The microbiota and chronic kidney diseases: a double-edged sword

Raphael Jose Ferreira Felizardo, Angela Castoldi, Vinicius Andrade-Oliveira, Niels Olsen Saraiva Câmara, Raphael Jose Ferreira Felizardo, Angela Castoldi, Vinicius Andrade-Oliveira, Niels Olsen Saraiva Câmara

Abstract

Recent findings regarding the influence of the microbiota in many inflammatory processes have provided a new way to treat diseases. Now, one may hypothesize that the origin of a plethora of diseases is related to the health of the gut microbiota and its delicate, although complex, interface with the epithelial and immune systems. The 'westernization' of diets, for example, is associated with alterations in the gut microbiota. Such alterations have been found to correlate directly with the increased incidence of diabetes and hypertension, the main causes of chronic kidney diseases (CKDs), which, in turn, have a high estimated prevalence. Indeed, data have arisen showing that the progression of kidney diseases is strictly related to the composition of the microbiota. Alterations in the gut microbiota diversity during CKDs do not only have the potential to exacerbate renal injury but may also contribute to the development of associated comorbidities, such as cardiovascular diseases and insulin resistance. In this review, we discuss how dysbiosis through alterations in the gut barrier and the consequent activation of immune system could intensify the progression of CKD and vice versa, how CKDs can modify the gut microbiota diversity and abundance.

Figures

Figure 1
Figure 1
Dysbiosis and IgA nephropathy. The balance of gut homeostasis is ruled by microbial composition and secretion of specific immunoglobulins, among them IgA. Gut microbial composition imbalance and the high secretion of under glycosylated oligomeric IgA against gut bacteria may trigger the development of IgA nephropathy. LPS, lipopolysaccharide.
Figure 2
Figure 2
Dybiosis and the evolution of kidney damage. In a healthy intestinal microflora, symbiotic bacteria coexist with pathogenic bacteria. The outnumbered presence of symbionts is supposed to maintain gut homeostasis by degrading resistant carbohydrates and proteins that escape from gastric metabolism. An imbalance of the gut biochemical milieu either due to the changes in dietary habits, in which the supply of non-metabolized proteins that reach the intestine is higher than the supply of carbohydrates, or due to the biochemical alterations resulting from reduced kidney function, which impairs the excretion of metabolism products such as urea or acid, may reinforce or contribute to dysbiosis. The reduction of mucus production, loss of tight junctions, leakage of the gut barrier and bacterial translocation initiated due to the overproduction of nitrogen products by urease and uricase-producing bacteria generate high levels of indole sulfate and p-cresil, which, along with endotoxins and LPS, cross the lamina propria to reach the kidneys. The activation of TLRs and other pattern recognition receptors by endotoxins as well as the binding of AhRs by indoxyl sulfate in podocytes are involved in podocyte death and, consequently, the loss of renal selectivity, increased permeability to high-molecular-weight proteins, such as albumin, and renal failure. The damage is propagated to other cells on subjacent glomeruli and progressively contributes to decreased renal clearance. Higher levels of nitrogen products in the blood achieve the intestinal lumen and reinforce, in a vicious cycle, dysbiosis. AhR, aryl hydrocarbon receptor; GBM, glomerular basement membrane. LPS, lipopolysaccharide; TLR, Toll-like receptor; Treg, regulatory T cell.

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