Gut microbiota regulates oxidative stress and inflammation: a double-edged sword in renal fibrosis

Abstract

Gut microbiota is a complex and dynamic system that plays critical roles in human health and various disease. Progressive chronic kidney disease (CKD) suggests that patients irreversibly progress to end-stage kidney disease and need renal replacement treatments, including dialysis and transplantation. Ample evidence indicates that local oxidative stress and inflammation play pivotal roles in the pathogenesis and progression of CKD and dysbiosis of gut microbiota. CKD is always accompanied by intestinal inflammation and oxidative stress, which lead to rapid systemic translocation of bacterial-derived uraemic toxins, including indoxyl sulphate, phenyl sulphate and indole-3-acetic acid, and the consequent development and aggravation of renal fibrosis. Although inflammation and oxidative stress have been extensively discussed, there is a paucity of reports on the effects of gut microbiota on renal fibrosis and gut microbiota mediation of oxidative stress and inflammation. This review provides an overview of gut microbiota on inflammation and oxidative stress in renal fibrosis, briefly discusses regulation of the gut flora using microecological preparations and natural products, such as resveratrol, curcumin and emodin as treatments for CKD, and provides a clear pathophysiological rationale for the design of promising therapeutic strategies.

Keywords: Chronic kidney disease; Gut-kidney axis; Inflammation; Microecological preparations; Natural products; Oxidative stress.

Fig. 1

Oxidative stress and inflammation mediate renal fibrosis. Kidney injury induces the production of ROS. As the balance between ROS and the antioxidant system is disrupted, oxidative stress and inflammation occur, leading to inflammation-related reactions that ultimately promote fibrosis. These pathways intricately link and reinforce each other. AP-1 activator protein 1

Fig. 2

Overview of the effect of gut microbiota dysbiosis in renal fibrosis. In the intestines, microbial dysbiosis leads to an increase in pathogens, resulting in elevated levels of LPS and gut-derived uremic toxins. These substances compromise the intestinal barrier, leading to "leaky gut," impairing mucosal immunity, and causing oxidative stress and inflammation in the intestinal mucosa. This stimulates the activation of immune cells that produce pro-inflammatory factors. Gut-derived uremic toxins are produced in the intestines and enter the circulatory system through the "leaky gut". They are metabolized by the liver and ultimately promote the development of renal fibrosis through the promotion of inflammation and oxidative stress. OAT organic anion transporter, PAI-1 plasminogen activator inhibitor-1, TLR4 Toll-like receptor 4

Fig. 3

Tryptophan-derived metabolites of intestinal microorganisms and their effects on host physiology and disease. The intestinal microbiota metabolizes tryptophan and produces specific metabolites. Here are shown 6 kinds of tryptophan-derived microbial metabolites that are capable of directly or indirectly activating AHR receptors, thereby triggering immune cells such as ILCs to promote inflammatory status. Indole and IPA may both mediate PXR to secrete TNF-α, with IPA being shown to enhance the stability of the intestinal mucosal barrier, while indole may regulate PXR via activation of toll-like receptors. Indole is metabolized into IS by CYP2E1 and sulfotransferases in the liver, which leads to uremic toxin accumulation and renal dysfunction. Indole also induces the release of GLP-1 in enteroendocrine L-cells, promoting the production of ICZ, which also activates AHR. Several tryptophan catabolites activate AHR in intestinal immune cells to alter innate and adaptive immune responses that maintain mucosal reactivity. Tryptophan serves as a ligand for 5-HT receptors to stimulate 5-HT secretion, thereby stimulating gastrointestinal motility. 5-HT serotonin, GLP-1 glucagon-like peptide-1, ICZ indole[3,2-b] carbazole, ILA indole-3-lactic acid, ILCs innate lymphocyte cells, PXR pregnane X receptor

Fig. 4

Regulatory role of SCFAs on oxidative stress and inflammation in gut microbiota dysbiosis during CKD. In the context of CKD, there is a disruption of the gut microbiota, which leads to an increase in toxins and a decrease in SCFAs. These changes compromise the intestinal barrier, leading to "leaky gut," impairing mucosal immunity, causing oxidative stress, and triggering systemic inflammation, ultimately promoting renal fibrosis. Supplementing with probiotics can increase the production of SCFAs. SCFAs help repair the intestinal barrier, promote the balance between Treg and Th17 cells, and reduce the production of uremic toxins and endotoxins, thereby inhibiting oxidative stress and inflammation. SCFAs can inhibit HDAC or bind to receptors such as GPR41, GPR43, and GPR109A, downregulating NF-ƙB and TGF-β, and promoting the expression of Nrf2 to suppress oxidative stress and inflammation, ultimately reducing the occurrence of renal fibrosis