Persistent systemic inflammation is a hallmark of chronic kidney disease (CKD) and several of its risk factors, including diabetes and hypertension. The gut microbiome is defined as the microorganisms and their genetic material in the intestinal tract. Emerging evidence has substantiated the gut microbiome as a key mediator of inflammation in various pathophysiologic states, including kidney diseases (1, 2). Patients with kidney failure on dialysis also exhibit bacterial translocation from the intestines to the circulation, contributing to microinflammation (3). Bacterial translocation is reported in other pathologies, including hypertension and autoimmunity (4, 5). Harnessing the power of the microbiome to treat diseases is promising, especially because this approach is already used as an alternative treatment option for life-threatening diseases such as recurrent Clostridioides difficile (6). Although research in the area of the microbiome has made tremendous progress, the mechanisms by which the microbiota (and alterations to gut bacteria) contribute to inflammation and its consequences in the setting of kidney diseases are not fully elucidated.
It is well accepted that there is a bidirectional relationship between the gut and kidney. However, the effect of this crosstalk on kidney function remains an active research question. For example, studies indicate an immunomodulatory role of gut-derived metabolites, including trimethylamine oxide and short-chain fatty acids (7). Alterations in the gut microbiome in mouse models by using antibiotics lead to diminished bacterial production of short-chain fatty acids. These short-chain fatty acids can directly stimulate olfactory receptors present on vascular smooth muscle cells leading to changes in blood pressure (4).
Bacteria in the gut also modulate inflammation through secondary modifications of molecules, such as bile acids and amino acids. For example, tyrosine and tryptophan undergo bacterial modification in the gut to form P-cresol and indole, which are subsequently metabolized by the liver to generate the uremic toxins P-cresyl sulfate and P-indoxyl sulfate. These metabolites highlight the potential importance of the kidney-gut axis in progressive CKD, because their production in the gut may harm the kidneys, just as the inability of the kidneys to clear them may worsen gut dysbiosis and inflammation (Figure 1). The exact mechanism by which these metabolites exert their effects is unclear, but evidence suggests a relationship with proteins involved in endothelial barrier function, the complement system, cell adhesion, phosphate homeostasis, and inflammation (8). Published human studies report a strong correlation between the uremic toxins and inflammatory markers, including monocyte chemoattractant protein 1 and soluble endothelium-associated adhesion molecule 1 (9–11). Moreover, P-cresyl sulfate and P-indoxyl sulfate are toxic in many cells, including intestinal epithelial cells, where direct exposure increases tumor necrosis factor, cyclooxygenase-2, inducible nitric oxide synthase expression, and nitrotyrosine formation (an end product of reactive oxygen species generation) (12).
The role of inflammation in the kidney-gut crosstalk in kidney diseases
Citation: Kidney News 14, 4
The role of inflammation in the kidney-gut crosstalk in kidney diseases
Citation: Kidney News 14, 4
The role of inflammation in the kidney-gut crosstalk in kidney diseases
Citation: Kidney News 14, 4
Let's segue to another closely linked system: the lymphatics. The lymphatic system plays an important role in the progression of a fibrotic response in the kidney by mediating inflammatory mechanisms. A recent experimental study by our group (13) using mice and rats suggests that the intestinal lymphatic system is a novel link among gut-generated metabolites, inflammation, and progressive kidney diseases. We demonstrated that proteinuric kidney injury (puromycin aminoglycoside-injected rats and Nphs1-hCD25 [podocytes expressing the interleukin-2 (IL-2) receptor] transgenic mice) alters the structure and function of intestinal lymphatics and the composition of the mesenteric lymph. These two models of proteinuric kidney injury demonstrated structural and functional alteration of the lymphatic system. This includes intestinal lymphangiogenesis (or mismatch between blood vessels and lymphatics), lymphatic vessel contractions, and activation of lymphatic endothelial cells.
In addition, the mesenteric lymph of kidney-injured mice had increased T helper 17 lymphocytes (which are pro-inflammatory) and production of several pro-inflammatory cytokines, notably IL-6, IL-10, and IL-17. Moreover, the reactive peroxidation product isolevuglandin (IsoLG) was elevated in mice with proteinuria kidney injury. Interestingly, although these cytokines and IsoLG were identified in the gut, they were not detected in concurrently sampled, peripherally collected plasma (13), suggesting origination from the gut. This concept is supported by findings that exposure of cultured intestinal epithelial cells to myeloperoxidase stimulates the production of IsoLG (Figure 1). In addition to gastrointestinal epithelial cells, dendritic cells stimulate IsoLG formation that activates T lymphocytes (14). In the kidney, lymphangiogenesis accelerates inflammation in the kidney, and blocking the lymphatic growth inhibits recruitment of activated dendritic cells into the renal draining lymph nodes and spleen and attenuates progressive kidney damage (15).
A better understanding of the gut microbiome in inflammation and kidney diseases has the potential to elucidate new therapeutic targets for CKD. Interventions such as administration of 2-aza-tyrosine, which blocks the conversion of tyrosine to phenol and reduces circulating levels of the toxic phenyl sulfate, reduces Coriobacteriales and Erysipelotrichales microbes that associate with kidney failure and lessens albuminuria in diabetic mice (16). Other strategies include personalized nutrition and synbiotics that can modulate gut-derived molecules, such as uremic toxins, to improve kidney function (17, 18). These strategies improve other diseases that are associated with gut dysbiosis, kidney damage, and inflammation, such as systemic lupus erythematosus (19). The gut clearly plays a role in modulating kidney health. More work is needed to delineate the mechanisms at play, particularly in humans.
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