive enzymes of necrosis acinar cells [ 32 , 33 ]. Inhibition of this could effectively reduce the inflammatory response and relieve the progression of AP [ 15 ]. Hence, it is vitally important to search for effective and therapeutic target drugs to reduce acinar cell necrosis both in basic research and in the clinic.…”

“…Increasing numbers of researchers have shown that necroptosis, a new concept of necrosis, is regulated by the RIP kinase family, including receptor interacting protein 3 (RIP3) and downstream molecule lineage kinase domain-like protein (MLKL), which are involved in the regulation of several inflammatory processes, including myocardial infarction [ 9 ], ischemia-reperfusion injury [ 10 ], inflammatory bowel disease [ 11 ], and chronic obstructive pulmonary disease [ 12 ]. Acinar cell necroptosis plays an important role in AP [ 13 – 15 ] and is related to the development of AP [ 16 ]. Notably, RIP3 deficiency or p-MLKL deletion could significantly reduce the acinar cell necroptosis induced by caerulein in AP mice [ 17 , 18 ].…”

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

“…typical Western diet) are linked with increased PD risk [ 102 , 103 ], and TLR4 is central to the inflammation and endoplasmic reticulum stress resulting from high-fat or high-cholesterol diets [ 104 , 105 ]. Interestingly, high-fat diets specifically increase the expression of intestinal TLR4 [ 95 ], and exacerbate intestinal barrier dysfunction in a TLR4-dependent manner in rats with severe acute pancreatitis [ 106 ]. Such diets not only encourage the growth of gram-negative, LPS-producing bacteria [ 107 ], but also increase the amount of lipids and free fatty acids, dietary components which, by themselves, can modulate TLR4 signalling [ 108 ] or rely on TLR4-priming for consequent lipid-induced inflammation [ 109 ].…”