Introduction

Currently, the prevalence of chronic kidney disease has reached 10%-15% of the global population, and most patients with chronic kidney disease will gradually progress to end-stage renal disease, ultimately requiring dialysis or kidney transplantation as alternative treatments. Chronic kidney disease has become another 'silent killer' threatening human life and health, following cardiovascular diseases, tumors, and diabetes.
The intestine is considered an endogenous 'organ' with metabolic activity, and the gut microbiota can participate in the regulatory processes of the body through various pathways, collectively maintaining the dynamic balance of the body. Therefore, an increasing number of scientific experiments are being conducted to study the mechanisms of gut microbiota and the gut-kidney-heart axis in chronic kidney disease, hoping to delay its progression by regulating the gut microbiota.
 

What is chronic kidney disease

The current international definition of chronic kidney disease is: chronic structural and functional impairment of the kidneys caused by various reasons (with a history of kidney damage lasting more than 3 months), including pathological damage with normal and abnormal glomerular filtration rates, abnormal blood or urine components, and abnormal imaging findings, or unexplained decline in glomerular filtration rate (<60ml/min·1.73m2) lasting more than 3 months.

Gut-kidney-heart axis
 

As kidney function gradually declines, chronic kidney disease often damages multiple systems, including the gastrointestinal, cardiovascular, and endocrine systems, with cardiovascular disease being the most common complication and a major cause of death, while gastrointestinal dysfunction is also a common complication and initial symptom of chronic kidney disease in many cases.

The kidneys, intestines, and cardiovascular systems of patients with chronic kidney disease are closely related:Renal insufficiency can lead to the accumulation of a large number of uremic toxins in the body, causing damage to the intestines and heart; conversely, intestinal dysfunction can lead to intestinal barrier disruption and microbial imbalance, promoting the production of uremic toxins, further exacerbating systemic inflammation, which is also an important trigger for kidney and cardiovascular damage.
 

These findings suggest that the gut, kidneys, and heart can interact as a whole, and dysregulation of the gut-kidney-heart axis will lead to a vicious cycle, resulting in the deterioration of chronic kidney disease.
 

Figure 1 Gut-kidney-heart axis hypothesis

The microbiota of patients with chronic kidney disease and cardiovascular disease is significantly different from that of healthy individuals.

In pathological physiological states, patients with chronic kidney disease and cardiovascular disease are prone to gastrointestinal dysfunction and intestinal microecological disorders. The intestinal microbial diversity of patients with chronic kidney disease is significantly reduced, and the microbial community is significantly different from that of healthy individuals (as shown in Table 1). Lactobacillus, Bifidobacterium, Faecalibacterium, Akkermansia, Ruminococcus, and Prevotella are significantly reduced in patients with chronic kidney disease, while Escherichia coli and Enterococcus proliferate.This indicates a reduction in beneficial bacteria and an increase in pathogenic bacteria (referred to as intestinal dysbiosis).

Table 1 Changes and functions of intestinal microbiota in chronic kidney disease

Uremic toxins produced by intestinal pathogenic bacteria metabolism can accelerate the progression of chronic kidney disease and cardiovascular disease.
 

MultipleGut microbiotaderived uremic toxins, including indole sulfate (IS), trimethylamine N-oxide (TMAO), and advanced glycation end products (AGEs), can participate in the progression of chronic kidney disease and cardiovascular disease (as shown in Figure 2).

Colonic microbes are responsible for protein fermentation. Ammonia and urea are products of protein catabolism, among which α-NH3 nitrogen (from amino acids and intermediates) can be converted into phenols and indoles, which are then metabolized into para-cresol sulfate (PCS) and indole sulfate (IS) or indole acetic acid (IAA). Under normal circumstances, these metabolites are excreted through the kidneys, but they accumulate in cases of renal insufficiency.PCS and IS can damage the cardiovascular system, accelerate the deterioration of chronic kidney disease, and increase the incidence of cardiovascular disease in patients.
 

TMAO is the final product of choline and carnitine metabolism,Under normal circumstances, TMAO in the bloodstream is excreted by the kidneys, but it increases in cases of renal insufficiency,one of the target organs is the cardiovascular system, whose pathophysiological effects include increased platelet hyperreactivity and thrombus formation potential, enhanced cholesterol accumulation in macrophages, and the development of atherosclerosis.

Advanced glycation end products (AGEs) are a group of proteins, lipids, or nucleic acids that are glycosylated and oxidized after contact with reducing sugars or short-chain aldehydes.Excessive intake of sugars, especially fructose, can lead to the formation of endogenous AGEs, which are associated with carotid artery thickening, ischemic heart disease, chronic kidney disease, and uremic cardiomyopathy.

Figure 2 Uremic toxins on the gut-kidney-heart axis

New therapies targeting gut microbiota in the gut-kidney-heart axis

Therapeutic strategies: Regulate the balance of gut microecology in the body and reduce its pathogenic metabolic products.

(1) Dietary intervention

A plant-based, fiber-rich, low-protein diet may lead to favorable changes in the gut microbiome, thereby regulating the production of uremic toxins.

(2) Probiotics

Due to the reduction of beneficial flora in the intestines of patients with chronic kidney disease, it is speculated that increasing probiotics in the intestines can improve gut microbiota dysbiosis, thereby alleviating systemic inflammatory responses.

Recent studies have shown thatBifidobacterium can slow the progression of chronic kidney disease by increasing the production of microbial metabolites (such as SCFAs).Lactobacillus can prevent chronic kidney disease by reducing fecal lipopolysaccharide (LPS) levels and inhibiting immune responses. The restoration of intestinal Prevotella helps improve the intestinal environment, thereby inhibiting the progression of chronic kidney disease and the accumulation of uremic toxins.

Rumen cocci are considered producers of butyrate.Butyrate is the preferred energy source for colonic epithelial cells and plays an important role in maintaining colon health. It can also delay chronic kidney disease and cardiovascular diseases by improving blood lipids and blood pressure.
 

(3) Prebiotics

Prebioticscan serve as an energy source for the microbiota in the intestine, specifically promoting the growth of certain beneficial bacteria. Many clinical trials and experimental studies on chronic kidney disease have also shown that taking prebiotics,probioticscan reduce uremic toxins and inflammatory mediators.
 

References:Huang Y, Xin W, Xiong J, et al. The Intestinal Microbiota and Metabolites in the Gut-Kidney-Heart Axis of Chronic Kidney Disease[J]. Frontiers in Pharmacology, 2022, 13:837500.
 

(The article is extracted from popular science literature and does not provide any medical guidance.)