A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition

Abstract

Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.

The potential of probiotics in the amelioration of hyperuricemia

“…Probiotic intervention is promising for modulating the NLRP3 pathways and has been verified by many studies. 154–157 NLRP3 activation was inhibited by probiotic supplementation, which stabilized osmotic pressure. 158 Lactobacillus also reduced ROS production by restoring the abnormal mitochondrial membrane potential, which alleviated NLRP3 activation.…”

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

“…A significant decrease in the highly oxidative enzyme, MPO was also observed. The elevated levels of MPO were previously linked to increased oxidative stress and inflammation ( Ndrepepa, 2019 ; Saber et al, 2021a ). MPO also acts as a mediator of oxidative stress by increasing the generation of ROS and reactive nitrogen species ( Chen et al, 2020 ).…”

The Supportive Role of NSC328382, a P2X7R Antagonist, in Enhancing the Inhibitory Effect of CRID3 on NLRP3 Inflammasome Activation in Rats with Dextran Sodium Sulfate-Induced Colitis

“…27 IL-1β, which is a pyroptosis product, has been considered a key component of inflammation and colon tissue damage. 28 Moreover, emerging evidence has pinpointed pyroptosis as an important trigger and endogenous regulator of colon inflammation. Similarly, IL-18 has been shown to contribute to the breakdown of the mucosal barrier, triggering inflammation and amplifying the damage elicited in the intestinal epithelium during disease.…”