Bacterial metabolites and cardiovascular risk in children with chronic kidney disease

Abstract

Cardiovascular complications are the major cause of the marked morbidity and mortality associated with chronic kidney disease (CKD). The classical cardiovascular risk factors such as diabetes and hypertension undoubtedly play a role in the development of cardiovascular disease (CVD) in adult CKD patients; however, CVD is just as prominent in children with CKD who do not have these risk factors. Hence, the CKD-specific pathophysiology of CVD remains incompletely understood. In light of this, studying children with CKD presents a unique opportunity to analyze CKD-associated mechanisms of CVD more specifically and could help to unveil novel therapeutic targets.Here, we comprehensively review the interaction of the human gut microbiome and the microbial metabolism of nutrients with host immunity and cardiovascular end-organ damage. The human gut microbiome is evolutionary conditioned and modified throughout life by endogenous factors as well as environmental factors. Chronic diseases, such as CKD, cause significant disruption to the composition and function of the gut microbiome and lead to disease-associated dysbiosis. This dysbiosis and the accompanying loss of biochemical homeostasis in the epithelial cells of the colon can be the result of poor diet (e.g., low-fiber intake), medications, and underlying disease. As a result of dysbiosis, bacteria promoting proteolytic fermentation increase and those for saccharolytic fermentation decrease and the integrity of the gut barrier is perturbed (leaky gut). These changes disrupt local metabolite homeostasis in the gut and decrease productions of the beneficial short-chain fatty acids (SCFAs). Moreover, the enhanced proteolytic fermentation generates unhealthy levels of microbially derived toxic metabolites, which further accumulate in the systemic circulation as a consequence of impaired kidney function. We describe possible mechanisms involved in the increased systemic inflammation in CKD that is associated with the combined effect of SCFA deficiency and accumulation of uremic toxins. In the future, a more comprehensive and mechanistic understanding of the gut–kidney–heart interaction, mediated largely by immune dysregulation and inflammation, might allow us to target the gut microbiome more specifically in order to attenuate CKD-associated comorbidities.

Exploring a Complex Interplay: Kidney–Gut Axis in Pediatric Chronic Kidney Disease

“…NO modulates a number of important physiological functions in the digestive system and appears to be a crucial mediator of tissue damage in a number of diseases. Patients with chronic kidney disease have lower levels of the antioxidant enzymes catalase and Cu-Zn superoxide dismutase [ 44 ]. This shows that inflammation and disruption of the epithelial tight junction by uremic toxins is linked to a weaker antioxidative system.…”

“…Sodium transporters: renal disease and high blood pressure have been linked to increased expression and activity of sodium transporters, leading to higher sodium reabsorption [ 44 , 45 ]. NO has been shown to inhibit the work of certain sodium transporters [ 46 ].…”

Gut-immune axis and cardiovascular risk in chronic kidney disease

“…When looking at the CKD microbiome, all of these key features can be observed: changes in microbiota composition with (i) reduced α-diversity; (ii) outgrowth of Enterobacteriaceae as paradigmatic example of pathobiont expansion; and (iii) loss of commensals illustrated by reduced Firmicutes abundance on phylum level [ 16 , 33–35 , 37–40 ]. The reasons for dysbiosis in CKD are not entirely uncovered, yet multiple factors are anticipated to contribute to dysbiosis and proteolytic fermentation in CKD including low fiber diet, muscle wasting, drug intake, uremia and constipation [ 41 ]. However, drawing conclusions from these data remains challenging due to the many bacterial phyla affected and conflicting findings that are most likely explained by the high inter-personal variability of the microbiome, especially when considering study populations from different regions.…”

“…Initially, saccharolytic and proteolytic fermentation were discovered as a consequence of different dietary regimens: plant-based diet induces saccharolytic fermentation and animal products proteolytic fermentation [ 46 ]. Low-fiber diet was traditionally used to limit potassium intake in CKD but is increasingly recognized as a risk factor for dysbiosis, promoting a shift from saccharolytic to proteolytic fermentation by direct induction of proteolytic bacteria via increased substrate availability [ 41 , 47 ]. Moreover, indirect mechanisms including posttranslational modification of bacterial enzymes can aggravate the metabolic imbalance, like modification of tryptophanase by sulfur-containing amino acids increasing microbial indole production and subsequently worsening kidney function [ 48 ].…”

Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation

“…Likewise, pancreatic cancer is tightly related to gut dysbiosis, showing downregulation of Firmicutes, while abundances of Actinobacteria and Proteobacteria, including Escherichia Coli, were upregulated [12][13][14]. Gut bacterial metabolites and toxins can enter portal and systemic circulation through paracellular diffusion or cotransport with chylomicrons [15][16][17]. Increased endotoxin levels were often found in the pancreatic tissue of PDAC patients, which was further related to the poor prognosis of PDAC under chemotherapy [18].…”