The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease

Abstract

Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

Fig. 1 |. The anatomy of the gut and its interactions with multiple systems.

The epithelial barrier, which is mainly composed of epithelial cells, goblet cells, Paneth cells and enteroendocrine cells, physically separates the gut mucosa from the submucosa. The gut mucosa is the most dynamic reservoir of the gut microbiota, which is constantly influenced and modified by factors including diet, toxins, pathogens and drugs. Tight junction proteins seal the epithelial layer and prevent translocation of pathogenic gut microorganisms across the epithelial barrier. Immune cells residing inside lymph nodes monitor the intestinal environment and maintain gut homeostasis. The enteric nervous system, which is composed of numerous nerve plexuses, perceives mechanical and chemical changes within the gut and communicates with the autonomic nervous system (ANS). Enterohormones, metabolites, immune cells and cytokines derived from this complex mucosal and submucosal network have systemic impacts on other organs such as the kidney, cardiovascular system, bone marrow and brain via the circulation. JAMs, junctional adhesion molecules.

Fig. 2 |. The metabolism-dependent and immune pathways of the gut-kidney axis.

In the metabolism-dependent pathway, dysbiosis induced by an imbalanced diet (for example, a diet that is low in dietary fibres and high in protein and animal fats) leads to overproduction and accumulation of p-cresyί and indoxyl sulfates in the intestine. This accumulation disrupts the gut barrier and thus increases gut permeability. Consequently, influx of endotoxins and uraemic toxins into the kidney via the circulation contributes to renal inflammation. In the immune pathway, immune cells originating from the bone marrow encounter dysbiotic microbiota and become overactivated within the intestine. Inflammatory cells, cytokines and soluble urokinase plasminogen activator surface receptor (suPAR) generated in the gut contribute to renal inflammation via the circulation. Crosstalk between metabolism-dependent and immune pathways is achieved through the contributory effects of dysbiotic metabolites on intestinal and renal immunity, inflammation-induced gut barrier disruption and the resultant influx of dysbiotic metabolites into the kidney through the circulation.

Fig. 3 |. The brain-gut-kidney axis hypothesis for the pathogenesis of hypertension and CKD.

Sympathetic activation is a common feature in disorders of the brain, gut and kidney. Persistent microglial activation and neuroinflammation in presympathetic regions of the brain responsible for sympathetic outflow contribute to an increase in blood pressure and to pathogenesis in the gut and kidney. Immune cells that develop in the bone marrow are activated by microbiota in the gut and enter the circulation; these cells contribute to gut and kidney inflammation. Local mucosal immunity is also regulated by the intestinal environment owing to close communication between the gut and the gut microbiota. Dysbiosis and disorders in intestinal metabolism result in an imbalance of intestinal homeostasis, which is characterized by increased mucosal inflammation, intestinal permeability and abnormal epigenetic modification of epithelial cells. A decline in renal function leads to reduced glomerular filtration rate (GFR), increased albuminuria and uraemic toxins and glomerular and tubuίointerstitiaί damage. These pathological events in the brain, gut and kidney substantially contribute to the development of hypertension and chronic kidney disease (CKD).